Energy Balance and Gastrointestinal Cancer

Energy Balance and Cancer

Series Editor: Nathan A. Berger, Case Western Reserve University, Cleveland, OH, USA

For further volumes: http://www.springer.com/series/8282

Sanford D. Markowitz

●

Nathan A. Berger

Editors

Energy Balance and Gastrointestinal Cancer

Editors Sanford D. Markowitz Case Western Reserve University Cleveland, OH, USA

Nathan A. Berger Case Western Reserve University Cleveland, OH, USA

ISBN 978-1-4614-2366-9 e-ISBN 978-1-4614-2367-6 DOI 10.1007/978-1-4614-2367-6 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2012932611 © Springer Science+Business Media, LLC 2012 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface

As the worldwide pandemic of overweight and obesity continues to expand, with over 1 billion overweight and 315 million obese adults estimated worldwide [1–3], obesity is increasingly recognized as a significant risk factor for cancer. In the USA, approximately 20% of all cancer deaths in women and 14% in men have been attributed to overweight and obesity [4]. Epidemiological studies indicate an association between obesity and specific malignancies in multiple organ systems including colon, postmenopausal breast, endometrial, esophageal adenocarcinoma and renal cell cancer [5–7]. In addition to colon and esophageal adenocarcinoma, more recent evidence supports an association of obesity with other gastrointestinal malignancies including pancreatic, gallbladder, and hepatocellular cancer [4, 7, 8]. In 2009, the American Cancer Society estimated that the combined deaths in the USA from gastrointestinal cancers, including pancreas, colon, and rectum, esophageal, liver, and bile ducts exceeded 135,000 [9]. During the same year, there were 100,000 new cases and 50,000 deaths from colon cancer [9]. The relative risk of mortality from colon cancer according to body mass index in a prospective population study of more than 900,000 US adults [4] was found to be 1.20 for overweight and 1.47–1.84 for obese men, and 1.1 for overweight and 1.3–1.46 for obese women. In contrast, a recent study showed that in men with nonmetastatic colorectal cancer at diagnosis, increased physical activity was associated with improved colorectal cancer mortality and overall mortality [10]. Thus, gastrointestinal cancer in general and colorectal cancer more specifically causes an enormous burden of morbidity and mortality in the USA with significant impact from obesity and benefit associated with physical activity. Persistence of this vexing problem both at the personal and public health levels can be attributed, in part, to the multicomponent and complex nature of the relation between energy balance and cancer in which many of the cytokines, hormones, and other obesity-associated factors may act in combination with environmental and lifestyle factors as both mutagens and cancer promoters. Persistence of the problem is associated also with the difficulty in implementing effective and sustainable biobehavioral interventions to control obesity and associated mediators and comorbidities. v

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Preface

This volume assembles a panel of leading investigators to present a transdisciplinary view of the state of the science regarding the linkages between gastrointestinal malignancy and energy balance. In addition to analyzing the extensive epidemiologic data associating energy balance with gastrointestinal malignancies, this volume details the significant progress being made to increase mechanistic understandings and to identify possible mediators of these relationships and the potential interventions that are just beginning to be identified and tested. Chapter 1 presents a comprehensive evaluation by Dr. Nora Nock of the epidemiologic association of obesity with major gastrointestinal malignancies. In Chap. 2, Dr. Graham Casey reviews both the common and the rare genetic changes associated with colon cancer susceptibility. In Chap. 3, Dr. Leonard Augenlicht and associates provide an overview of their ongoing research on the effects of dietary modulation, especially of vitamin D, calcium, and fat, on the incidence of colon cancer in the mouse and new insights on potential mechanisms influenced by diet focused on cellular interactions between macrophages and intestinal epithelial cells. In Chap. 4, Dr. Nathan Berger provides an overview of mouse model studies investigating the effect of exercise on gastrointestinal malignancies. In Chaps. 5 and 6, Drs. Rom Leidner, Amitabh Chak, and Donghui Li review recent studies investigating the relation between obesity, Barrett’s esophagus, esophageal cancer, and pancreatic cancer. In Chaps. 7 and 8, Dr. Li Li explains the important contribution of insulin resistance pathways to the relation of obesity and colon cancer and Drs. Fred Bunz and Nickolas Papadopoulos explain the relation of Ras/Raf mutation to the process. Dr. Jeffrey Meyerhardt, in Chap. 9, evaluates studies on the effect of energy balance on colorectal cancer recurrence and survival in clinical situations and Dr. Monica Bertagnolli describes the role of chronic inflammation in colorectal malignancies. Overall, this volume should provide an important basis for studies to advance the state of the science linking energy balance to gastrointestinal malignancy and serve, also, as a background to develop new therapeutic interventions for prevention and control. Cleveland, OH, USA

Sanford D. Markowitz Nathan A. Berger

References 1. Caterson ID, Gill TP (2002) Obesity: epidemiology and possible prevention. Best Pract Res Clin Endocrinol Metab 16:595–610 2. Ogden CL, Carroll MD, Curtin LR et al (2008) Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 295:1549–1555 3. World Health Organization (2003) World cancer report. IARC Nonserial Publication, Geneva 4. Calle EE, Rodriguez C, Walker-Thurmond K et al (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348(17): 1625–1638

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5. World Health Organization (2000) Obesity: preventing and managing the global epidemic. Report of a WHO consultation. Rep. 894, World Health Organization 6. World Cancer Research Fund and American Institute for Cancer Research (2007) Food, nutrition, physical activity, and the prevention of cancer: a global perspective. AICR, Washington, DC 7. Renehan AG, Tyson M, Egger M et al (2008) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371: 569–578 8. Li D, Morris JS, Liu J et al (2009) Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA 301:2553–2562 9. American Cancer Society (2009) Cancer facts & figures 2009. American Cancer Society, Atlanta. http://www.cancer.org/downloads/STT/500809web.pdf 10. Meyerhardt JA, Giovannucci EL, Ogino S, Kirkner GS, Chan AT, Willett W, Fuch CS (2009) Physical activity and male colorectal cancer survival. Arch Intern Med 169:2102–2108

Contents

1

Obesity and Gastrointestinal Cancers: Epidemiology........................ Nora L. Nock

1

2

Genetics of Colon Cancer Susceptibility .............................................. Graham Casey

23

3

Dietary Modulation of Colon Cancer: Effects on Intermediary Metabolism, Mucosal Cell Differentiation, and Inflammation ................................................................................... Lidija Klampfer, Barbara G. Heerdt, Anna Velcich, Erin Gaffney-Stomberg, Donghai Wang, Elaine Lin, and Leonard H. Augenlicht

4

The ApcMin/+ Mouse Model to Study the Effects of Exercise on Gastrointestinal Malignancy............................................................ Nathan A. Berger

47

65

5

Obesity and the Pathogenesis of Barrett’s Esophagus........................ Rom Leidner and Amitabh Chak

77

6

Obesity and Pancreatic Cancer ............................................................ Donghui Li

93

7

Obesity, Insulin Resistance Pathway Factors, and Colon Cancer .................................................................................. Li Li

8

Ras/Raf and Their Influence in Glycolysis in Colon Cancer ............. Fred Bunz and Nickolas Papadopoulos

111 131

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Contents

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Energy Balance and Other Modifiable Host Factors on Colorectal Cancer Prognosis............................................................ Jeffrey Meyerhardt

141

Cyclooxygenase-2 and Chronic Inflammation: Drivers of Colorectal Tumorigenesis .................................................... Monica M. Bertagnolli

157

Index ................................................................................................................

183

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Contributors

Leonard H. Augenlicht Montefiore Medical Center and Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA Nathan A. Berger Center for Science, Health and Society, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA Monica M. Bertagnolli Division of Surgical Oncology, Dana Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Fred Bunz Department of Radiation Oncology and Molecular Radiation Sciences, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA Graham Casey Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Amitabh Chak Department of Medicine, Case Western Reserve University, Cleveland, OH, USA Erin Gaffney-Stomberg Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA Barbara G. Heerdt Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA Lidija Klampfer Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA Rom Leidner Department of Medicine, Case Western Reserve University, Cleveland, OH, USA Donghui Li Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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Contributors

Li Li Department of Family Medicine—Research Division, Case Western Reserve University, Cleveland, OH, USA Elaine Lin Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA Jeffrey Meyerhardt Division of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Nora L. Nock Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA Nickolas Papadopoulos The Ludwig Center for Cancer Genetics and Therapeutics, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA Anna Velcich Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA Donghai Wang Department of Hematology, Peking University First Hospital, Beijing, China

Chapter 1

Obesity and Gastrointestinal Cancers: Epidemiology Nora L. Nock

Abstract There is strong and consistent evidence for associations between obesity and multiple gastrointestinal (GI) cancers. The most consistent and compelling evidence exists for the association between obesity and colon cancer; however, there is emerging evidence for associations between obesity and esophageal adenocarcinoma and, pancreatic and liver cancers. The number of studies evaluating obesity and gastric and gallbladder cancers is limited and results, thus far, have been inconsistent. In this chapter, the epidemiological evidence linking obesity to the development and survival of GI cancers is reviewed. Because obesity plays an integral role in manifestation of the Metabolic Syndrome (MetSyn), epidemiological evidence for associations between MetSyn and GI cancers is also summarized. Other environmental and genetic risk factors for GI cancers and the putative mechanisms linking obesity, MetSyn, and GI cancers are discussed in subsequent chapters of this book.

1

Obesity: Definitions

Obesity is often defined using surrogates of body size, most commonly, body mass index (BMI), which is expressed as weight adjusted for height in units of kilograms (kg) per meter squared (m2). The most widely adopted definitions of adult overweight and obesity are those established by the World Health Organization (WHO) [1] as follows:

N.L. Nock, Ph.D. (*) Department of Epidemiology and Biostatistics, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106-7281, USA e-mail: [email protected] S.D. Markowitz and N.A. Berger (eds.), Energy Balance and Gastrointestinal Cancer, Energy Balance and Cancer 4, DOI 10.1007/978-1-4614-2367-6_1, © Springer Science+Business Media, LLC 2012

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1. 2. 3. 4.

N.L. Nock

Overweight: BMI ³ 25.0 to <30.0 kg/m2 Class I obesity: BMI ³ 30.0 to <35.0 kg/m2 Class II obesity: BMI ³ 35.0 to <40.0 kg/m2 Class III obesity: BMI ³ 40.0 kg/m2

Non-standardized definitions of overweight or obesity, such as BMI percentiles (e.g., quartiles) or unit changes in BMI (e.g., 5 kg/m2), have also been extensively utilized which makes drawing conclusions across studies more challenging. Nevertheless, as discussed in the subsequent sections, associations between obesity (predominantly measured using BMI) and certain GI cancers are quite strong regardless of the definition or threshold applied. Central obesity has been assessed using waist circumference and waist-to-hip ratio (WHR) measures. Waist circumference and WHR essentially serve as a proxy for visceral fat, which is more biologically active than subcutaneous fat [2–4]; and, individuals with more visceral vs. subcutaneous fat are at markedly higher risk of developing insulin resistance, metabolic syndrome (MetSyn) and cancer [5–8]. The threshold values or “cut-points” for waist circumference, however, are quite inconsistent across studies, in part, because of substantial sex- and ethnic-specific differences in body size and composition. In the most recent joint interim statement for harmonizing the definition of MetSyn, it was proposed that central obesity be defined using sex-, ethnic-, and population-specific cut-points of waist circumference [9]. For example, for Caucasian women in the USA, a waist circumference of ³88 cm would confer central obesity and an increased risk of type II diabetes mellitus (T2DM) and cardiovascular disease (CVD), while a circumference of ³80 cm would increase the risk of insulin resistance. For Caucasian men in the USA, a waist circumference of ³102 cm and ³94 cm would confer central obesity and an increased risk of T2DM/CVD and insulin resistance, respectively. In contrast, Asian men and women with a waist circumference ³90 cm and ³80 cm, respectively, would be classified as having central obesity and an increased risk of metabolic diseases [9, 10]. Obesity can be more accurately defined in terms of body fat. Dual energy X-ray absorptiometry (DXA) scans can differentiate between total and regional fat, lean and bone mass, and; computed tomography (CT) and magnetic resonance imaging (MRI) scans can provide direct estimates of visceral adiposity [11, 12]. However, because these technologies are more costly and less convenient than simple anthropometric measures, very few studies have utilized these types of scans in large(r) epidemiological studies to evaluate obesity and GI carcinogenesis.

2

Obesity Rates

The rates of overweight (BMI ³ 25.0 to <30.0 kg/m2) and obesity (BMI ³ 30.0 kg/ m2) are increasing in epidemic proportions in both developed and developing nations with an estimated one billion overweight and 315 million obese adults worldwide [13–15].

1 Obesity and Gastrointestinal Cancers: Epidemiology

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In a more recent review using data from over 9.1 million adults (20 years and older) and 199 countries, it was estimated that, in 2008, there were 1.46 billion overweight or obese adults worldwide and, of these, 205 million adult men and 297 million adult women were obese with most countries showing an increase in BMI of over 2 kg/m2 per decade in adult men since 1980 [16]. With over two-thirds of the adult (18 years and older) population being overweight and over one-third of the adult population estimated to be obese, with a clear upward shifting of the mean BMI over the past 20 years [17], not surprisingly, the USA had the highest BMI among all of the “high-income” countries [16]. Using the National Health and Nutrition Examination Survey (NHANES) data from 2007 to 2008, the prevalence of obesity in the USA is estimated to be 32.2% among adult men and 35.5% among adult women [18]. The prevalence of Class II and Class III obesity in the USA in 2007 to 2008 was 10.7 and 4.2%, respectively, among adult men and 17.8 and 7.2%, respectively, among adult women, with the highest rates of Class II and Class III obesity being observed among Non-Hispanic Black men at 14.4 and 7.0%, respectively, and Non-Hispanic Black women at 27.9 and 14.2%, respectively [18]. In Europe, approximately 43% of adult (16 years and older) men and 33% of adult women were overweight and 22% of adult men and 23% of adult women were obese in 2003 [19]. More recent estimates suggest higher obesity rates among adult men (up to 28.3%) and women (up to 36.5%) and, considerable geographic variation with prevalence rates in Central, Eastern, and Southern Europe being higher than those in Western and Northern Europe [20]. Approximately 17.6 million children under 5 years are estimated to be overweight worldwide [15]. The NHANES 2003–2004 data indicates a threefold rise in obese adolescents and a fourfold rise in obese children since 1970 and, currently, over 12 million children are estimated to be obese in the USA [21]. International trends of increased rates of childhood obesity are similar to those in the USA and coincide with economic transitions to industrialized and urban lifestyles [21]. Interestingly, the prevalence of obesity in 5 to 12 year-old children in Thailand rose about 4% in just 2 years [15]. Brazil has also experienced a rise in overweight and obesity rates from 2.9 to 13.1% in boys and from 5.3 to 14.8% in girls (both aged 6–18 years) between 1974 and 1997. Mexico ranked second only to the USA with 30.5% of boys and 31.5% of girls overweight or obese in 2006 [21]. Trajectories in the USA and other developed nations including England and other parts of Europe appear to have begun to level off [21], which is encouraging since overweight and obese children tend to become obese adults [22].

3

Gastrointestinal Cancers: Incidence Rates

Approximately 12.7 million new cancer cases are estimated to have occurred worldwide in 2008, with 56% of the new cases occurring in economically developed or developing countries [23]. Colorectal cancer (1.2 million cases), stomach cancer (990,000 cases), and liver cancer (748,000 cases) are among the most common cancers

4

N.L. Nock

worldwide [24]. Esophageal cancer (including both adenocarcinoma and squamous cell carcinoma types) is the eighth most common cancer worldwide with 482,000 new cases (3.8% of the total) estimated in 2008 and about 83% of the cases occurring in developed or developing countries [24]. Colorectal cancer rates are two times higher in developed countries compared with developing countries, which may be attributed to differences in diagnostic and screening practices as well as lifestyle risk factors, while the opposite was found for stomach and liver cancers, which are known to have viral or infection-related risk factors [23]. Worldwide, in men, colorectal cancer is the third leading cancer with 663,600 new cases estimated to have occurred in 2008 followed by stomach, liver, and esophageal cancers with an estimated number of new cases in 2008 of 640,600, 522,400 and 326,600, respectively [23]. In females, colorectal cancer is the second leading cancer worldwide with 570,100 new cases, while stomach cancer and liver cancer are ranked fifth and seventh at an estimated 349,000 and 225,900 new cases, respectively [23]. In the USA, colorectal cancer is the third most common cancer with an estimated number of 71,850 (colon: 48,940) new cases in men and 69,360 (colon: 52,400) new cases in women in 2011 [25]. Pancreatic cancer is the tenth leading cancer in the USA with an estimated 20,050 new cases in men and 21,980 new cases in women in 2011. Cancers arising in the stomach and small intestine are more rare with an estimated 13,120 and 3,990 new cases, respectively, in men, and 8,400 and 3,580 new cases, respectively, in women expected in 2011 [25]. Incidence rates of colorectal and liver cancer are higher in African-American (67.2 and 13.5 per 100,000 population, respectively) compared to Caucasian (56.1 and 8.2 per 100,000, respectively) men [25]. African-American women also have higher incidence rates of colorectal and liver cancer (50.7 and 3.9 per 100,000, respectively) compared to Caucasian women (41.4 and 2.8 per 100,000, respectively) [25]; however, the magnitude of the difference between these rates is not as great as that observed among men. In the USA, colorectal cancer incidence rates have declined approximately 3.1% in males and 2.2% in females during the period of 1998–2007 in the USA, which likely reflects increased colonoscopy and sigmoidoscopy screening that can detect and remove precancerous polyps [25]. In 1975, about 75% of esophageal cancers in the USA were squamous-cell carcinomas and 25% were adenocarcinomas; however, during the past 20 years, the incidence of squamous-cell carcinomas has decreased substantially in African-Americans and Caucasians, particularly among men, while the rate of adenocarcinoma has increased by 450% in Caucasian men and has increased by 50% in African-American men [26]. The rising rates of esophageal adenocarcinoma (ECA) are believed to be caused, at least in part, by the raising rates of obesity [26–28]. In the UK, during the 10-year period from 1984 to 1993, the age- and sex-standardized incidence rates of esophageal cancer increased from 4.6 to 5.4 cases per 100,000 with the proportion of adenocarcinomas increasing from 29.1 to 52.2% [29]. During this 10-year period, gastric cancer decreased in the UK from 12.8 to 10.5 per 100,000 [29]. The age-adjusted incidence rates of liver cancer have also been increasing in the USA since the mid-1980s [30].

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The continuing growth and aging of the worldwide population suggest that the current (2008) rates of cancer will continue to increase [24] and, it is believed that a significant proportion of the worldwide cancer burden could be prevented through implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns that decrease obesity by promoting physical activity and healthier dietary patterns [23].

4

Gastrointestinal Cancers: Mortality Rates

In economically developed countries, cancer is the leading cause of death and, in developing countries, the second leading cause of death [31]. In 2008, 7.6 million cancer deaths are estimated to have occurred in 2008 worldwide [23]. In 1999, cancer replaced heart disease as the leading cause of death among men and women 85 years and younger in the USA [25]. Worldwide, the second and third leading causes of cancer death are stomach cancer (738,000 deaths, 9.7%) and liver cancer (696,000 deaths, 9.2%) [24]. Stomach cancer mortality rates are highest in Eastern Asia (28.1 per 100,000 in men and 13.0 per 100,000 in women) and lowest in Northern America (2.8 per 100,000 in men and 1.5 per 100,000 in women) [24]. Cancer survival generally tends to be poorer in developing countries, most likely because of the combination of a later stage at diagnosis and limited access to timely and standard treatments [23]. Worldwide, in men, liver cancer is the second leading cause of cancer death with 478,300 new deaths estimated to have occurred in 2008 followed by stomach, colorectal, and esophageal cancers with an estimated number of new deaths in 2008 of 464,400, 320,600, and 276,100, respectively [23]. Pancreatic cancer is the eighth leading cause of cancer death in men worldwide with an estimated 138,100 new deaths in 2008 [23]. In females, colorectal cancer is the third leading cause of cancer death worldwide with 288,100 new deaths in 2008, while stomach cancer and liver cancer are ranked fifth and sixth with an estimated 273,600 and 217,600 new deaths, respectively [23]. Esophageal and pancreatic cancers are the eighth and ninth leading cause of cancer death in women worldwide with an estimated 130,700 and 127,900 new deaths, respectively, in 2008 [23]. In the USA, deaths from colorectal cancer are the third leading cause of cancer death in males and females with an estimated number of new cancer deaths in 2011 of 25,250 and 24,130, respectively [25]. Pancreatic cancer is the fourth leading cause of cancer death among men and women with an estimated 19,360 and 18,300 new deaths expected in 2011, respectively [25]. Liver cancer is the fifth and esophageal cancer is the seventh leading cause of cancer death in men with an estimated 13,260 and 11,910 new deaths, respectively, in 2011. In women in the USA, liver cancer is the ninth leading type of cancer death with 6,330 new deaths expected in 2011 [25]. Death rates from stomach and small intestinal cancers are more rare in the USA, with an estimated and 6,260 and 610, respectively, new deaths expected in males and 4,080 and 490 new deaths in females, respectively [25].

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N.L. Nock

In the USA, colorectal cancer mortality rates are higher in African-American men (30.5 per 100,000) and women (21.0 per 100,000) compared to Caucasian men (20.6 per 100,000) and women (14.4 per 100,000) [25]. Mortality rates for liver and gastric cancers are also higher in African-American compared to Caucasians and, the 5-year survival rate is lower in African-Americans than Caucasians for every stage of diagnosis for colorectal, esophageal, and pancreatic cancer [25]. Mortality rates have continued to decrease for many GI cancers in the USA, including colorectal cancer in both males and females, which likely reflects a combination of earlier diagnosis and improved treatments; however, pancreatic (and lung) cancers have shown the least improvement in survival over the past 30 years [25]. Furthermore, in US males, death rates for liver and ECA have continued to increase since 1990 and, in females, death rates for liver and pancreatic cancer have increased since 1990 [25]. In Europe, mortality rates declined for colorectal and stomach cancers in both men and women and, the increasing trend previously observed for pancreatic cancer mortality rates among women in 2004 is now estimated to level off in 2011 [32]. In the Netherlands, “optimal progress,” which was defined as decreasing incidence and/or increasing survival trends since 1989, was observed for colon, rectal, stomach, and gallbladder cancers in men and in women [33]. However, suboptimal progress was found for esophageal cancer in males and esophageal and pancreatic cancer in females [33].

5

Obesity and Metabolic Syndrome

Overweight and obesity lead to adverse metabolic effects on blood pressure, cholesterol, triglycerides, and insulin resistance and, 90% of individuals with T2DM are overweight or obese [15]. The MetSyn is a clustering of metabolic traits including obesity as well as insulin resistance or dysglycemia (high fasting glucose), dyslipidemia [high density lipoprotein cholesterol (HDL-C), high serum triglycerides (TG)] and hypertension [raised systolic and/or diastolic blood pressure (BP)]. Obesity and central obesity are formally defined within the context of MetSyn. However, multiple diagnostic definitions have been proposed for MetSyn by organizations including the WHO [34], European Group Insulin Resistance (EGIR) [35], National Cholesterol Education Program Adult Treatment Panel III [36], International Diabetes Federation (IDF) [37], American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) [38]. The most recent joint interim statement proposed by the AHA/NHLBI, IDF, and others provides researchers and clinicians further clarity on what factors and cut-points should be applied to define and diagnose MetSyn [9]. Although these recommendations differ widely on the obesity component, the prevalence of MetSyn is rising worldwide, which may be attributed, in part, to the rising rates of overweight and obesity [9, 39]. According to the NHANES III (1988–1994) in the USA, which used the NCEP ATP III criteria, the age-adjusted prevalence of MetSyn was approximately 23.7% [40]; however, these rates vary depending on which definition is applied [41]. Patients with MetSyn

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have a fivefold increase in risk of developing T2DM and are at twice the risk of developing CVD over the next 5–10 years compared with individuals without the syndrome [9]. In the presence of both MetSyn and T2DM, the prevalence of CVD is markedly increased [odds ratio (OR) = 3.04, 95% confidence interval (CI) of OR: 1.98–4.11] in comparison to those with neither of these conditions [42].

6

Obesity and Gastrointestinal Cancers: Epidemiological Evidence

Systematic reviews and meta-analyses have revealed that there is a strong, consistent association between obesity and colorectal cancer and emerging evidence for associations between obesity and ECA and liver and pancreatic cancers. Some studies suggest an association between obesity and gallbladder and gastric cancers, particularly for cardia and not non-cardia adenocarcinoma gastric cancers; however, the number of studies are substantially fewer than for the other GI cancers and the results are inconsistent across studies. Results from previously published metaanalyses between obesity and each of these GI cancers are reviewed in this section and summarized in Table 1.1.

6.1

Obesity and Colorectal Cancers

In a meta-analysis including approximately 70,000 incident cases of colorectal cancer from 31 studies, 23 of which were cohort and 8 of which were case–control studies, the risk of colorectal cancer in obese (BMI ³ 30 kg/m2) compared to normal weight individuals was 1.19 (95% CI: 1.08–1.30) and, 1.41 (95% CI: 1.30–1.54) among men and 1.08 (95% CI: 0.98–1.18) among women after correcting for publication bias [45]. Effect sizes for colon are generally larger than those for rectal cancer and effect sizes for men are generally larger than those observed for women. In the Moghaddam et al. [45] meta-analysis, the association between obesity and colon cancer, when stratified by gender, remained significant in men (OR = 1.53; 95% CI: 1.33–1.75) but not in women (OR = 1.09; 95% CI: 0.93–1.28). Similar differences by gender were observed for the association between obesity and rectal cancer (men: OR = 1.27, 95% CI: 1.17–1.37; women: OR = 1.02, 95% CI: 0.85– 1.22). In perhaps, the most comprehensive meta-analysis evaluating obesity-related measures and multiple cancer sites, including 282,137 incident cancer cases (154,333 men and 127,804 women) from 67 cohort studies and 6 nested case– control studies, a 5 kg/m2 increase in BMI conferred a greater risk for colon cancer in men (22 studies: RR = 1.24, 95% CI: 1.20–1.28) compared to women (19 studies: RR = 1.09, 95% CI: 1.05–1.13); however, the association observed for rectal cancer in men (18 studies: RR = 1.09, 95% CI: 1.06–1.12) was not statistically significant

Colon: 45,116 Rectal: 22,232

69,619

2,050

Larsson and Wolk [44]

Moghaddam et al. [45]

Renehan et al. [46]

Men: 22 Colon; 11 rectal Women: 19 Colon; 12 Rectal

23 Cohort; 8 Case–control

30 Cohort

Table 1.1 Obesity and gastrointestinal (GI) cancers: Summary of meta-analyses Study reference Cases Studies Colorectal cancer Dai et al. [43] 6,458 15 Cohort Colon: Men: 1.71 (1.33–2.19) Women: 1.10 (0.92–1.32) Rectal: Men: 1.75 (1.17–2.62) Women: 1.12 (0.84–1.49) Colon: Men: 1.68 (1.36–2.08) Women: 1.48 (1.19–1.84) Rectal: Men: 1.26 (0.90–1.77) Women: 1.23 (0.81–1.86) Colon: Men: 1.30 (1.25–1.35) Women: 1.12 (1.07–1.18) Rectal: Men: 1.12 (1.09–1.16) Women: 1.03 (0.99–1.08) Colon: Men: 1.53 (1.33–1.75) Women: 1.09 (0.93–1.28) Rectal: Men: 1.27 (1.17–1.37) Women: 1.02 (0.85–1.22) Colon: Men: 1.24 (1.20–1.28) Women: 1.09 (1.05–1.13) Rectal: Men: 1.09 (1.06–1.12) Women: 1.02 (1.00–1.05)

BMI: ³30 kg/m2

BMI: ↑ 5 kg/m2

BMI: ³30 kg/m2

BMI: ↑ 5 kg/m2

Waist: Highest vs. lowest quintiles

RR (95% CI of RR)

Obesity definition

8 N.L. Nock

2,488

2,050

3,288

2,039

1,142

9,492

5,039

2,070

Renehan et al. [46]

Gallbladder cancer Larsson and Wolk [49]

Renehan et al. [46]

Gastric cancer Renehan et al. [46]

Yang et al. [50]

Liver cancer Larsson and Wolk [51]

Renehan et al. [46]

Colon: 43,415 Rectal: 23,946

Harriss et al. [47]

Esophageal adenocarcinoma Kubo and Corley [48]

Cases

Study reference

Men: 4 Women: 1

11 Cohort

Men: 8 Women: 5 10 Cohort

8 Cohort; 3 Case–control Men: 4 Women: 2

2 Cohort; 12 Case–control Men: 5 Women: 3

26 Cohort; 3 Nested (N.) Case–control

Studies

5 kg/m2 ↑ in BMI

BMI: ³ 30 kg/m2

5 kg/m2 ↑ in BMI BMI: ³30 kg/m2

BMI: ³30 kg/m2 5 kg/m2 ↑ in BMI

5 kg/m2 ↑ in BMI

BMI: ³28 kg/m2

2

BMI: ↑ 5 kg/m

Obesity definition

Men: 2.42 (1.83–3.20) Women: 1.67 (1.37–2.03) Men: 1.24 (0.95–1.62) Women: 1.07 (0.55–2.08) (continued)

Men: 0.97 (0.88–1.06) Women: 1.04 (0.90–1.20) Men: 1.41 (1.08–1.83) Women: 1.16 (0.89–1.51) Cardia: 2.06 (1.63–2.61) NonCardia: 1.26 (0.89–1.78)

Men: 1.35 (1.09–1.68) Women: 1.88 (1.66–2.13) Men: 1.09 (0.99–1.23) Women: 1.59 (1.02–2.47)

Men: 2.40 (2.00–2.80) Women: 2.10 (1.40–3.20) Men: 1.52 (1.33–1.74) Women: 1.51 (1.31–1.74)

Colon: Men: 1.24 (1.20–1.28) Women: 1.09 (1.04–1.12) Rectal: Men: 1.09 (1.05–1.14) Women: 1.02 (0.99–1.04)

RR (95% CI of RR) 1 Obesity and Gastrointestinal Cancers: Epidemiology 9

8,062

4,443

Larsson et al. [53]

Renehan et al. [46]

Modified from Donohoe et al. [54] with permission

6,391

Cases

Pancreatic cancer Berrington de et al. [52]

Table 1.1 (continued) Study reference Men: 4 Women: 1 8 Cohort; 6 Case–control 20 Cohort; 1 N. Case–control Men: 12 Women: 11

Studies Men: 1.03 (1.01–1.06) Women: 1.01 (1.00–1.03) All: 1.19 (1.10–1.29) Men: 1.16 (1.05–1.28) Women: 1.10 (1.02–1.19) Men: 1.07 (0.93–1.23) Women: 1.12 (1.02–1.22)

5 kg/m2 ↑ in BMI 5 kg/m2 ↑ in BMI

RR (95% CI of RR)

1 kg/m2 ↑ in BMI; 30 vs. 22 kg/m2

Obesity definition

10 N.L. Nock

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in women (14 studies: RR = 1.02, 95% CI: 1.00–1.05) [46]. Among individual studies, as illustrated in the review by Frezza et al. [55], nine out of ten studies showed substantially larger effect sizes between obesity and colon cancer in men compared to women. Using estimates for the prevalence of excess body weight (BMI ³ 25 kg/m2) from 30 European countries in 1992 (i.e., a 10-year lag period), the estimated population attributable risk (PAR) in the year 2002 would be 10.92% for men and 2.57% for women, resulting in 10,386 incident colon cancer cases in men and 2,274 colon cancers in women [56]. We observed an increased colon cancer risk for changes in BMI of 5–10 kg/m2 between the 30s age decade and recruitment (OR = 1.54, 95% CI: 1.02–2.34) and for BMI changes >10 kg/m2 (OR = 2.40, 95% CI: 1.23–4.66) (P-trend = 0.01); however, stratification by gender revealed that BMI changes greater than 10 kg/m2 increased risk in women but not men [57]. There is evidence for an increased risk among men compared to women for central obesity measures as well. In a meta-analysis involving only cohort studies where the highest compared to the lowest quartile of waist circumference was compared, men had a higher risk of colon cancer compared to women (men: OR = 1.68, 95% CI: 1.36–2.08; women: OR = 1.48, 95% CI: 1.19–1.84) but the association was not statistically significant in men or women for rectal cancer (men: OR = 1.26, 95% CI: 0.90–1.77; women: OR = 1.23, 95% CI: 0.81–1.86) [43]. Stronger associations between obesity and proximal compared to distal colon cancers have been reported; however, the results are not entirely consistent across studies. In Dai et al. [43] meta-analysis, the relative risk (RR) between obesity and proximal colon cancer was 1.41 (95% CI = 0.66–3.01) vs. 1.23 (95% CI = 0.80–1.90) for the distal colon. In terms of central obesity, for those in highest vs. the lowest quantile of waist circumference, the RR was 2.05 (95% CI = 1.23–3.41) for the proximal colon and 1.86 (95% CI = 1.05–3.30) for the distal colon [43]. Some studies have shown that the stronger effect sizes for the proximal vs. distal colon sites occurs only for BMI and that effect sizes are similar for central obesity measures [58]. Obesity has been associated with colorectal adenomas, which are precursor lesions to most colorectal cancers. In a pooled analysis with 8,213 participants from seven prospective studies, obesity was significantly associated with lesions among men (OR = 1.36, 95% CI: 1.17–1.58) but not among women (OR = 1.10, 95% CI: 0.89– 1.37) [59]. However, in the multiethnic Insulin Resistance Atherosclerosis Study (IRAC), the association between obesity at the time of colonoscopy was statistically significant in women (OR = 4.42, 95% CI: 1.53–12.78) but not in men (OR = 1.26, 95% CI: 0.52–3.07) [60]. Furthermore, among the 17,391 women of the French Etude epidemiologique des femmes de la Mutuelle Generale de l’Education Nationale (E3N)-European Prospective Investigation into Cancer and Nutrition (EPIC) cohort who underwent a colonoscopy during 1993–2002, obesity was associated with an increased colorectal adenoma risk (HR = 1.53, 95% CI: 1.21–1.94) [61]. In the IRAC study, they also found that the risk of adenomas increased among those who gained weight over 5 (OR = 2.30, 95% CI: 1.25–4.22) or 10 (OR = 2.12, 95% CI: 1.25–3.62) years compared with those who maintained weight during these periods [60]. In the French female EPIC Cohort study, mean weight gain over 0.5 kg/year was associated with a 23% increased colorectal adenoma risk [61].

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In addition, they found that waist circumference was positively associated with colorectal adenomas, specifically left colon adenomas but not with rectal or right colon adenomas [61]. Additional studies appear needed to better understand how changes in weight by gender, ethnicity and lesion type and location affect the risk of development of colorectal adenomas and their potential progression to colorectal cancer. Consistent with patterns in colorectal cancer, associations between obesity and colorectal adenomas appear to be stronger for proximal compared to distal lesions. In the pooled analysis of seven prospective studies, statistically significant trends were observed for increasing BMI and proximal neoplasia but not for distal neoplasia [59]. Interestingly, there is also evidence for differences by gender in colorectal screening rates when comparing obese to overweight individuals. Overweight and Class I obese men were more likely to have obtained a screening sigmoidoscopy within the previous 5 years (Overweight: OR = 1.25, 95% CI: 1.05– 1.51; Class I Obese: OR = 1.21, 95% CI: 1.03–1.75), while women with Class I (OR = 0.86, 95% CI: 0.78–0.94) and Class II (OR = 0.88, 95% CI: 0.79–0.99) obesity were less likely to have obtained a screening sigmoidoscopy compared to normal weight women [62].

6.2

Obesity and Esophageal Cancer

As mentioned briefly above, the rising rates of ECA, which have surpassed the rates of squamous cell esophageal cancer, appear to be driven, in part, to the rising rates of obesity [26–28]. In a meta-analysis including 2 cohort and 12 case–control studies and 2,488 esophageal cancers, obesity was associated with ECA in males (OR = 2.4, 95% CI: 1.9–3.2) and females (OR = 2.1, 95% CI: 1.4–3.2) with similar effect sizes [48]. In a meta-analysis including five studies in men and three studies in women, a 5 kg/m2 increase in BMI resulted in a significant association with ECA in men (RR = 1.52, 95% CI: 1.33–1.74) and women (RR = 1.51, 95% CI: 1.31–1.74) [46]. Interestingly, this meta-analysis also revealed that a 5 kg/m2 increase in BMI was associated with decreased risk of squamous cell esophageal cancer in men (RR = 0.71, 95% CI: 0.60–0.85) and women (RR = 0.57, 95% CI: 0.47–0.69) [46]. Using data from 30 countries in Europe, the PAR for excess weight (BMI ³ 25 kg/ m2) in males was estimated at 26.70 and 24.46% in females, resulting in 1,799 new esophageal cancer cases in males and 2,288 in females in 2002 [56]. There is a fairly consistent association between obesity and gastroesophageal reflux disease (GERD) [63]. Obesity can increase intraabdominal pressure affecting the mechanics of the lower esophageal sphincter, which may predispose obese people to GERD; however, a few studies have shown that obesity is associated with ECA even in the absence of reflux [64]. Obesity is also associated with Barrett’s esophagus, a condition whereby a metaplastic epithelium replaces the normal squamous epithelium in the esophagus; and, although it has been reported that patients with Barrett’s have a 30- to 40-fold increased risk of ECA, many never

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progress to cancer [27]. In a meta-analysis of nine studies that documented use of histopathology to confirm the diagnosis, obesity was found to significantly increase the risk of Barrett’s esophagus (OR = 1.35, 95% CI: 1.15–1.59) [65]. Further discussion of the relations and putative mechanisms linking obesity, GERD, Barrett’s esophagus, and esophageal cancer can be found in Chap. 5.

6.3

Obesity and Gastric Cancer

The association between obesity and gastric cancers is equivocal. In a meta-analysis involving eight studies in men and five studies in women, the association between a 5 kg/m2 increase in BMI was not associated with gastric cancer in men (RR = 0.97, 95% CI: 0.88–1.06) or women (RR = 1.04, 95% CI: 0·90–1·20) [46]. However, some studies suggest an association between obesity and gastric cardia adenocarcinoma but not between obesity and gastric non-cardia adenocarcinoma. In a meta-analysis including 10 cohort studies and 9,492 gastric cancer cases, obesity (OR = 1.36, 95% CI: 1.21–1.54) and overweight and obesity combined (OR = 1.22, 95% CI: 1.06–1.41) were associated with an increased risk of gastric cancer but stratification by cancer sub type revealed that the latter association only remained significant among cardia (OR = 1.55, 95% CI: 1.31–1.84) and not non-cardia (OR = 1.18, 95% CI: 0.96–1.45) gastric cancers [50]. In this meta-analysis, they found that neither association remained significant when stratified by gender (males: OR = 1.22, 95% CI: 0.96–1.55; females: OR = 1.13, 95% CI: 0.65–1.94); however, stratification by ethnicity revealed the association was significant only among all non-Asian ethnic groups combined (OR = 1.24, 95% CI: 1.14–1.36) and not among Asians (OR = 1.17, 95% CI: 0.88–1.56) [50].

6.4

Obesity and Gallbladder Cancer

In a meta-analysis including eight cohort and three case–control studies including a total of 3,288 cases, obesity increased the risk of gallbladder cancer (OR = 1.66, 95% CI: 1.47–1.88) and, the association was stronger in women (OR = 1.88, 95% CI: 1.66–2.13) than in men (OR = 1.35, 95% CI: 1.09–1.68) [49]. In a meta-analysis including four studies in men and two studies in women, a 5 kg/m2 increase in BMI resulted in a significant association with gallbladder cancer in women (RR = 1.59, 95% CI: 1.02–2.47) but not in men (RR = 1.09, 95% CI: 0.99–1.21) [46], which is consistent with the higher (two to five times) incidence of gallbladder cancer observed in women compared to men. An estimated 30% of gallbladder cancer cases among women and 12% among men may be attributable to excess body weight (BMI ³ 25 kg/m2) [49]. Using data from 30 countries in Europe, the PAR for excess body weight (BMI ³ 25 kg/m2) in females was estimated to be 18.16%, resulting in 2,163 incident gallbladder cancer cases in 2002 [56].

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Obesity increases the risk for gallstones [66] and, gallstones increase the risk for gallbladder cancer, particularly in females [67]. However, evidence substantiating whether obesity is an independent predictor of gallbladder cancer or, if gallstones mediate the relation between obesity and gallbladder cancer, is lacking.

6.5

Obesity and Liver Cancer

In a meta-analysis of ten cohort studies including 6,042 cases, obesity was associated with liver cancer (RR = 1.89, 95% CI: 1.51–2.36) [51]. In a meta-analysis including four studies in men and one study in women, a 5 kg/m2 increase in BMI was associated with an increased risk of liver cancer in men (RR = 1.24, 95% CI: 0.95–1.62) and women (RR = 1.07, 95% CI: 0.55–2.08) but neither association was statistically significant [46]. It has been estimated that 28% of liver cancer cases among men and 27% among women are attributable to excess body weight (BMI ³ 25 kg/m2) [51]. Non-alcoholic fatty liver disease (NAFLD), a chronic liver disease that occurs in nondrinkers, affects one in three adults and one in ten children/adolescents in the USA [68] and, rates may be ever higher among Hispanic populations [69]. NAFLD is characterized by tissue changes ranging from small accumulations of fat in the liver to non-alcoholic steatohepatitis (NASH), cirrhosis and, ultimately, liver cancer. It is estimated that up to 90% of obese individuals have some degree of fatty liver and approximately 25–30% have NASH [70]. Therefore, it has been hypothesized that the increased risk of liver cancer associated with excess body weight may be mediated through the development of NAFLD [51]; however, more elegant mediation models are needed to statistically validate this hypothesis.

6.6

Obesity and Pancreatic Cancer

In a meta-analysis of eight cohort and six case–control studies including 6,391 cases, obesity was associated with an increased risk of pancreatic cancer (OR = 1.19, 95% CI: 1.10–1.29) [52]; however, this risk estimate was based upon a BMI unit increase (comparing 30–22 kg/m2). In a meta-analysis including 12 studies in men and 11 studies in women, a 5 kg/m2 increase in BMI resulted in a significant association with pancreatic cancer in women (RR = 1.12, 95% CI: 1.02–1.22) but not in men (RR = 1.07, 95% CI: 0.93–1.23) [46]. In a pooled analysis of seven cohort studies including 458,070 men and 485,689 women and 2,454 incident pancreatic cancer cases, Class I obesity was associated with an increased risk of pancreatic cancer (RR = 1.19, 95% CI: 1.05–1.35) and, associations were stronger in females (RR = 1.34, 95% CI: 1.11–1.64) than in males (RR = 1.11, 95% CI: 0.95–1.30) [71]. In a pooled analysis of the Pancreatic Cancer Consortium (PANSCAN), which comprised a nested case–control study with 2,170

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cases and 2,209 controls, Class I (OR = 1.20, 95% CI: 1.00–1.44) and Class II or greater (OR = 1.55, 95% CI: 1.16–2.07) obesity was associated with an increased risk of pancreatic cancer [72]. Significant associations were found for Class II or greater obese females (OR = 1.61, 95% CI: 1.12–2.33) but not males [72]. Consistent with other reports, the association between BMI and pancreatic cancer was stronger in obese nonsmokers (OR = 1.37, 95% CI: 1.06–1.78) than in smokers (OR = 1.14, 95% CI: 0.91–1.78) [72]. Using data from 30 countries in Europe, the PAR for excess body weight (BMI ³ 25 kg/m2) in females was estimated to be 7.82% resulting in 2,127 incident pancreatic cancer cases in 2002 [56]. Obesity has been associated with higher risk of developing pancreatitis, which may increase the risk of pancreatic cancer via the “Chronic Inflammatory Hypothesis;” however, most patients with chronic pancreatitis are no longer obese by the time they present which makes studying putative associations between obesity and chronic pancreatitis difficult [73]. In a meta-analysis of 12 studies and 609 patients, obesity was found to be associated with severe acute pancreatitis (OR = 2.6, 95% CI: 1.5–4.6) [74]. Moreover, obesity has been associated with pancreatic steatosis or infiltration of fat into the pancreas (more specifically, into the in islet or acinar cells) and may increase the risk of pancreatic cancer but others purport that there is insufficient evidence to support the theory of non-alcoholic fatty steatopancreatitis (NASP) as a precursor to pancreatic adenocarcinoma [75]. Obesity has also been linked to surgical complications in pancreatectomy or pancreatic resections. In a recent meta-analysis including 17 studies, increasing BMI was associated with higher rates of pancreatic fistulas [76]. More details on the putative mechanisms driving the association between obesity and pancreatic diseases and cancer can be found in Chap. 6.

7

Obesity and Gastrointestinal Cancer Mortality: Epidemiological Evidence

The association between obesity and all-cause mortality and all-cancer mortality are well established [77, 78]. In a meta-analysis of 74 cohorts encompassing 388,622 individuals and 60,374 deaths, obesity was associated with an increased risk of allcause mortality in males (RR = 1.20, 95% CI: 1.12–1.29) and females (RR = 1.28, 95% CI: 1.18–1.37) and, obesity was associated with an increased risk of all-cancer mortality in females (RR = 1.10, 95% CI: 1.001–1.22) but not males (RR = 1.06, 95% CI: 0.98–1.14) [78]. Much less, however, is known about how obesity affects cancer mortality in specific tissues/organs and how obesity or weight gain at different ages along the disease continuum affects cancer survival in these different tissues/organs. In a landmark study (Cancer Prevention II) involving more than 900,000 US adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, the proportion of all deaths from cancer in the US population attributable to

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overweight and obesity ranged from 4.2 to 14.2% in men and 14.3 to 19.8% in women, with the lowest rates generated from total population estimates and the highest rates from those who never smoked [79]. In men, Class I obesity at enrollment was associated with an increased risk of death from colorectal cancer (RR = 1.47, 85% CI: 1.30–1.66), esophageal cancer (RR = 1.28, 95% CI: 1.00–1.63), gallbladder cancer (RR = 1.76, 95% CI: 1.06–2.94), liver cancer (RR = 1.90, 95% CI: 1.46–2.47), and pancreatic cancer (RR = 1.41, 95% CI: 1.19–1.66) 16 years later [79]. Class II obesity in men was associated with increased mortality from colorectal cancer (RR = 1.84, 95% CI: 1.39–2.41), liver cancer (RR = 4.52, 95% CI: 2.94–6.94), and stomach cancer (RR = 1.94, 95% CI: 1.21–3.13), and marginally significant for pancreatic cancer (RR = 1.49, 95% CI: 0.99–2.22) [79]. Among women, Class I and Class II obesity were associated with an increased risk of death from colorectal (Class I: RR = 1.33, 95% CI: 1.17–1.51; Class II: RR = 1.36, 95% CI: 1.06–1.74), and pancreatic (Class I: RR = 1.28, 95% CI: 1.07–1.52; Class II: RR = 1.41, 95% CI: 1.01–1.99) cancer [79]. Class I obesity increased the risk of death from gallbladder cancer in women (RR = 2.13, 95% CI: 1.56–2.90). Significant positive linear trends in death rates were observed for colorectal, gallbladder, liver, and pancreatic cancers in men and women [79]. In a subsequent study, obesity (HR = 1.45, 95% CI: 1.14–1.85) and waist circumference (highest vs. lowest tertile: HR = 1.37, 95% CI: 1.02–1.85) were shown to be positively associated with colon cancer mortality in females [80]. Moreover, obesity was associated with increased overall mortality (HR = 1.34, 95% CI: 1.07– 1.67) in women but not in men (HR = 0.94, 95% CI: 0.77–1.15) with colon cancer [81]. Class I (HR = 1.00, 95% CI: 0.72–1.40) and Class II or III (HR = 1.24, 95% CI: 0.84–1.83) obesity was not associated with decreased survival in Stage III colon cancer patients after the analysis was adjusted for tumor-related prognostic factors [82]. Class II (HR = 1.32, 95% CI: 1.08–1.62) and Class III (HR = 1.60, 95% CI: 1.26– 2.04) obesity have been associated with decreased pancreatic cancer survival [83]. In addition, patients obese in the year prior to recruitment had reduced overall pancreatic cancer survival regardless of disease stage or tumor resection status (HR = 1.86, 95% CI: 1.35–2.56) [84]. However, overweight was not an independent prognostic factor for long-term survival in the Polish Gastric Cancer Study Group, which included 1,992 patients with resectable gastric cancer treated between 1986 and 1998 [85]. Obesity does not significantly decrease ECA survival in similar preoperative disease stages and studies suggest 5-year overall and disease-free survival may actually be longer in obese patients [86, 87]. Thus, additional studies examining the effects of obesity and weight gain at different points in the disease continuum are needed to better understand the role of obesity on survival of GI cancers in men and women within various major ethnic groups.

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17

Metabolic Syndrome and Gastrointestinal Cancers: Epidemiological Evidence

Because of the strong associations observed between obesity and GI cancers and, because obesity plays a key role in manifestation of insulin resistance and the MetSyn, we review emerging evidence for associations between MetSyn and GI cancers. In the EPIC Study, dysregulated glucose metabolism was associated with both colon (RR = 2.05, 95% CI: 1.57–2.68) and rectal (RR = 2.07, 95% CI: 1.45–2.96) cancer and, the MetSyn, using the NCEP ATP III criteria, was associated with colon (RR = 1.91, 95% CI: 1.47–2.42) but not rectal (RR = 1.45, 95% CI: 1.02–2.06) cancer [88]. However, in the MetSyn and Cancer Project (Me-Can) that is following a cohort of 578,700 men and women, a MetSyn z-score was associated with colorectal cancer in men (RR = 1.25, 95% CI: 1.18–1.32) and women (RR = 1.14, 95% CI: 1.06–1.22) [89]. In a recent meta-analysis involving five (four cohort, one case–control) studies, MetSyn was associated with an increased risk of pancreatic cancer (RR = 1.55, 95% CI: 1.19–2.01) [90]. However, additional studies are needed to better understand potential differences in risk between men and women such as the significant association observed between MetSyn z-scores and pancreatic cancer in women (RR = 1.58, 95% CI: 1.34–1.87) but not men (RR = 1.07, 0.94–1.22) in the Me-Can cohort [91]. According to a recent review, there are no studies examining the association between MetSyn and upper GI cancers including ECA; however, one study reported that 46% of Barrett’s esophagus patients were found to have MetSyn [92]. Another study reported the presence of MetSyn in Barrett’s patients was greater than in GERD patients, but percentages varied depending on the definition applied (NCEP ATP III: 30% vs. 20%; IDF: 42% vs. 37%) [93]. Using information from the Surveillance, Epidemiology, and End Results (SEER) Medicare database from 1993 to 2005, MetSyn was significantly associated with increased risk of liver cancer [hepatocellular carcinoma (HCC): OR = 2.13, 95% CI: 1.96–2.31 and intrahepatic cholangiocarcinoma (ICC): OR = 1.56, 95% CI: 1.32– 1.83] [94]. In the Me-Can cohort study, MetSyn z-score was associated with an increased risk of liver cancer (RR = 1.35, 95% CI: 1.12–1.61) [95]. The literature examining associations between MetSyn and most GI cancers, especially ECA and gastric cancers, is scant. Therefore, additional studies are needed to fill this research gap.

9

Conclusions

There is consistent and compelling evidence for an association between obesity, MetSyn, and several GI cancers, particularly, colon cancer. Evidence is emerging for associations between obesity, MetSyn and ECA and obesity, MetSyn and pancreatic and liver cancers. There is a limited number of studies examining obesity, MetSyn

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and gastric and gallbladder cancers and, thus far, results have been inconsistent. Additional studies examining the effects of obesity, weight gain, and MetSyn at different points in the carcinogenesis continuum are needed to better understand their role on GI cancer survival in men and women and among major ethnic groups. Acknowledgments This work was supported, in part, from the National Institutes of Health (NIH) National Cancer Institute (NCI) K07CA129162 awarded to NLN.

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17. Ogden CL, Yanvoski SZ, Carroll MD, Flegal KM (2007) The epidemiology of obesity. Gastroenterology 132:2087–2102 18. Flegal KM, Carroll MD, Ogden CL, Curtin LR (2010) Prevalence and trends in obesity among US adults, 1999–2008. JAMA 303:235–241 19. Zaninotto P, Wardle H, Stamatakis E, Mindell J, Head J (2006) Forecasting obesity to 2010. National Centre for Social Research/Department of Health, London 20. Berghofer A, Pischon T, Reinhold T, Apovian CM, Sharma AM, Willich SN (2008) Obesity prevalence from a European perspective: a systematic review. BMC Public Health 8:200 21. Orsi CM, Hale DE, Lynch JL (2011) Pediatric obesity epidemiology. Curr Opin Endocrinol Diabetes Obes 18:14–22 22. The NS, Suchindran C, North KE, Popkin BM, Gordon-Larsen P (2010) Association of adolescent obesity with risk of severe obesity in adulthood. JAMA 304:2042–2047 23. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90 24. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917 25. Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61:212–236 26. Enzinger PC, Mayer RJ (2003) Esophageal cancer. N Engl J Med 349:2241–2252 27. Corley DA (2007) Obesity and the rising incidence of oesophageal and gastric adenocarcinoma: what is the link? Gut 56:1493–1494 28. Pera M, Manterola C, Vidal O, Grande L (2005) Epidemiology of esophageal adenocarcinoma. J Surg Oncol 92:151–159 29. Wayman J, Forman D, Griffin SM (2001) Monitoring the changing pattern of esophago-gastric cancer: data from a UK regional cancer registry. Cancer Causes Control 12:943–949 30. Howe HL, Wu X, Ries LA, Cokkinides V, Ahmed F, Jemal A, Miller B, Williams M, Ward E, Wingo PA, Ramirez A, Edwards BK (2006) Annual report to the nation on the status of cancer, 1975–2003, featuring cancer among U.S. Hispanic/Latino populations. Cancer 107:1711–1742 31. World Health Organization (2008) The Global Burden of Disease: 2004 Update. World Health Organization, Geneva 32. Malvezzi M, Arfe A, Bertuccio P, Levi F, La VC, Negri E (2011) European cancer mortality predictions for the year 2011. Ann Oncol 22:947–956 33. Karim-Kos HE, Kiemeney LA, Louwman MW, Coebergh JW, Vries ED (2011) Progress against cancer in the Netherlands since the late 1980s: an epidemiological evaluation. Int J Cancer 2011 Jul 25. doi: 10.1002/ijc.26315 34. Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553 35. Balkau B, Charles MA (1999) Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 16:442–443 36. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486–2497 37. Alberti KG, Zimmet P, Shaw J (2005) The metabolic syndrome—a new worldwide definition. Lancet 366:1059–1062 38. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F (2006) Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Curr Opin Cardiol 21:1–6 39. Halpern A, Mancini MC, Magalhaes ME, Fisberg M, Radominski R, Bertolami MC, Bertolami A, de Melo ME, Zanella MT, Queiroz MS, Nery M (2010) Metabolic syndrome, dyslipidemia, hypertension and type 2 diabetes in youth: from diagnosis to treatment. Diabetol Metab Syndr 2:55

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40. Ford ES, Giles WH, Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287:356–359 41. Cook S, Auinger P, Li C, Ford ES (2008) Metabolic syndrome rates in United States adolescents, from the National Health and Nutrition Examination Survey, 1999–2002. J Pediatr 152:165–170 42. Athyros VG, Mikhailidis DP, Papageorgiou AA, Didangelos TP, Ganotakis ES, Symeonidis AN, Daskalopoulou SS, Kakafika AI, Elisaf M (2004) Prevalence of atherosclerotic vascular disease among subjects with the metabolic syndrome with or without diabetes mellitus: the METS-GREECE Multicentre Study. Curr Med Res Opin 20:1691–1701 43. Dai Z, Xu YC, Niu L (2007) Obesity and colorectal cancer risk: a meta-analysis of cohort studies. World J Gastroenterol 13:4199–4206 44. Larsson SC, Wolk A (2007) Obesity and colon and rectal cancer risk: a meta-analysis of prospective studies. Am J Clin Nutr 86:556–565 45. Moghaddam AA, Woodward M, Huxley R (2007) Obesity and risk of colorectal cancer: a metaanalysis of 31 studies with 70,000 events. Cancer Epidemiol Biomarkers Prev 16:2533–2547 46. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M (2008) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371:569–578 47. Harriss DJ, Atkinson G, George K, Cable NT, Reilly T, Haboubi N, Zwahlen M, Egger M, Renehan AG (2009) Lifestyle factors and colorectal cancer risk (1): systematic review and meta-analysis of associations with body mass index. Colorectal Dis 11:547–563 48. Kubo A, Corley DA (2006) Body mass index and adenocarcinomas of the esophagus or gastric cardia: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 15:872–878 49. Larsson SC, Wolk A (2007) Obesity and the risk of gallbladder cancer: a meta-analysis. Br J Cancer 96:1457–1461 50. Yang P, Zhou Y, Chen B, Wan HW, Jia GQ, Bai HL, Wu XT (2009) Overweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studies. Eur J Cancer 45:2867–2873 51. Larsson SC, Wolk A (2007) Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer 97:1005–1008 52. Berrington de GA, Sweetland S, Spencer E (2003) A meta-analysis of obesity and the risk of pancreatic cancer. Br J Cancer 89:519–523 53. Larsson SC, Orsini N, Wolk A (2007) Body mass index and pancreatic cancer risk: A metaanalysis of prospective studies. Int J Cancer 120:1993–1998 54. Donohoe CL, Pidgeon GP, Lysaght J, Reynolds JV (2010) Obesity and gastrointestinal cancer. Br J Surg 97:628–642 55. Frezza EE, Wachtel MS, Chiriva-Internati M (2006) Influence of obesity on the risk of developing colon cancer. Gut 55:285–291 56. Renehan AG, Soerjomataram I, Leitzmann MF (2010) Interpreting the epidemiological evidence linking obesity and cancer: a framework for population-attributable risk estimations in Europe. Eur J Cancer 46:2581–2592 57. Nock NL, Thompson CL, Tucker TC, Berger NA, Li L (2008) Associations between obesity and changes in adult BMI over time and colon cancer risk. Obesity (Silver Spring) 16:1099–1104 58. Moore LL, Bradlee ML, Singer MR, Splansky GL, Proctor MH, Ellison RC, Kreger BE (2004) BMI and waist circumference as predictors of lifetime colon cancer risk in Framingham Study adults. Int J Obes Relat Metab Disord 28:559–567 59. Jacobs ET, Ahnen DJ, Ashbeck EL, Baron JA, Greenberg ER, Lance P, Lieberman DA, McKeown-Eyssen G, Schatzkin A, Thompson PA, Martinez ME (2009) Association between body mass index and colorectal neoplasia at follow-up colonoscopy: a pooling study. Am J Epidemiol 169:657–666 60. Sedjo RL, Byers T, Levin TR, Haffner SM, Saad MF, Tooze JA, D’Agostino RB Jr (2007) Change in body size and the risk of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 16:526–531 61. Morois S, Mesrine S, Josset M, Clavel-Chapelon F, Boutron-Ruault MC (2010) Anthropometric factors in adulthood and risk of colorectal adenomas: the French E3N-EPIC prospective cohort. Am J Epidemiol 172:1166–1180

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62. Heo M, Allison DB, Fontaine KR (2004) Overweight, obesity, and colorectal cancer screening: disparity between men and women. BMC Public Health 4:53 63. Anand G, Katz PO (2008) Gastroesophageal reflux disease and obesity. Rev Gastroenterol Disord 8:233–239 64. Lin SW, Freedman ND, Hollenbeck AR, Schatzkin A, Abnet CC (2011) Prospective study of self-reported diabetes and risk of upper gastrointestinal cancers. Cancer Epidemiol Biomarkers Prev 20:954–961 65. Kamat P, Wen S, Morris J, Anandasabapathy S (2009) Exploring the association between elevated body mass index and Barrett’s esophagus: a systematic review and meta-analysis. Ann Thorac Surg 87:655–662 66. Stinton LM, Myers RP, Shaffer EA (2010) Epidemiology of gallstones. Gastroenterol Clin North Am 39:157–169, vii 67. Rustagi T, Dasanu CA (2011) Risk factors for gallbladder cancer and cholangiocarcinoma: similarities, differences and updates. J Gastrointest Cancer 2011 May 20 68. Angulo P (2007) Obesity and nonalcoholic fatty liver disease. Nutr Rev 65:S57–S63 69. Carrion AF, Ghanta R, Carrasquillo O, Martin P (2011) Chronic liver disease in the Hispanic population of the United States. Clin Gastroenterol Hepatol 9(10):834–841 70. Neuschwander-Tetri BA, Caldwell SH (2003) Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 37:1202–1219 71. Jiao L, de Berrington GA, Hartge P, Pfeiffer RM, Park Y, Freedman DM, Gail MH, Alavanja MC, Albanes D, Beane Freeman LE, Chow WH, Huang WY, Hayes RB, Hoppin JA, Ji BT, Leitzmann MF, Linet MS, Meinhold CL, Schairer C, Schatzkin A, Virtamo J, Weinstein SJ, Zheng W, Stolzenberg-Solomon RZ (2010) Body mass index, effect modifiers, and risk of pancreatic cancer: a pooled study of seven prospective cohorts. Cancer Causes Control 21:1305–1314 72. Arslan AA, Helzlsouer KJ, Kooperberg C, Shu XO, Steplowski E, Bueno-de-Mesquita HB, Fuchs CS, Gross MD, Jacobs EJ, Lacroix AZ, Petersen GM, Stolzenberg-Solomon RZ, Zheng W, Albanes D, Amundadottir L, Bamlet WR, Barricarte A, Bingham SA, Boeing H, BoutronRuault MC, Buring JE, Chanock SJ, Clipp S, Gaziano JM, Giovannucci EL, Hankinson SE, Hartge P, Hoover RN, Hunter DJ, Hutchinson A, Jacobs KB, Kraft P, Lynch SM, Manjer J, Manson JE, McTiernan A, McWilliams RR, Mendelsohn JB, Michaud DS, Palli D, Rohan TE, Slimani N, Thomas G, Tjonneland A, Tobias GS, Trichopoulos D, Virtamo J, Wolpin BM, Yu K, Zeleniuch-Jacquotte A, Patel AV (2010) Anthropometric measures, body mass index, and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Arch Intern Med 170:791–802 73. Gumbs AA (2008) Obesity, pancreatitis, and pancreatic cancer. Obes Surg 18:1183–1187 74. Martinez J, Sanchez-Paya J, Palazon JM, Suazo-Barahona J, Robles-Diaz G, Perez-Mateo M (2004) Is obesity a risk factor in acute pancreatitis? A meta-analysis. Pancreatology 4:42–48 75. Smits MM, van Geenen EJ (2011) The clinical significance of pancreatic steatosis. Nat Rev Gastroenterol Hepatol 8:169–177 76. Ramsey AM, Martin RC (2011) Body mass index and outcomes from pancreatic resection: a review and meta-analysis. J Gastrointest Surg 15(9):1633–1642 77. Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW Jr (1999) Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 341:1097–1105 78. McGee DL (2005) Body mass index and mortality: a meta-analysis based on person-level data from twenty-six observational studies. Ann Epidemiol 15:87–97 79. Calle EE, Rodriquez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638 80. Prizment AE, Flood A, Anderson KE, Folsom AR (2010) Survival of women with colon cancer in relation to precancer anthropometric characteristics: the Iowa Women’s Health Study. Cancer Epidemiol Biomarkers Prev 19:2229–2237 81. Meyerhardt JA, Catalano PJ, Haller DG, Mayer RJ, Benson AB III, Macdonald JS, Fuchs CS (2003) Influence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma. Cancer 98:484–495

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82. Meyerhardt JA, Niedzwiecki D, Hollis D, Saltz LB, Mayer RJ, Nelson H, Whittom R, Hantel A, Thomas J, Fuchs CS (2008) Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: findings from Cancer and Leukemia Group B 89803. J Clin Oncol 26:4109–4115 83. McWilliams RR, Matsumoto ME, Burch PA, Kim GP, Halfdanarson TR, de AM, ReidLombardo K, Bamlet WR (2010) Obesity adversely affects survival in pancreatic cancer patients. Cancer 116:5054–5062 84. Li D, Morris JS, Liu J, Hassan MM, Day RS, Bondy ML, Abbruzzese JL (2009) Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA 301:2553–2562 85. Kulig J, Sierzega M, Kolodziejczyk P, Dadan J, Drews M, Fraczek M, Jeziorski A, Krawczyk M, Starzynska T, Wallner G (2010) Implications of overweight in gastric cancer: A multicenter study in a Western patient population. Eur J Surg Oncol 36:969–976 86. Madani K, Zhao R, Lim HJ, Casson SM, Casson AG (2010) Obesity is not associated with adverse outcome following surgical resection of oesophageal adenocarcinoma. Eur J Cardiothorac Surg 38:604–608 87. Melis M, Weber JM, McLoughlin JM, Siegel EM, Hoffe S, Shridhar R, Turaga KK, Dittrick G, Dean EM, Karl RC, Meredith KL (2011) An elevated body mass index does not reduce survival after esophagectomy for cancer. Ann Surg Oncol 18:824–831 88. Aleksandrova K, Boeing H, Jenab M, Bueno-de-Mesquita HB, Jansen E, van Duijnhoven FJ, Fedirko V, Rinaldi S, Romieu I, Riboli E, Romaguera D, Overvad KK, Ostergaard JN, Olsen A, Tjonneland AA, Boutron-Ruault MC, Clavel-Chapelon F, Morois S, Masala G, Agnoli C, Panico S, Tumino R, Vineis P, Kaaks R, Lukanova A, Trichopoulou A, Naska A, Bamia C, Peeters PH, Rodriguez L, Buckland G, Sanchez MJ, Dorronsoro M, Huerta JM, Barricarte GA, Hallmans G, Palmqvist R, Khaw KT, Wareham NJ, Allen NE, Tsilidis KK, Pischon T (2011) Metabolic syndrome and risks of colon and rectal cancer: the European Prospective Investigation into Cancer and Nutrition Study. Cancer Prev Res (Phila) 4(11):1873–1883 89. Stocks T, Lukanova A, Bjorge T, Ulmer H, Manjer J, Almquist M, Concin H, Engeland A, Hallmans G, Nagel G, Tretli S, Veierod MB, Jonsson H, Stattin P (2010) Metabolic factors and the risk of colorectal cancer in 580,000 men and women in the metabolic syndrome and cancer project (Me-Can). Cancer 2010 Dec 17 90. Rosato V, Tavani A, Bosetti C, Pelucchi C, Talamini R, Polesel J, Serraino D, Negri E, La VC (2011) Metabolic syndrome and pancreatic cancer risk: a case–control study in Italy and metaanalysis. Metabolism 60(10):1372–1378 91. Johansen D, Stocks T, Jonsson H, Lindkvist B, Bjorge T, Concin H, Almquist M, Haggstrom C, Engeland A, Ulmer H, Hallmans G, Selmer R, Nagel G, Tretli S, Stattin P, Manjer J (2010) Metabolic factors and the risk of pancreatic cancer: a prospective analysis of almost 580,000 men and women in the Metabolic Syndrome and Cancer Project. Cancer Epidemiol Biomarkers Prev 19:2307–2317 92. Ryan AM, Duong M, Healy L, Ryan SA, Parekh N, Reynolds JV, Power DG (2011) Obesity, metabolic syndrome and esophageal adenocarcinoma: epidemiology, etiology and new targets. Cancer Epidemiol 35:309–319 93. Healy LA, Ryan AM, Carroll P, Ennis D, Crowley V, Boyle T, Kennedy MJ, Connolly E, Reynolds JV (2010) Metabolic syndrome, central obesity and insulin resistance are associated with adverse pathological features in postmenopausal breast cancer. Clin Oncol (R Coll Radiol) 22:281–288 94. Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA (2011) Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEERmedicare database. Hepatology 54:463–471 95. Borena W, Strohmaier S, Lukanova A, Bjorge T, Lindkvist B, Hallmans G, Edlinger M, Stocks T, Nagel G, Manjer J, Engeland A, Selmer R, Haggstrom C, Tretli S, Concin H, Jonsson H, Stattin P, Ulmer H (2011) Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults. Int J Cancer 2011 Jul 29. doi: 10.1002/ijc.26338 96. Nock NL, Berger NA (2010) Obesity and cancer: overview of mechanisms. In: Berger NA (ed) Cancer and energy balance, epidemiology and overview. Springer, New York, NY, pp 129–179

Chapter 2

Genetics of Colon Cancer Susceptibility Graham Casey

Abstract Colorectal cancer (CRC) exhibits a strong familial risk with first-degree relatives of cases having a two to three times greater risk of developing CRC than the general population. An estimated 35% of CRC cases are due to genetic factors. Highly penetrant predisposing genes have been identified for several inherited CRC syndromes (e.g., FAP, Lynch syndrome, and juvenile polyposis) through genetic linkage studies. However, despite these considerable successes, mutations in these rare syndromes explain less than 6% of CRCs and only a small fraction of familial risk. While two recently described syndromes, MUTYH-associated polyposis, with its pattern of recessive inheritance, and familial CRC type X, account for additional genetic burden, they still account for only a small fraction of CRC risk. In the last few years, considerable effort has been directed toward the identification of common, low-penetrance mutations through the promising approach of genome-wide association studies (GWAS). With respect to CRC, 15 novel disease loci have been identified through GWAS including several genes involved in the TGFb signaling pathway. The familial and population risks explained by these loci remain small, but it is expected that additional novel susceptibility markers will be identified as larger ongoing and pooled GWAS are completed. While the role of the majority of susceptibility genes identified through linkage studies and GWAS in energy balance remains unclear, a pattern is emerging of a possible link given that several TGFbrelated genes have been implicated in energy balance including susceptibility genes identified through linkage analyses or GWAS.

G. Casey, Ph.D. (*) Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA e-mail: [email protected] S.D. Markowitz and N.A. Berger (eds.), Energy Balance and Gastrointestinal Cancer, Energy Balance and Cancer 4, DOI 10.1007/978-1-4614-2367-6_2, © Springer Science+Business Media, LLC 2012

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Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is an autosomal, dominantly inherited condition with the defining clinical feature of the development of hundreds to thousands of adenomatous polyps throughout the colon in childhood and adolescence [1, 2]. FAP exhibits nearly 100% penetrance [3] with equal gender distribution [4] and accounts for nearly 1% of all colorectal cancers (CRCs) [5]. FAP has a variable degree of clinical expression [6], including attenuated (10–100 polyps), sparse (100–500 polyps), and profuse (>2,000 polyps) forms. Attenuated FAP (AFAP) [7] shows a delayed onset of CRC, occurring on average 12 years later than classic/ profuse FAP [8, 9]. Patients with FAP can develop a variety of extracolonic tumors including upper gastrointestinal tract malignancies and cancers of the thyroid, pancreas, biliary tree, brain, and hepatoblastomas [8]. A diagnosis of FAP that also includes medulloblastoma is termed Turcot’s syndrome [10], and the association of polyposis with osteomas and desmoid tumors has been referred to as Gardner’s syndrome. FAP patients can also develop a variety of extracolonic manifestations, including duodenal and fundic gland polyps or retinal epithelium abnormalities as seen in congenital hypertrophy of retinal pigment epithelium (CHRPE) [11]. Many of these extracolonic manifestations correlate with APC-specific mutations (see later in this section). The gene responsible for FAP, the Adenomatous Polyposis Coli (APC) gene on chromosome 5q21, was cloned in 1991 following linkage analysis in families with FAP [12–15]. APC is a large gene that encodes a protein of 2,843 amino acids [16]. It functions as a tumor suppressor and has been implicated in a number of cell processes [16–18], but the best-characterized role for APC is as part of a scaffolding protein complex that negatively regulates Wingless/WNT signaling [16, 19, 20]. This pathway has been reviewed extensively elsewhere [17, 18] and is summarized here only briefly. APC and the transcription coregulator b-catenin play central roles in the WNT signaling pathway. In normal cells, in the absence of WNT signaling, APC, along with Axin, glycogen synthase kinase 3 b (GSK3 b) and casein kinase, recruit b-catenin into a destruction complex where it is phosphorylated by GSK3 b, leading to b-catenin degradation by the ubiquitin-mediated proteosome pathway. This cellular process leads to the maintenance of low levels of free cytosolic b-catenin in the cytoplasm. When the WNT signaling pathway is activated the APC/Axin/GSK3b complex disassociates, allowing stabilization of cytosolic b-catenin. Accumulated b-catenin associates with T-cell factor (TCF) and lymphoid-enhancer factor (LEF) and the resulting complex enters the nucleus and activates transcription. Once it enters the nucleus the b-catenin/TCF/LEF proteins provide a potent transcriptional complex leading to transactivation of a number of critical genes including MYC and cyclin D1 [18, 21, 22]. Loss of control of this pathway through mutation and inactivation of APC leads to aberrant accumulation of b-catenin, and transcriptional activation of b-catenin/TCF/LEF complexes resulting in aberrant activation of target genes [16]. APC also participates in a number of other cellular processes related to cytoskeletal organization, in particular microtubule stability [22]. The genetic evidence of the importance of deregulation of the b-catenin signaling pathway in CRC strongly implicates a central role for the WNT/APC/b-catenin pathway in CRC development.

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More than 800 different disease-causing APC germ-line mutations have been reported in FAP [23]. The majority of mutations occur between codons 1250 and 1464 in the 5¢ region of exon 15, a region known as the mutation cluster region (MCR) [23]. Mutations at codons 1061 and 1309 (“hot spots”) account for approximately 11 and 17%, respectively, of all germ-line APC mutations [23]. The majority of the remaining mutations occur between codons 200 and 1600 with only a few mutations falling outside this region [16]. The majority of mutations are frameshift or nonsense mutations that lead to an inactive truncated protein product [16, 24]. Approximately 10–30% APC mutations are de novo [25]. A common missense mutation (I1307K) in APC has also been reported in the Ashkenazi Jewish population [26]. While this missense mutation does not appear to have any effect on APC function, carriers do have an increased risk of CRC but not polyposis or any other extra colonic manifestations of FAP [26]. As discussed earlier, there is marked variability in the clinical phenotype of FAP, with severity of disease often correlating with location of the APC mutation [27]. For example, mutations in codon 1250 to codon 1464 and particularly codon 1309 mutations correlate with profuse polyposis where symptoms usually occur 10 years earlier than milder forms [28–34]. Mutations at the extreme 5¢ and 3¢ ends of the APC gene are generally associated with AFAP where patients develop fewer than 100 colon polyps and cancer onset is delayed [6, 35–39]. The appearance of extracolonic manifestations also correlates with the location of APC mutation. For example, mutations between codons 1310 and 2011 are associated with the appearance of desmoid tumors [28], with the highest severity occurring between codons 1444/5 and 1580/1 [29, 40–42]. Mutations between codons 140 and 1309 are often associated with the occurrence of papillary thyroid cancer [43], whereas CHRPE is often associated with mutations in codons 457–1444 [12, 44]. Gardner’s syndrome involving severe desmoids, osteomas, epidermoid cysts, and upper gastrointestinal polyps is generally associated with APC mutations in codons 1403 and 1578 [44, 45]. While no consistent genotype correlation has been found for duodenal adenomas, FAP patients with APC mutations in codons 976–1067 have been reported to have a three- to fourfold increased risk [28]. Mouse models support a critical role for APC in the development of intestinal neoplasia. Although mice homozygous for inactivated Apc are embryonic lethal, mice heterozygous for Apc (the Multiple intestinal neoplasia or Min mouse) invariably develop multiple intestinal tumors [46]. While there are some differences in the tissue specificity and morphogenesis between Min mice and FAP, Min mice have proven an important model for intestinal tumorigenesis.

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Hereditary Nonpolyposis Colon Cancer/Lynch Syndrome

Hereditary nonpolyposis colorectal cancer (HNPCC) (more commonly referred to as Lynch syndrome) is a clinically heterogeneous disease that has historically been diagnosed based on family history criteria (Amsterdam and Bethesda criteria) that are not very accurate [47–49]. Lynch syndrome is characterized by a high incidence

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of CRC and endometrial cancer in families. The lifetime risk for colon cancer in Lynch syndrome subjects is approximately 50–60% [50]. There is increased incidence of extracolonic cancers in both males and females including those of the small bowel, stomach, pancreas, ovary, renal pelvis, ureter, bladder, brain, appendix, liver, bile duct, gall bladder, and skin [49, 51, 52]. Colon cancers arising in Lynch syndrome families have a propensity toward left sidedness with two-thirds arising in the proximal colon [51–53]. These tumors show a variety of common histologic features including tumor-infiltrating lymphocytes, mucinous or signet ring differentiation, and a medullary growth pattern [48, 49, 53, 54]. Like FAP, Lynch syndrome is an autosomal, dominantly inherited condition. However, Lynch syndrome is more challenging to diagnose than FAP because the clinical phenotype is far more varied and more genes are involved. The majority of Lynch syndrome cases are accounted for by mutations in one of four genes (MSH2, MLH1, MSH6, or PMS2) involved in DNA mismatch repair (MMR). Of those cases with defective MMR, approximately 80–90% have germ line mutations in one of these genes. The majority of cases are due to mutations in MSH2 and MLH1 that play central and critical roles in DNA MMR [55], with MSH2 forming a heterodimer with MSH6 (and to a lesser extent MSH3), and MLH1 with PMS2. In newly replicated DNA, mismatches such as G > T [56] are recognized by MSH2–hMSH6 heterodimers (MutS alpha in yeast), whereas insertion–deletion loops are recognized primarily by MSH2–MSH6 heterodimers, but can also be mediated by the less abundant MSH2–MSH3 (MutS beta) heterodimeric protein complex that appears to function as a backup in the absence of MSH6. Loss of MSH2 therefore leads to the accumulation of aberrant length repeat sequences such as (A)n or (CA)n and high levels of Microsatellite Instability (MSI). Once the MSH2–MSH6 heterodimer recognizes DNA mismatches, this complex undergoes an ATP-dependent conformational change converting it to a sliding DNA clamp capable of moving away from the repair site [57, 58]. This is followed by the recruitment to the complex of MLH1–PMS2 heterodimers (MutL-alpha) [59]. This is then followed by exonuclease degradation of a few hundred bases of the newly synthesized mutant DNA strand followed by resynthesis of the complementary strand by DNA polymerase. As mutations in MSH2, MLH1, MSH6, and PMS2 do not appear to account for all MMR deficient cases it is possible that other MMR genes have yet to be identified [59]. A detailed description of the role of these proteins in DNA MMR and their specific roles in Lynch syndrome can be found in several reviews [60, 61]. Defective MMR repair was recognized as the underlying genetic basis for Lynch syndrome following the observation by three independent groups that MSI was a hallmark feature of tumors arising in Lynch syndrome family members [62–65]. MSI, also referred to as a replication error (RER) or “mutator” tumor phenotype [62, 63, 65], occurs as a result of failure to repair of errors in copying during DNA replication. Thousands of microsatellite short tandem repeat DNA sequences (mono-, di-, tri-, or tetranucleotides) exist throughout the human genome, and errors can occur during DNA replication when copying these sequences. Typically such misalignment errors would be repaired by the DNA MMR system. However, in cells with defective MMR repair, these errors are not repaired effectively, and tumor DNAs of

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Lynch syndrome family members reveal a “stuttering” (loss or gain of one or more repeats) pattern of microsatellite markers when compared with DNA from normal cells from the same subject. Once it was recognized that the MSI phenotype was similar to the mutational spectrum seen in yeast caused by deletion or mutation of MMR genes, the MSH2 and MLH1 genes that account for the majority of Lynch syndrome cases were identified within a year [56, 66]. Germ-line mutations in MLH1 and MSH2 account for the majority of mutations found in families with Lynch syndrome with a smaller minority attributable to mutations in MSH6 and PMS2. Germ line testing remains a challenge as mutations can occur throughout any of these relatively large genes and are not localized to any mutation hot spots as in the APC gene. MSH2 consists of 935 amino acids over 16 exons, MLH1 consists of 756 amino acids over 19 exons, MSH6 consists of 1,360 amino acids over 10 exons, and PMS2 consists of 862 amino acids over 15 exons. A wide range of types of mutations has been reported in these genes including missense, nonsense and splice site mutations. In addition, a number of large genomic deletions or rearrangements involving several exons have also been reported [67–73]. Testing for PMS2 germ-line mutations is not straightforward as there are several highly homologous PMS2 pseudogenes, the majority of which have homology with at least some of the ten exons at the 3¢ end of the gene [74–77]. A comprehensive listing of MMR gene mutations can be found on the Mismatch Repair Genes Variant Database [78] and the MMR Gene Unclassified Variants database (http:// www.mmrmissense.net/), which focuses more on functional assays and other types of data to support the interpretation of the unclassified variants in MMR genes. Nearly 90% of Lynch syndrome colon tumors exhibit high levels of MSI [62, 65, 79], and there exists a strong correlation between MSI and loss of staining of MMR proteins using immunohistochemistry (IHC). As a result, IHC of the four MMR proteins along with an assessment of family history has been recommended as a starting point for diagnosing Lynch syndrome [79, 80]. However, it should be noted that the sensitivity of IHC staining is not as high as MSI analysis as not all MMR mutations lead to a loss of protein expression [81–83]. While defects in MMR are seen in nearly 15% of CRCs, tumors with MMR germ-line mutations account for less than 5% of all cases. This is because MMR defects are also seen in a subset of “sporadic” CRCs through somatic hypermethylation and inactivation of MLH1 [84]. “Sporadic” MSI-H tumors share many of the characteristics of those arising in MMR mutation carriers, including a tendency toward a proximal location in the colon and a mucinous phenotype, but they usually occur later in life. Although these cancers generally arise in the absence of a positive family history, a vertical transmission in some families has been reported [85–87]. There is some evidence that MLH1 and MSH2 mutation families exhibit different clinical expression. Several studies have been published, with overall findings of greater CRC risk, earlier CRC onset, and fewer extracolonic tumors in MLH1 mutation carriers compared with MSH2 mutation carriers [50, 88–95]. Clinically, identification of an MMR gene defect, whether occurring within the context of Lynch syndrome or sporadically, is important as it affects response to some chemotherapeutic agents and ultimately prognosis [96–99].

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MUTYH-Associated Polyposis

Recent studies have identified germ-line mutations in the mutY homologue MUTYH (also called MYH) with a recessive mode of inheritance associated with high risk of multiple adenomatous polyps (10–1,000) and CRC in up to 50% of APC-negative polyposis cases [100–102]. MUTYH mutations account for nearly 1% of all CRC cases [103]. The majority of cases are associated with a relatively small number of common variants (around 0.2% population frequency in Caucasians) [104–106]. Biallelic carriers develop multiple polyps by 45–55 years, although this may be an overestimate as large population-based studies have not yet been conducted [103, 105, 107]. The MUTYH gene was implicated in CRC risk following the observation in tumors of APC mutation-negative multiple polyposis families that the APC gene harbored an excess of somatic G:T transversions [100]. Such mutations are hallmarks of oxidative DNA damage. This led Al-Tassan and coworkers to investigate a possible role for a constitutional defect in base excision repair (BER) and the subsequent identification of two germ-line variants (Y179C and G396D) in MUTYH that segregated with disease in family members [100]. The majority of MUTYH carriers are accounted for by these two common missense mutations (44 and 24%, respectively) with a number of additional rare MUTYH missense mutations including some truncating mutations accounting for a small fraction [101–106, 108–112]. The Y179C MUTYH variant correlates with a more severe phenotype than G396D, manifesting at an earlier age of onset of polyposis and a greater risk of developing CRC than the Y179C allele [104]. Some studies have suggested that monoallelic MUTYH mutations may be associated with an increased risk of CRC, but this remains controversial [102, 104–106, 111, 113–116]. MUTYH is involved in BER of DNA damage caused by reactive oxygen species (ROS) produced through cellular metabolism or exposure to ionizing radiation. Among the lesions caused by oxidative DNA damage is 8-oxoguanine (8-oxoG). 8-oxoG is stable and highly mutagenic product prone to post-DNA replication mispairing. MUTYH is a DNA glycosylase involved in the identification and removal of mismatched adenines incorporated opposite 8-oxoG during replication. Failure to correct 8-oxoG:A mispairing leads to characteristic G:C to T:A transversions in the next cycle of DNA replication [117, 118]. Two other enzymes, MTH1 and OGG1, also play critical roles in BER [119, 120], but to date no mutations in these genes have been linked convincingly to increased risk of either colorectal polyposis or CRC [121]. There are few discriminatory features to MUTYH-related CRC. While CRC can occur throughout the colon in MUTYH carriers [104, 105], there is an excess of proximal cancers [101–103, 109, 122]. There are no characteristic histopathology or clinicopathologic features [103–105, 123], and tumors are microsatellite stable [104, 105, 109, 124]. Gastroduodenal polyposis has been observed in nearly 20% of MUTYH biallelic carriers [125–127], but this is likely to be an overestimate as these studies were conducted in highly selected polyposis registry families. MUTYH variants have been implicated in a number of cancers including lung, breast, gastric, and endometrial cancers. However, there remains no definitive evidence for an elevated risk of such cancers.

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Familial Colorectal Cancer Type X

Over the last few years, there has been growing recognition that many families that fulfill HNPCC Amsterdam 1 criteria do not harbor an inherited MMR mutation [93, 128]. Growing evidence suggests that this may reflect a separate syndrome. In a large study using the resources of the Colon Cancer Family Registry [129], Lindor et al. compared 90 Amsterdam I families with MMR-deficient tumors with 71 Amsterdam I families with MMR-proficient tumors and showed that families with MMR-deficient tumors had a statistically significantly elevated risk of developing colorectal, endometrial, gastric, small intestine, and kidney cancers as expected for Lynch syndrome. In contrast, while there was a twofold increased risk of CRC in the families with MMR-proficient tumors, there was no increased risk of any other cancer site [130]. The average age at diagnosis of CRC was also later (61 years) in families with normal MMR compared to families with MMR deficiency (49 years). Based on these data, the authors concluded the normal MMR families that met Amsterdam I should not be considered Lynch syndrome families and coined the name “familial colorectal cancer type X” (FCCTX) [130]. A number of studies have now been published that support these findings and strongly imply that FCCTX should be regarded as a distinct syndrome(s) rather than a missed diagnosis of Lynch syndrome [131–133]. In support of this, FCCTX cases are more likely to be diagnosed at a later age than Lynch syndrome cases despite having a similar incidence of adenomas, are less likely to develop multiple primary tumors, and tumors are less likely to have Lynch syndrome characteristics such as a propensity toward right-sidedness, or a mucinous or tumor-infiltrating lymphocyte pathology [113, 134–136]. While the molecular phenotype of FCCTX tumors appears to differ from that of Lynch syndrome tumors, the phenotype does not appear to be distinct from that of sporadic CRC [137, 138]. FCCTX is likely to be a heterogenous group including families with a chance aggregation of CRC, families with an undiagnosed syndrome such as MUTYHassociated polyposis [113] or MSI-variable families [139], and families with an as yet to undiscovered syndrome.

5

Hamartomatous Polyposis and Other Rare Syndromes

Several familial syndromes have been described that are characterized by multiple hamartomatous polyps in the intestinal tract including Cowden disease, Peutz–Jeghers syndrome, and juvenile polyposis syndrome. Hamartoma refers to an excessive focal overgrowth and distorted architecture of cells and tissues native to the organ in which it occurs. These rare syndromes are all inherited in an autosomal dominant fashion, and specific genetic mutations have been identified. A more extensive review of these syndromes has recently been published [140]. Cowden disease is an autosomal dominant disease characterized by intestinal hamartomas, facial trichilemmomas, oral papillomas, goiter, and esophageal glycogenic

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acanthosis [141–143] with an estimated incidence of 1 in 200,000. Breast and thyroid cancer risk is also pronounced in Cowden disease, with CRC developing in up to 10% of patients. Cowden disease and several related syndromes such as Bannayan–Ruvalcaba–Riley syndrome, proteus syndrome, and proteus-like syndrome are all associated with germ-line mutations in the PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene. Clinical features include benign and malignant neoplasms of the thyroid, breast, uterus, and skin as well as hamartomatous intestinal polyps [144]. PTEN modulates G1 cell cycle progression through negatively regulating the survival signal mediated by the phosphatidylinositol 3-kinase (PI3K)/AKT pathway [145]. Inactivation of PTEN though mutation or deletion leads to the activation of AKT [146], increased cell proliferation and reduced apoptosis. Germ-line mutations in PTEN have been identified in approximately 80% of subjects diagnosed with Cowden syndrome. PTEN promoter mutations may account for at least another 10% of Cowden cases [147], and the remaining cases may arise from as yet undiscovered mutations in PTEN [148]. There appears to be a different pattern of mutation in Bannayan–Ruvalcaba–Riley syndrome cases. PTEN germ-line mutations account for 50–60% of patients, and large genomic deletions or rearrangements of exons of PTEN have been reported in Bannayan–Ruvalcaba–Riley syndrome patients but not Cowden syndrome patients. In addition, PTEN promoter mutations are uncommon in Bannayan–Ruvalcaba–Riley syndrome patients [143, 147, 149]. Peutz–Jeghers syndrome is a rare (approximately 1 in 200,000) autosomal dominant disorder characterized by the presence of pigmentation of the lips, buccal mucosa, hands, and feet; hamartomatous polyps throughout the gastrointestinal tract; and increased risk for gastrointestinal, breast, ovarian, and testicular cancers [150, 151] The cumulative risk is around 30% for CRC and 50% for breast cancer [6]. Nearly half of Peutz–Jeghers cases are due to germ-line mutations in STK11/ LKB1 [152, 153]. STK11/LKB1 is a serine–threonine kinase that phosphorylates and activates AMP-activated protein kinase an essential positive regulator the mTOR pathway that is also implicated in the PTEN hamartomatous syndrome [146]. Genotype–phenotype correlation suggests that patients with Peutz–Jeghers, who have a truncation mutation in STK11/LKB1, have a significantly earlier age of onset than those who have a missense mutation or when no mutation is detected in STK11/LKB1 [154]. There are some families with Peutz–Jeghers syndrome that did not show linkage to the STK11/LKB1 chromosomal region suggesting genetic heterogeneity of this disease [155, 156]. Juvenile polyposis syndrome is a rare (1 in 100,000 births) autosomal dominant condition. It is characterized by juvenile polyps, which are distinctive hamartomas that have a smooth surface and are covered by normal colonic epithelium [157]. The polyps may affect not only the colon and rectum but also the proximal gastrointestinal tract. The clinical diagnosis consists of the following criteria: more than five juvenile polyps of the colorectum, or multiple juvenile polyps throughout the gastrointestinal tract, or any number of juvenile polyps and a family history of juvenile polyps [158]. The lifetime risk approaches 60% and patients are also at risk of developing cancers of the stomach and small intestine [159]. Germ-line mutations

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in the TGFb signaling genes SMAD4/MADH4 and BMPR1A account for around 20% of juvenile polyposis cases each [160–164]. More recently, mutations have been identified in a third gene, ENG, but the frequency remains unknown [165, 166]. Clinically, patients with an SMAD4 / MADH4 mutation are more likely to develop large gastric polyps than those with a BMPR1A mutation and these patients usually have a family history of upper gastrointestinal polyposis [36, 167]. Hereditary mixed polyposis syndrome (HMPS) is characterized by colonic polyps of mixed hyperplastic, adenomatous, and occasional juvenile types that eventually lead to the development of CRC [168]. The syndrome is similar to FAP in that it is an autosomal dominantly inherited condition. However, unlike the excessive number of adenomas seen in FAP, the polyps in HMPS are fewer in number, of mixed histology, and appear to be confined to the large bowel. Using a linkage approach, the BMPR1A gene was identified and an 11-bp deletion in the BMPR1A gene found in one family [168]. BMPR1A mutations were later confirmed in other families [169, 170]. Germ-line mutations in BMPR1A have been previously associated with a subset of juvenile polyposis syndrome patients [36, 161, 162]. However, the phenotypic features of the two families in this study differ from JPS. Just as germ-line mutations in APC can cause diverse phenotypic manifestations including those of Turcot and Gardner syndromes, it is perhaps not surprising that mutations in BMPR1A could be responsible for two different syndromes.

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Genome-Wide Association Studies and Low-Penetrance Mutations

Over the last 5 years, genome-wide association studies (GWAS) have provided a powerful new approach for identifying susceptibility loci. Rather than focusing on the highly penetrant rare mutations described above, GWAS focus on the identification of common, low-penetrance mutations. As with linkage studies, GWAS represents an agnostic survey of the genome, but unlike linkage analyses that use a relatively small number of markers to screen cancer-dense families, GWAS employs SNP arrays containing hundreds of thousands of SNPs to screen relatively large populations. GWAS have only become possible in recent years due to major technological advances in the development of genotyping platforms that allow cost-effective high throughput genotyping of large sample sets. This approach has begun to reveal novel findings that are improving our understanding of the contribution of common alleles to risk of many complex genetic disorders including CRC. GWAS have met with unprecedented success for a range of complex diseases [171]. As of the second quarter of 2011, there have been 1449 published genome-wide associations (at p < 5× 10−8) for 237 traits [172] and this number is expected to increase substantially over the next few years. With respect to CRC, as of January 2011, 15 novel disease loci have been identified in European populations [173–180]. Table 2.1 summarizes the

981/1,002

922/927

940/965 930/960 1,257/1,336

Tenesa, Nat Genet [181]

Tomlinson, Nat Genet [177]

Broderick, Nat Gen [174] Tomlinson, Nat Genet [175] Zanke, Nat Genet [173]

b

a

Illumina [up to 548,586]

1,902/1,929

Houlston, Nat Genet [179]

NHGRI GWAS database (http://www.genome.gov). All studies in Caucasians Cases/controls

Affymetrix [547,647] Illumina [547,647] Illumina and Affymetrix [99,632]

Illumina [547,647]

Illumina [541,628]

Genotyping platform [SNPs] Illumina [various]

Table 2.1 Published GWA studies of CRCa Study reference Initial sample b Houlston, Nat Genet [180] 3,334/4,638 SNP rs6691170 rs6687758 rs10936599 rs11169552 rs7136702 rs4925386 rs961253-A rs4444235-C rs10411210-C rs9929218-A rs4939827-T rs7014346-A rs3802842-C rs10795668-A rs16892766-A rs6983267 rs4779584 rs4939827 rs4939827-T rs6983267-G rs10505477-A rs719725

Gene/region 1q41 1q41 3q26.2 12q13.13 12q13.13 20q13.33 20p12.3 14q22.2 19q13.11 16q22.1 18q21 SMAD7 8q24 11q23 10p14 8q23.3 EIF3H 8q24.21 15q13.3 18q21.1 18q21 SMAD7 8q24 8q24 9p24

OR 1.06 1.09 0.93 0.92 1.06 0.93 1.12 1.11 1.15 1.10 1.20 1.19 1.11 1.27 1.25 1.24 1.23 1.18 1.16 1.21 1.17 1.14

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published findings from these studies, and without exception the risks conferred have been low with odds ratios between 1.1 and 1.3 [173–180]. To date these studies have been limited to individuals of European ancestry. So what candidate genes have been identified through CRC GWAS? Of the 15 SNPs identified to date, 6 map to regions that include TGFb signaling pathway genes, a pathway that previously has been implicated in CRC. These include SMAD7 [174, 179], GREM1 [176], RHPN2, the bone morphogenetic protein genes BMP2 and BMP4 [179], and most recently LAMA5 that is required for the production of noggin, a secreted BMP antagonist [180]. TGFb proteins play critical roles in proliferation, differentiation, cell migration, adhesion, and extracellular matrix (ECM) production [182, 183], and also energy balance (see below), and several lines of evidence support a key role for the TGFb pathway in CRC susceptibility. For example rare, high-penetrance variants in other TGFb-related genes (SMAD4 and the BMP receptor BMPR1A/ALK3) have been reported for juvenile polyposis [36, 161, 162] and for HMPS [169, 170]. In addition, somatic mutations of SMAD4 and the TGFb receptor TGFBR2 have been identified in CRC tumors. The cancer initiation properties of TGFb seem to be distinct from those of progression, as activation of the TGFb signaling pathway leads to enhanced tumor growth and increased metastatic potential [184]. In addition to TGFb signaling candidates, there are intriguing findings for some of the other CRC loci identified through GWAS. For example, 8q24 is a gene desert region that has been identified as a risk locus for several different cancers including CRC [173, 175, 185–188]. While no known genes map to this region, the MYC oncogene maps within 300–400 kb of several independently associated SNPs. Replication, sequencing, and fine-mapping studies of this locus have identified rs6983267 as the most promising variant for functional assessment in CRC and other cancers [189]. This SNP lies in a sequence that is highly conserved across vertebrates and is predicted to have regulatory function [189]. Its relative proximity to MYC makes it plausible that it may disrupt a putative enhancer. However, while MYC is often amplified in CRC, this variant has not been found to correlate with MYC expression in CRC tumors or lymphoblastoid cell lines [190], although tissuespecific long-range chromatin loops between putative enhancer elements in this region and MYC have been shown [191]. Many of the other associated loci (e.g., 9p24, 10p14, 11q23.1, 18q23, and 20p12.3) also lie in intergenic or gene desert regions with no known biological relevance. It is important to note that any candidate genes identified through GWAS, including those belonging to the TGFb signaling pathway, have not yet been confirmed as causal, and there is growing emphasis on dissecting the functional consequences of GWAS findings [192]. One of the challenges for GWAS is that they rarely identify the causal variant or gene, as the SNPs that are included on commercial SNP arrays are chosen to capture regions of linkage disequilibrium (LD) identified through the HapMap project [193] rather than for any functional or putative functional role. As a result, the nearest gene mapping adjacent to an associated SNP may not be the causal gene. Considerable work is needed before functionality can be assigned to any susceptibility SNPs. This is not a trivial task as most effect sizes

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are relatively small and the functional effect of any causal SNP is likely to be subtle. In addition, the majority of disease-associated SNPs identified through GWAS map to intergenic regions or gene “deserts” such as the 8q24 region [194] described above, suggesting that they affect regulatory elements such as enhancers, posing even greater challenges. Undoubtedly, a large amount of work will be needed to clarify the biological implications of these associations. Only limited data are available with regards to the epidemiological characteristics of GWAS associations. Rs3802842 at 11q23 and rs4939827 (SMAD7) have been reported to be more strongly associated with rectal cancer than colon cancer [178]. No differences in risk have been reported by tumor molecular subtypes for the published variants, with the exception of rs4444235 (BMP4) for which the association was found to be significantly stronger for MMR proficient than deficient tumors [179]. Low-penetrance susceptibility alleles may function as modifier genes contributing to the severity of CRC in high-risk subjects. In two large studies of Lynch syndrome, two GWAS hits (rs16892766 on 8q23.3 and rs3802842 on 11q23.1) were significantly associated with an increased CRC risk in these patients [195, 196]. The familial and population risks explained by CRC GWAS loci remain small accounting for less than 10% of overall inherited risk and less than 1% of familial risk [179], and as a result they are not yet useful for risk prediction. However, it is expected that risk prediction will improve as additional susceptibility alleles are identified once ongoing, larger and pooled GWAS analyses as well as studies in other ethnic populations are completed [173–180]. In terms of risk, studies suggest that around 100 SNPs would be required to achieve 80% accuracy of prediction of CRC genetic risk [181], accounting for ~17% of the phenotypic variance providing useful predictive value. This does not take into account the contribution of rare or private variants and their effect on risk are unknown. It will take several years to more fully comprehend the impact of rare variants on CRC risk as these types of studies can only be accomplished through next generation sequencing GWAS that are just being contemplated. It is clear that CRC etiology has a very strong environmental component [197, 198] and there are several ongoing studies examining the relationship between lifestyle risk factors for CRC and interactions with the risk alleles identified through GWAS (gene × environment interactions). Pooling of GWAS data through collaborative efforts should improve power to detect both gene × environment and gene × gene interactions [199].

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CRC Susceptibility Genes and Energy Balance

As discussed above, while promising progress has been made in identifying CRC susceptibility genes through linkage analyses and GWAS, the susceptibility alleles identified to date still only account for a small fraction of CRC risk. Despite this, a growing understanding of the genetic etiology of CRC is beginning to emerge as

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a significant number of susceptibility genes or candidate susceptibility genes belong to the TGFb/BMP superfamily, including SMAD4, BMPR1A/ALK3, SMAD7, GREM1, RHPN2, BMP2, BMP4, and LAMA5. The TGFb family of proteins is a well-known key regulator of many biological processes, and several lines of evidence implicate TGFb1 signaling in energy balance. A review of the role of TGFb in regulating adiposity and energy expenditure was recently published [200]. TGFb is a negative regulator of adipogenesis, promoting preadipocyte proliferation while simultaneously inhibiting differentiation [201], a process augmented by SMAD7 (and SMAD6), a negative regulator of TGFb signaling. TGFb may also influence adipogenesis indirectly through upregulation of WNT signaling, a cascade that also inhibits adipocyte differentiation [202]. That APC mutations lead to the activation of WNT signaling may also implicate APC in energy balance. TGFb1 expression also correlates with body mass index and visceral fat obesity, which along with insulin resistance, plays a central role in metabolic syndrome [203–207], and elevated serum TGFb1 levels are associated with incident type 2 diabetes [208]. These findings are supported by observations in genetically engineered mice [209]. Several lines of evidence also support a role for BMPs in adipogenesis [210]. BMPs appear to play dual roles in this process. The candidate CRC susceptibility gene BMP4 is best recognized for its role in the earliest stages of white adipocyte differentiation [211, 212]. BMP4 promotes the formation of white adipocytes in a dose-dependent manner in mouse embryonic stem cells [211, 213] a finding supported by mouse studies [214]. Several lines of evidence suggest that BMP4 is an important risk factor for metabolic syndrome [215, 216]. BMP4 was associated with increased adiposity [217], recognized as being essential for energy balance [218], and white fat differentiation [212, 214, 219]. Serum BMP4 levels also correlated with body mass index, waist circumference, waist-to-hip ratio, triglycerides, HDL cholesterol, and fasting plasma insulin [216]. BMP4 mRNA expression has also been shown to correlate with obesity in ob/ob transgenic mice [219]. The CRC candidate susceptibility gene BMP2 has also been implicated in adipogenesis both as a pro- and anti-adipogenic protein. BMP2 has been shown to promote osteoblast differentiation while suppressing adipocyte development [220]. In contrast, BMP2 can also stimulate adipocyte differentiation [221–223]. The cellular response to BMP2 and BMP4 is mediated by ligand binding to cell surface receptors including BMPR1A [224, 225], a gene that has been implicated in both HMPS and JPS patients. BMPR1A has been shown to be involved in adipocyte differentiation in vitro [105]. BMPR1A has been strongly implicated in obesity, where BMPR1A mRNA expression was elevated in patients with obesity, type 2 diabetes, and components of metabolic syndrome including body mass index, body mass, and waist-to-hip ratio [216]. Furthermore, BMPR1A mRNA levels were elevated in adipose tissues of obese and overweight adults and three SNP variants in the BMPR1A gene were associated with increased body mass index [225]. A pattern is, therefore, emerging of a possible link between some CRC susceptibility genes and energy balance that warrants further investigation. Based on growing evidence of a link between TGFb-related genes, CRC susceptibility and the

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development of features of metabolic syndrome, modulation of TGFb signaling may represent a valuable therapeutic approach in at-risk individuals.

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205. Spencer M, Yao-Borengasser A, Unal R et al (2010) Adipose tissue macrophages in insulinresistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab 299:E1016–E1027 206. Alessi MC, Bastelica D, Morange P et al (2000) Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 49:1374–1380 207. Porreca E, Di Febbo C, Vitacolonna E et al (2002) Transforming growth factor-beta1 levels in hypertensive patients: association with body mass index and leptin. Am J Hypertens 15:759–765 208. Herder C, Zierer A, Koenig W, Roden M, Meisinger C, Thorand B (2009) Transforming growth factor-beta1 and incident type 2 diabetes: results from the MONICA/KORA casecohort study, 1984–2002. Diabetes Care 32:1921–1923 209. Samad F, Pandey M, Loskutoff DJ (1998) Tissue factor gene expression in the adipose tissues of obese mice. Proc Natl Acad Sci USA 95:7591–7596 210. Tseng YH, Kokkotou E, Schulz TJ et al (2008) New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454:1000–1004 211. Taha MF, Valojerdi MR, Mowla SJ (2006) Effect of bone morphogenetic protein-4 (BMP-4) on adipocyte differentiation from mouse embryonic stem cells. Anat Histol Embryol 35:271–278 212. Bowers RR, Kim JW, Otto TC, Lane MD (2006) Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: role of the BMP-4 gene. Proc Natl Acad Sci USA 103:13022–13027 213. Dani C, Smith AG, Dessolin S et al (1997) Differentiation of embryonic stem cells into adipocytes in vitro. J Cell Sci 110(Pt 11):1279–1285 214. Tang QQ, Otto TC, Lane MD (2004) Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA 101:9607–9611 215. Matsuzawa Y, Funahashi T, Nakamura T (1999) Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances. Ann N Y Acad Sci 892:146–154 216. Son JW, Kim MK, Park YM et al (2011) Association of serum bone morphogenetic protein 4 levels with obesity and metabolic syndrome in non-diabetic individuals. Endocr J 58(1):39–46 217. Huang H, Song TJ, Li X et al (2009) BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA 106:12670–12675 218. Mohamed-Ali V, Pinkney JH, Coppack SW (1998) Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord 22:1145–1158 219. Bowers RR, Lane MD (2007) A role for bone morphogenetic protein-4 in adipocyte development. Cell Cycle 6:385–389 220. Skillington J, Choy L, Derynck R (2002) Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes. J Cell Biol 159:135–146 221. Chen D, Ji X, Harris MA et al (1998) Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol 142:295–305 222. Sottile V, Seuwen K (2000) Bone morphogenetic protein-2 stimulates adipogenic differentiation of mesenchymal precursor cells in synergy with BRL 49653 (rosiglitazone). FEBS Lett 475:201–204 223. Hata K, Nishimura R, Ikeda F et al (2003) Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor gamma during bone morphogenetic protein 2-induced adipogenesis. Mol Biol Cell 14:545–555 224. ten Dijke P, Yamashita H, Sampath TK et al (1994) Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 269:16985–16988 225. Bottcher Y, Unbehauen H, Kloting N et al (2009) Adipose tissue expression and genetic variants of the bone morphogenetic protein receptor 1A gene (BMPR1A) are associated with human obesity. Diabetes 58:2119–2128

Chapter 3

Dietary Modulation of Colon Cancer: Effects on Intermediary Metabolism, Mucosal Cell Differentiation, and Inflammation Lidija Klampfer, Barbara G. Heerdt, Anna Velcich, Erin Gaffney-Stomberg, Donghai Wang, Elaine Lin, and Leonard H. Augenlicht

Abstract We review the profound effects that components of diets commonly consumed in western societies and linked through population studies to risk for colon cancer have on the development of intestinal cancer in humans and in mouse models. Focus is particularly on levels of vitamin D, interactive with calcium and fat, in establishing probability of tumor development even in mouse genetic models in which there is high penetrance of the disease. These dietary factors have also been used to develop a mouse model of dietary-induced sporadic colon cancer

L. Klampfer, Ph.D. • B.G. Heerdt, Ph.D. • A. Velcich • E. Gaffney-Stomberg, Ph.D. • E. Lin, Ph.D. Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467, USA e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected] D. Wang, M.D. Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467, USA Department of Hematology, Peking University First Hospital, Beijing 100034, China e-mail: [email protected] L.H. Augenlicht, Ph.D. (*) Montefiore Medical Center and Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA e-mail: [email protected] S.D. Markowitz and N.A. Berger (eds.), Energy Balance and Gastrointestinal Cancer, Energy Balance and Cancer 4, DOI 10.1007/978-1-4614-2367-6_3, © Springer Science+Business Media, LLC 2012

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which exhibits similar lag, incidence, and frequency of tumor development, and relative incidence of carcinomas and adenomas, as seen for >90% of colon tumors that arise in the general population later in life. Potential mechanisms influenced by diet that alter probability of tumor development are outlined, including altered patterns of intermediary metabolism, differentiation, and inflammation in the intestinal mucosa, all apparent in the histopathologically normal intestinal mucosa well before neoplastic changes become detectable. This includes pathways by which macrophages signal to intestinal epithelial cells, revealing a new paradigm for how vitamin D may influence tumor development.

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Introduction

The probability for development and progression of colon cancer is profoundly influenced by both patterns of dietary exposure and by inflammation. The themes of this chapter are: how do nutrients modulate inflammation and how does altered inflammation contribute to tumorigenesis? In a bias dictated by our own research, we focus on the effects of dietary levels of vitamin D and calcium on the intestinal mucosa in the context of higher dietary fat. An important area that will not be addressed is the complexity of genetic background that may influence how the host responds to altered levels of these nutrients.

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Links of Intestinal Tumor Models to Inflammation

In humans, chronic inflammation predisposes for development of intestinal tumors, a striking example being inflammatory bowel disease (IBD), in which elevated risk for colon cancer is a function of duration and severity of inflammation [1]. Moreover, sporadic colon cancers that do not develop as a complication of IBD are also driven by inflammation, established by the fact that regular use of nonsteroidal antiinflammatory drugs (NSAIDs) lowers mortality from sporadic colon cancers and causes regression of adenomas in familial adenomatous polyposis (FAP) patients [2]. Most experimental models of intestinal tumorigenesis in rodents have also been linked to inflammation. For example, in the classic model of AOM (azoxymethane)induced colon tumors in the mouse and rat, tumors and early aberrant crypt foci can be decreased by NSAIDs such as celocoxib [3, 4]. Furthermore, the tumor phenotype is accelerated and increased by challenging the mice with dodecyl sodium sulfate (DSS), which induces damage and dramatic inflammation in the colon [5–8]. Finally, TLR4 signaling, which mediates host intestinal response to commensal bacteria in the gut, can be inhibited by vitamin D3, which reduces colon cancer induced by the combination of AOM and DSS [9]. Genetic models of intestinal tumors confirm the linkage of tumorigenesis to inflammation. In the ApcMin/+ model of intestinal cancer, NSAIDs inhibit tumor

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development [10, 11], and depletion of mast cells, macrophages, or anti-TNFa treatment significantly suppressed polyposis in mice that inherit a mutant Apc allele [12, 13], confirming the role of macrophage-derived factors in the progression of intestinal tumors. Moreover, inactivation of glutathionine S transferase pi in ApcMin/+ mice induces the expression of proinflammatory genes in the colonic mucosa and colon tumor formation [14]. This is similar to the compromise of detoxification systems and induction of chronic low-level inflammation seen in the Muc2−/− mouse. In this mouse, the genetic inactivation of the Muc2 gene, which encodes the principal colonic mucin, eliminates the physical and chemical mucus barrier in the GI tract, and gives rise to tumors in the small and large intestine and in the rectum [15, 16]. While deficiency of the Muc2 protein does not lead to overt inflammation, analysis of mucosal cell expression profiles was consistent with a low-level, chronic inflammatory response of the mucosa [17]. A direct effect of inflammation on tumor development is seen in a new Stat3-IKO model of colon cancer [18]. Here, inactivation of Stat3 is directly targeted to macrophages, although there is also inactivation in some T- and B cells. This causes colitis of the colonic epithelium, and the development of tumors in the regions of inflammation, due to an mTOR–Stat3-mediated response of the epithelial cells [18]. Remarkably, both the inflammation and the tumors are resolved by aggressive antibiotic treatment, pointing to an important role of the intestinal microbiota in inflammatory-mediated effects on tumorigenesis [18]. Finally, a dramatic example of the association of inflammation with intestinal tumorigenesis, and its modification by diet, comes from a mouse in which the gene that encodes the fucosyltransferase Pofut1 is inactivated specifically in the intestinal tract. This enzyme (and its homologue Ofut1 in Drosophila) catalyzes the fucosylation of Notch receptors, a modification that is necessary for the efficient interaction of these receptors with Delta and Jagged ligands presented by neighboring cells. Thus, inactivation of Pofut1 leads to a very efficient elimination of signaling through all Notch receptors [19]. When targeted to the intestine, this results in a massive secretory cell metaplasia, including enormous expansion of goblet cells and the elaboration of a very thick mucus gel [20]. After about 9 months, these mice exhibit extensive inflammation throughout the large and small intestine. While its cause is unknown, this may be due to trapping of intestinal microbes in the mucus gel, thus again implicating the intestinal microbiota. In initial reported experiments, the mice were maintained on standard chow diet; under these conditions, while all mice developed inflammation, only 1 of 11 mice at 9 months exhibited a single flat adenoma [20]. However, it is now clear that maintenance of these mice on a defined AIN76A diet, or a western-style diet that is higher in fat and lower in calcium and vitamin D, causes very rapid development of inflammation, with 100% of the mice also exhibiting extensive dysplasia, adenomas, and invasive carcinomas by 3 months (Peregrina and Augenlicht, unpublished). Wild-type mice fed a high-fat diet (HFD—59% fat) exhibit elevated levels of proinflamatory cytokines, including IL6, TNF, and IL1, both in tumors and in the circulation, and enhanced IL6 production and TNR1 signaling have been shown to be required for HFD-induced tumor promotion in a mouse model of hepatocelullar carcinomas [21], consistent with the hypothesis that an HFD promotes tumorigenesis

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through its proinflammatory effect. We found that mice fed a western-style diet have increased levels of circulating IL1b, CCL2 (MCP1), and CCL5 (Rantes), but when the diet was supplemented with higher levels of vitamin D3 and calcium, the plasma levels of IL1, CCL2, and CCL5 were reduced concomitant with the elimination of dietary-induced tumor formation [22].

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The Importance of Nutrients, in Particular Vitamin D and Calcium, in Human Colon Cancer

It is clear from epidemiological data that patterns of nutrient intake have a dramatic effect on colon tumor incidence. There are numerous studies that demonstrate a relationship of dietary patterns and colon tumor incidence in different countries, with colon cancer much more frequent in developed countries in which individuals consume a “western-style” diet than in undeveloped countries [23, 24]. Furthermore, as dietary patterns change, for example, as the Japanese and the Chinese develop a more western-style culture and dietary habits, the incidence of colon cancer has increased in these populations [24]. Finally, and perhaps most impressive, is the fact that migratory populations rapidly develop the cancer profile of their new locale. Again, for example, the Japanese historically exhibited a low incidence of colon cancer and high incidence of gastric cancer. However, upon moving to the Hawaiian Islands, the incidence of colon cancer begins to rise within one generation concomitant with adoption of a western life-style, including patterns of food consumption, and within two generations the incidence of colon cancer becomes equivalent to that in US males [24]. It is difficult to attribute this rapid rise to a shift in population genetics, emphasizing the dramatic role of environmental factors in modulating tumor development. Moreover, the US population had about a tenfold higher incidence of colon cancer than did the indigenous Japanese, demonstrating that it is theoretically possible to reduce colon cancer incidence—and attendant morbidity and mortality—by 90% if it was understood what needed to be done in terms of altering nutritional patterns. However, it is also important to recognize that implementing such changes in dietary habits would require both societal and personal commitments. Interest in the impact of vitamin D in colon cancer was greatly stimulated by reports of a clear association of colon cancer incidence with latitude throughout the USA and other western societies, providing intriguing evidence linking sunlight exposure, and as a consequence, low endogenous vitamin D levels to increased risk for colon cancer [25]. There have been a great many epidemiological studies supporting this, and data in human populations that suggest low dietary vitamin D and calcium levels, which are linked physiologically, to higher incidence of colon cancer have been reviewed [26]. In this regard, it is difficult to separate the role of vitamin D from that of calcium: a principle effect of vitamin D—but certainly not the only, or even, necessarily, the most important in terms of cancer risk—is the stimulation of intestinal uptake of calcium via activation of the calcium transport

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proteins (TRPV 5/6 and calbindin D-9K). Thus, low intake of calcium induces secondary hyperparathyroidism and increases conversion of 25(OH)VitD to its active metabolite, 1,25(OH)2VitD (vitamin D3) to augment intestinal calcium absorption to maintain serum calcium levels. In addition to promoting intestinal calcium absorption, elevated parathyroid hormone increases bone resorption and can lead to decreased bone mineral density (BMD) and osteoporosis. This intimate physiological relationship between calcium and vitamin D3 levels may also be reflected in the results of cancer intervention studies in the human. Thus, it was reported that in a randomized trial of calcium supplementation for prevention of colon tumor recurrence, calcium supplementation reduced tumor recurrence only among subjects who had higher vitamin D levels, leading to the conclusion that the two nutrients together impact on functions that reduce recurrence [27]. There has been a resurgence of interest in the role of vitamin D in colon cancer based on recent observations that >80% of patients presenting with late stage colon cancer exhibit very low, and likely inadequate, levels of serum 25(OH)vitamin D and that the outcome for these patients is much poorer than for those with higher circulating vitamin D levels [28, 29]. This raises the issue of what levels of vitamin D are necessary for reducing colon cancer incidence and recurrence [26]. A recent Institute of Medicine report concluded that current levels of vitamin D and calcium intake are likely adequate for the maintenance of bone density and minimization of risk for osteoporosis and bone fractures, but hedged discussion of levels that might be necessary for other health considerations, including reduction of cancer risk [30]. Indeed, this has been a subject of considerable discussion, with some investigators concluding that levels of up to 4,000 IU of vitamin D3/day—far exceeding the RDA of 600 IU—may be necessary [31]. This is a complex issue for which conclusive data are not yet available and which also involves consideration of toxicities at higher pharmacological doses. However, it seems clear that much higher levels than the RDA are necessary to have an impact on cancer [31], with a recent metaanalysis of data suggesting that a daily intake of 1,000–2,000 IU could reduce colon cancer incidence significantly by raising 25(OH)D levels to >33 ng/mL [26]. Unfortunately, most intervention studies that have thus far tested the effects of vitamin D on polyp recurrence in human populations have been fundamentally flawed in that the population was not monitored for serum 25(OH)D levels and/or baseline levels of vitamin D intake or sun exposure, or the trials were not of sufficient duration to produce a conclusive result. Thus, conclusive evidence for the efficacy of vitamin D and for the necessity of combining it with increased calcium intake in cancer prevention is not yet available. Studies of 25(OH)D levels in the population emphasize the extent of the problem, and hence the potential impact on cancer incidence that could be achieved. According to the most recent NHANES data, only between 31 and 65% of US adults 19 years and older consume adequate calcium from food and supplement sources combined and only 22–59% consume adequate vitamin D [32]. It is of particular interest that deficient levels are seen at high frequency in pediatric populations (NHANES study, 2001–2004 [33]), and may characterize ~40% of young African-American women [34] and ~30% of young white men and women [35]. Moreover, when they give

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birth, a remarkable 50% of black women and 65% of their infants may be vitamin D deficient [36]. Additionally, 80% of nursing home residents not taking supplements are deficient by the end of winter [37], perhaps in part due to the compromised ability of the elderly to generate vitamin D utilizing sunlight. Thus, vitamin D deficiency is wide-spread in the most vulnerable segments of human populations.

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Insight on Nutrition and Intestinal Cancer from Mouse Models

The inheritance of a mutant allele of the adenomatous polyposis coli gene (Apc) leads to the development of early and multiple intestinal tumors in the human (FAP) and in the mouse, with the number and timing of tumor development dependent upon the particular mutation in the Apc gene. This phenotype is of very high penetrance, affecting 100% of individuals or of mice that inherit the mutant allele. However, the phenotype can be dramatically modulated by both dietary and genetic means. For example, targeted inactivation of the cyclin-dependent kinase inhibitor p21Waf1/cip1 does not produce a tumor phenotype, but it accelerates and amplifies tumor development in Apc+/− mice as a function of p21 gene dosage [38]. The same is true of maintaining Apc+/− mice on a western-style diet (WD) that is higher in fat and lower in calcium and vitamin D3, at levels calculated on the basis of nutrient density to reflect levels commonly consumed by large segments of the US population [39]. Moreover, when the mice are fed the WD, similar dietary-induced increases in tumor development are seen regardless of genotype—that is, in Apc+/− mice that are either p21+/+, p21+/−, or p21−/− [38]. This indicates that the dietary and genetic modulation of intestinal tumorigenesis initiated by inheritance of an Apc mutation are additive regardless of p21 genotype and influence tumor development by distinct mechanisms. Remarkably, the dietary-induced increases were completely prevented by elevating calcium and vitamin D3 in the diet to levels associated with lower risk for colon cancer in humans, thus identifying these nutrients as key modulators of tumor development in the mouse, consistent with the epidemiological data in humans [38, 40]. Essentially the same influence of these dietary factors are seen regardless of genetic mutation that leads to intestinal tumors, including targeted inactivation of mismatch repair genes, another cdki p27Kip1, or Muc2, the gene that encodes the principle intestinal mucin [17, 41]. However, >90% of human colon cancers are not associated with inheritance of mutations in oncogenes or tumor suppressor genes. While such mutations often develop somatically in these sporadic colon tumors, these tumors generally arise after five to six decades of life. Further, during these 50–60 years, individuals adhere to different dietary patterns, involving multiple macro- and micronutrients that epidemiologically are linked to significantly elevated risk for colon cancer later in life. This raises fundamental basic and clinical questions: what is happening during this long period under the influence of different nutrients to increase the probability of a single tumor arising “stochastically” from more than one trillion cell divisions that

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take place in the mucosa over this period? When do key changes take place during this period? Can these changes be useful in evaluating risk for cancer development in individuals and hence be important factors in clinical care? Are the changes reversible, and if so, how late in life can altering dietary patterns for an individual be effective in altering risk for tumor development? Answering these questions can have a major impact on incidence and management of colon cancer. A major obstacle to addressing these issues has been the lack of mouse models that accurately reflect the etiology and development of sporadic intestinal tumors, in contrast to the commonly used genetic models in which inherited gene mutations rapidly lead to tumors. To address this, Newmark and Lipkin tested the effects of long-term feeding of a modification of the western-style diet—the NWD1—in normal C57Bl6 mice, a strain that very rarely develops intestinal tumors over its approximately 2.5 year lifespan. This diet was formulated to provide levels of intake of a number of dietary constituents that were similar, on the basis of nutrient density [42], to the levels of intake in large segments of western populations at higher risk for colon cancer (i.e., higher fat, reduced vitamin D3, calcium and donors to the single carbon pool—folate, methionine and choline). They reported that after about 1 year on the NWD1, there was an increase in the number of colonic and intestinal tumors, and that this was prevented by elevating levels of vitamin D3 and calcium in the diet to levels associated with lower risk in humans [43]. We collaborated with Lipkin and Newmark in repeating this experiment in a larger number of mice, and fundamentally obtained the same results: while mice fed control AIN76A diet rarely developed intestinal tumors, in mice fed the NWD1 tumor incidence and frequency increased by 1.5 years, and at 2 years, 25% of the mice exhibited 1–3 tumors [40] (Fig. 3.1). This incidence and frequency is similar to that seen in the general population when screened by colonoscopy after the age of 50, or about 2/3 of the organism’s life span. Moreover, the approximately 10% incidence of carcinomas among the dietary-induced tumors in the mouse was similar to that seen in the general human population when routinely screened by endoscopy [44]. Thus, based on the similar dietary etiology, tumor incidence, frequency, and histopathology, this is an important model of sporadic intestinal cancer—both of the small and large intestine—the form of the disease responsible for >90% of intestinal cancer in the USA and other western populations. Importantly, elevating calcium and vitamin D3 in the diet from the lower levels equivalent to 220 mg calcium and 200 IU vitD3 in a 2,000 kcal/day human diet, to higher levels equivalent to a human intake of 3,000 mg and 1,000 IU per day, respectively, completely prevented the dietary induction of colon and small intestinal tumors [40, 43] (Fig. 3.1). This observation was confirmed independently by another group [45]. We recently addressed the issue of differences in mechanisms by which Apc or p21 mutation, or the NWD1, affect tumor development that leads to additive effects of these stimuli [38], as we reviewed earlier. Using a well-validated method that permits isolation of cells according to their position along the crypt-luminal axis [46], we investigated the altered expression profiles in the histopathologically normal mucosa of cells isolated from the top of the villus and from the bottom of the crypt in Apc+/− mice, p21−/− mice, and control wild-type mice fed the NWD1.

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Dietary Initiation of Colon Tumors b

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Fig. 3.1 Large intestinal tumors that arise in C57Bl6 mice fed control AIN76A diet, a new westernstyle diet (NWD) or the NWD supplemented with elevated vitamin D and calcium. (a) Gross pathology of two tumors that arose after 1.5 years of feeding the NWD from weaning and histopathology of one of these; (b) tumor frequency; and (c) tumor incidence. (b, c) are data first published by Yang et al. [40]

There were several striking observations [47]. First, the alterations in cell reprogramming in both villus and crypt cells were highly distinct for each stimulus when assayed at the individual gene or functional group level. Second, while the genetic alterations (Apc+/− and p21−/− mice) primarily altered gene expression in crypt cells, feeding the NWD1 altered gene expression primarily in villus cells. These findings reflect distinct perturbations in mucosal homeostasis introduced by each of the stimuli and explain why they are additive in inducing tumors. There are a number of changes in the flat mucosa of the C57Bl6 mice consuming the NWD1, and many of these are prevented by elevating calcium and vitamin D3 in the diet (NWD2) that prevents eventual tumor development. For example, we reported that there was a downregulation of genes in the tricarboxylic acid cycle that was prevented by the elevation of vitamin D3 and calcium [40]. Additionally, we have found decreased expression of the mitochondrial genome accompanied by diminished activity of oxidative phosphorylation enzyme complexes, both of which are also eliminated by elevation of dietary vitamin D3 and calcium (Heerdt and Houston, unpublished).

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This raised the possibility that the histologically normal mucosa exhibited an early shift toward glycolysis, a metabolic adaptation known to characterize colonic and other tumors. Recent evidence from metabolomic data is consistent with this, demonstrating altered metabolic profiles and an increase in lactate production induced in the colonic mucosa by the NWD1 that can be prevented by elevating vitamin D3 and calcium (Heerdt, Gaffney-Stomberg and Augenlicht, unpublished). Moreover, it is clear that diet can rapidly alter the intestinal microbiome [48] and that when fed the NWD1, the histologically normal mucosa exhibits oxidative stress and an inflammatory response [49]. We investigated the pattern of expression changes in the mucosa induced by the NWD1 in comparison to the alterations induced by targeted inactivation of Apc or p21 [47]. We found that one of the unique characteristics of both the intestinal villi and colonic crypts of mice fed the NWD1 was the ectopic expression of markers of the Paneth cell lineage, a cell type that is normally not expressed in these compartments but only at the bottom of the small intestinal crypt. Moreover, in each case, this was accompanied by elevated expression of the Wnt receptor Fzd5, the receptor reported to be necessary for the differentiation of the Paneth cell lineage, and this was associated with elevated Wnt signaling. Finally, elevating vitamin D3 and calcium in the diet to levels that prevent the eventual development of dietary-induced tumors by the NWD1 also prevented all of these changes [47]. These data are important for a number of fundamental reasons. First, the data suggest that elevated dietary-induced risk for “sporadic colon cancer” may be assessed by expression of these aspects of the Wnt signaling pathway and/or by ectopic expression of markers of the Paneth cell lineage. Second, Lgr5+ intestinal stem cells, which are nestled at the bottom of the crypt in a manner that maximizes their heterotypic contacts with Paneth cells, in fact require signals from Paneth cells for their viability and expression of stem cell functions [50]. Thus, the ectopic expression of Paneth cell markers in the villus and colonic crypt cell compartments may also encompass expression of Paneth cell factors that cause an expansion of cells with stem-like properties in these compartments, leading to an elevated target cell population for tumor initiation and hence elevated probability of tumor development. Finally, Paneth cells are fundamental in mediating the interaction of gut commensal bacteria with the intestinal mucosa, and hence are an important determinant of if and how the mucosa mounts an inflammatory response. Moreover, dietary factors can rapidly change the composition of the gut microflora [48]. However, the extent to which these changes are mechanistically linked either to potential dietary-induced changes in the intestinal microbiome or to the dietaryinduced inflammatory response is not yet known.

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Cellular and Molecular Effects of Diet and Inflammation on Intestinal Tumorigenesis

Preclinical studies have suggested that the chemopreventive properties of vitamin D stem from its ability to inhibit proliferation and angiogenesis and to induce apoptosis, autophagy, and differentiation in tumor cells [51, 52]. Vitamin D3 has been shown

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to downregulate the expression of Toll-like receptors 2 and 4 (TLR2 and TLR4) on human monocytes resulting in hyporesponsiveness to TLR-activating ligands [53], which contributes to anti-inflammatory properties of vitamin D on which we will focus. The complex role of inflammatory cells and molecules in colon cancer has been reviewed [54, 55] and the potential of targeting the tumor microenvironment for chemoprevention has been emphasized [56]. The particular focus here will be on the anti-inflammatory activity of vitamin D in the colon and its potential role in the prevention of colon cancer. It has recently been established that >80% of colon cancer patients at diagnosis have levels of serum 25(OH)D that would be classified as insufficient to deficient and that the low vitamin D levels are associated with poor outcome [28, 29, 57]. This is also true of patients with IBD, a risk factor for colon cancer [58]. Several studies have addressed mechanisms through which vitamin D deficiency may be part of the network linking inflammation and increased risk of colon cancer. The emerging picture suggests that vitamin D effects on both intestinal epithelial and immune cells contribute to inflammatory responses that impact on tumorigenesis. Mice with a targeted inactivation of the vitamin D receptor do not develop overt inflammation, yet the presence of increased proinflammatory cytokines (TNFa and IL1b) in their colon is indicative of an increased inflammatory background in their mucosa [59]. Interestingly, in mice fed the NWD, low in calcium and vitamin D, we detected an increased circulating level of these same cytokines, as reviewed earlier. Moreover, colitis induced by DSS or by IL10 inactivation in the mouse is exacerbated by inactivating the vitamin D receptor [60, 61], and in the IL10−/− colitis model, the inflammation is moderated by elevating dietary levels of vitamin D and is further ameliorated by elevating calcium levels as well [61]. In addition, not only are T cells more readily reactive and display an inflammatory phenotype [59], but also there are fewer intraepithelial T cells with anti-inflammatory activity in VDR knockout mice due to abnormalities in T-cell homing [62]. On the other hand, VDR deficiency can also compromise mucosal barrier function due to an impairment of tight junctions [63], and this may be linked to increased levels of oxidative stress detected in the colon of VDR knockout mice [64]. Interestingly, moderate disfunction of the intestinal barrier has been documented in mice fed a high-fat diet (reviewed in [65]), while VDR polymorphisms have been linked to increased risk of IBD development [66, 67]. Taken together, these data suggest that abnormalities in levels of vitamin D or its utilization have the dual effect of not only weakening the intestinal mucosal barrier resulting in increased exposure to luminal contents and bacteria but also decreasing the level of immune tolerance resulting in increased intestinal inflammation. Among inflammatory cells in tumors and in the mucosa are macrophages, an important cell that can produce a variety of proinflammatory cytokines and that can have pronounced effects on tumor development and phenotype [68, 69]. These cells can stimulate a variety of processes that promote tumor development and progression, including cell migration, invasion, metastasis, and neovascularization [70, 71]. Klampfer and colleagues have recently defined a paracrine loop between macrophages and colon tumor cells [72–74] as a mechanism by which tumor-associated

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AN AMPLIFYING LOOP BETWEEN COLON CANCER CELLS AND MACROPHAGES AND ITS SHORT CIRCUIT BY VITAMIN D3

Apoptosis

c-myc

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EMTmetastasis

Proliferation

versican

Snail

b-catenin

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AKT

pSTAT1

pGSK-3β

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Fig. 3.2 The network of signals that are exchanged and perturbed by the interaction of colon tumor cells with macrophages. Summarized from data of Kaler et al. [72–74, 96]

macrophages can become educated by intestinal tumor cells to stimulate growth, chemotherapeutic resistance, and metastatic properties of the tumor cells (summarized in Fig. 3.2). The loop is initiated by the release of versican from the tumors which stimulates IL1b secretion from macrophages via the activation of Stat1 by phosphorylation. In turn, macrophages and IL1 stimulate epithelial cell growth by elevating Wnt signaling in tumor cells via an NFkB–AKT-dependent inhibition of GSKb phosphorylation. Similarly, TNFa activation of Wnt signaling by macrophages was identified in gastric cancer [13], and it was reported that PI3K/AKT signaling activates Wnt signaling in intestinal epithelial cells in the IL10−/− mouse model of inflammation-induced intestinal dysplasia [75]. Increased Wnt signaling in tumor cells has multiple consequences (Fig. 3.2). (a) Tumor cell growth is stimulated through the activation of growth promoting genes, such as c-myc. (b) Snail expression is stimulated, potentially mediating an epithelial–mesenchymal transition promoting progression. (c) TRAIL-induced apoptosis of tumor cells is inhibited [72–74]. Importantly, versican and Snail are Wnt target genes, establishing this as a selfamplifying loop between the epithelial cells and the macrophages. Since genetic depletion of macrophages in ApcD716 mice decreases intestinal tumors [13], this role of macrophages may be fundamental in intestinal cancer. This paracrine loop is linked to nutrition by the striking observation that the cross-talk can be short-circuited by the treatment of the macrophages with vitamin

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D3, which, through a VDR-dependent mechanism, interferes with Stat1 activity in the macrophages, and thus prevents synthesis and secretion of IL1b (Fig. 3.2). Consequently, all of the downstream effects of IL1b on the tumor cells are abrogated [72–74]. This is a new paradigm for how vitamin D may act as a chemopreventive molecule for colon cancer.

6

Concluding Remarks

Although highly complex, understanding how nutrients modulate probability for development and progression of colon cancer can have profound impact on both understanding mechanisms of tumorigenesis and clinical approaches to the disease. As regards clinical implications, mouse genetic models of intestinal cancer have been extremely valuable in dissecting fundamental molecular and cellular changes necessary for tumor development—e.g., mutations or epigenetic modulation of the Apc gene and its attendant effects on Wnt signaling in colon tumorigenesis in FAP syndrome and most sporadic colon tumors, or of mismatch repair genes in hereditary non-polyposis colon cancer (HNPCC) [76–78]. These are singular accomplishments with potential high-impact for screening and therapeutic approaches. However, as previously discussed, such genetic models generally reflect how tumors arise in rare genetic risk groups with very high incidence and rapidity of disease development, rather than much more common sporadic colon cancer in which one or two tumors develop over lengthy periods (e.g., five to six decades), where environmental factors have a major impact. The early stages in the pathophysiology of the colon cancer may differ markedly in these situations. For example, as illustrated in Fig. 3.3, in mice or in Familial Polyposis patients that inherit a mutant APC allele, the mutation is present from conception, and clearly has a subtle impact on how the mucosa functions [79, 80]. At some point in individual cells, this mutation is reduced to genetic/functional homozygosity, and these focal changes than initiate the development of tumors. However, the vast majority of patients that will develop colon cancer are wild-type at the APC locus from conception, through parturition, and on into adult life. We do not know when the first mutation (or “hit”) in the APC gene happens, presumably randomly, in very few cells during the many months or decades of life in the mouse and human, respectively, nor when this is reduced to homozygosity to initiate tumor formation. The former may be only after 50% or more of the life span, and the latter likely between 1 and 10 years before the tumor becomes detectable. During this lengthy period, the mucosa is exposed continuously to nutrient influences on its function and ability to maintain homeostasis. These stimuli, in particular nutrients, can affect the composition and functioning of the intestinal microbiome, the differentiation and balance of different cell types, and metabolic adaptation. Since there are over 1012 cell divisions in the mucosa during this time, and yet only one or two will give rise to a tumor, it is clear that perturbations in the mucosa that are very subtle can be highly important in the stochastic processes that result in a clinically detectable neoplasm. Thus, the mucosa is likely primed by

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Inherited APC Mutation (Familial Adenomatous Polyposis, ApcMin mice) – 1% of CRC

conception birth 2ndhit tumor APC+/-

APC-/-

0

b

15-20 years (in the mouse, weeks)

Sporadic Colon Cancer – >90% of CRC

conception birth

1sthit

2ndhit tumor APC+/-

WT APC

APC-/-

environmental factors 0

50-60+ years (in the mouse, weeks)

Fig. 3.3 Depiction of the differences in kinetics of tumor development and underlying alterations in the APC gene in human and mice that inherit a mutation of the APC gene compared to the development of sporadic colon cancer

nutrients and other environmental and genetic influences as to the ultimate fate of mutated cells that have the potential to give rise to tumors. This is akin to the seed:soil hypothesis for metastasis, in which it is postulated that sites of cancer metastasis are adapted to provide a favorable environment for the seeding and growth of cells originating from the primary tumor. Thus, changes that are present in the mucosa long before tumors appear can be important markers of relative risk for tumor development, as well as targets for chemo- and nutritional prevention. For example, we [40, 47] and others [81–85] showed that vitamin D modulates the intensity of Wnt signaling, a major oncogenic signaling pathway in colon cancer. Human colon tumors display heterogeneous levels of Wnt activity [86] and it has been shown that only cells with higher levels of Wnt signaling display colon cancer stem cell (CSC) properties [87]. Significantly, myofibroblast-derived factors have been shown to impose the CSC phenotype by promoting Wnt signaling in tumor cells. Because CSCs mediate tumor growth and often elude therapeutic approaches, understanding how dietary factors regulate their “stemness” will help to improve clinical approaches for colorectal cancer patients. In addition to the impact that understanding these preneoplastic events can have clinically, the changes are profoundly important in understanding mechanisms that give rise to tumors. A prime example of just how interesting it can be to consider these issues comes from the study of HNPCC (Lynch syndrome). It is now understood that this syndrome is due to defects in mismatch repair, and in some populations and pedigrees, the particular gene and mutation have been identified [88–92], as well as some of the consequences of this defective repair (generation of mutations in the TGFb receptor, for example) [93]. This syndrome was first recognized in the

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early 1900s by Warthin, in considering a family in which there was a high incidence of gastric and uterine cancer [94]. However, when this family was revisited by Lynch six decades later, members exhibited a high incidence and clear inheritance of colon, not gastric, cancer [95]. Coincidentally, the major intestinal cancer in the general population had shifted over that period from gastric to colon cancer. Thus, risk was established by inherited mutation in a gene involved in mismatch repair, but environment profoundly influenced the tissue-specific penetrance of the tumor phenotype—a profound example of environmental (diet)–gene interaction that it would be fascinating to understand.

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Chapter 4

The ApcMin/+ Mouse Model to Study the Effects of Exercise on Gastrointestinal Malignancy Nathan A. Berger

Abstract Epidemiologic evidence in humans supports a strong relationship between energy balance and colorectal cancer. Obesity is associated with an increased incidence of both colon adenomas and carcinomas; physical activity and exercise are associated with decreased incidence and better prognosis. Animal models to study the association of energy balance with colorectal cancer focus on the ApcMin/+ mouse model, which carries a mutation in the Adenomatous Polyposis Coli gene, which is known to be mutated early in the development of colorectal cancer in the human hereditary disorder, Familial Adenomatous Polyposis, as well as in sporadic colon cancer. The ApcMin/+ mouse, which has provided a robust model for studying factors that affect the development of colorectal cancer, serves as the focus of this review of a mouse model to study the effects of exercise on gastrointestinal malignancy.

Extensive epidemiological evidence indicates that obesity is associated with an increased risk of colon cancer in humans (see Chap. 1) [1], whereas physical activity and exercise are associated with a decreased risk [2]. In fact, in the recent summary by the World Cancer Research Fund/American Institute for Cancer Research, colon cancer was considered the only malignancy for which there was convincing evidence that physical activity was associated with decreased risk of cancer [2]. At the same time, the evidence that physical activity decreases the risk of postmenopausal breast cancer or endometrial cancers was considered probable [2]. Epidemiological evidence also indicates that higher levels, greater frequency, and increased intensity of exercise are more protective, suggesting that physical activity exerts a dose–response effect [2]. Postulated mechanisms include reduction in insulin levels, lowered levels of circulating tumor-promoting cytokines and adipokines, reduced body fatness,

N.A. Berger, M.D. (*) Center for Science, Health and Society, Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4971, USA e-mail: [email protected] S.D. Markowitz and N.A. Berger (eds.), Energy Balance and Gastrointestinal Cancer, Energy Balance and Cancer 4, DOI 10.1007/978-1-4614-2367-6_4, © Springer Science+Business Media, LLC 2012

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decreased gut transport time, effects on endogenous steroid hormone levels, and others [2]. Overall it is estimated that, in the USA, 45% of colorectal cancers are preventable by appropriate control of food, nutrition, physical activity, and body fatness [3]. Clinical studies also indicate that physical activity affects prognosis, time to recurrence and survival in patients already diagnosed with colorectal cancer (see Chap. 9) [4]. Although epidemiological evidence for prevention is convincing and a limited number of observational studies provide support for the beneficial effects of physical activity in patients with established diagnosis of colorectal cancer, studies to understand mechanisms, dose–response, effect of different types of exercise, impact of gender, potential surrogate endpoints, biomarkers, mediators, and confounding factors are difficult to study in human populations. Moreover, controlled randomized trials on this subject are difficult, if not impossible in humans. Animal models are useful for this purpose, especially if animal tumors are (1) genetically and pathologically similar to the human condition, (2) animals are affordable, readily accessible and subject to interventions such as exercise, and (3) studies are highly reproducible. Additionally, mouse models can be readily utilized for sample collection of body fluids and cell and tissue harvesting and for systematic biochemical, molecular, physiologic and pathologic analysis, and behavioral monitoring, and manipulation. The ApcMin/+ mouse provides a frequently used and effective model for these types of studies that satisfies most of the requirements outlined above. However, although some insights regarding the effects of physical activity and exercise on colorectal cancer have been investigated using this model, studies require improved standardization to make experiments utilizing the ApcMin/+ mouse valuable in understanding the role of physical activity and exercise in disease. The Min mutation was identified in a mouse lineage derived from a mating between an ethylnitrosourea (ENU)-treated C57BL/6J (B6) male with an AKR/J female, which was then backcrossed to the B6 strain for more than ten generations. The resulting phenotype is characterized by progressive adult onset anemia, bloody feces and multiple, variable sized polyps in the small intestine, leading to intestinal obstruction and early death [5]. In this model, polyps occur also at a low frequency in the colon. Histologically these polyps may be polypoid, papillary or sessile adenomas and occasionally may progress to show small areas of adenocarcinoma in older mice; however, metastasis is generally not seen. On a fixed B6 background, heterozygous mice can develop polyps in both the small intestine and colon that can reach anywhere from 100 to 300 total polyps and typically start to appear around 5–10 weeks of age. The life span of mice with these polyps was found to average 119 ± 31 days [5]. In the original description of this chemically induced mutation, the authors noted that since all cells in the animal contained the mutated gene, but only a limited number of tumors appeared, somatic interactions must be required for tumor development [5]. The mouse gene located on chromosome 18 bearing the Min mutation was subsequently shown to be homologous to the human adenomatous polyposis coli (APC) gene, located on human chromosome 5 [6–10]. The human APC gene contains the germ-line mutation responsible for familial adenomatous polyposis

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(FAP), an inherited cancer syndrome in which patients develop multiple intestinal adenomatous polyps, which if not treated, can progress to colon adenocarcinomas [10]. The human APC gene is also mutated early in the course of most cases of sporadic intestinal cancer [11]. These observations suggest that the mouse ApcMin/+ model should be useful to study human colon cancer, especially in its early stages and in prevention studies. The Min mutation in mice results in a nonsense mutation in codon 850 of APC, resulting in a truncated inactive peptide [10, 12] similar to most common human mutations of APC. Phenotypic expression of the genetic ApcMin/+ mutation requires, in most cases, inactivation of the normal Apc allele, which may occur by deletion or mutation [13]. A small percentage of genetic ApcMin/+ mice may develop phenotypic expression without apparent loss of the normal allele, potentially in association with other factors that result in allelic suppression [13]. A series of nonallelic modifiers have been identified, modifiers of Min, (Mom) that may enhance or suppress polyp number or growth [14]. Under normal physiologic conditions, the protein product of the APC gene serves as a tumor suppressor in the Wnt signaling pathway. The APC protein complexes with several cytoplasmic proteins including beta-catenin that target the latter for cytoplasmic degradation in a ubiquitin-dependent process [15]. When APC is inactive as in the case of mutation, beta-catenin accumulates in the cytoplasm and translocates to the nucleus where it can activates transcription factors involved in cell proliferation, growth and initiation of the intestinal polyp process. When the mutated APC gene is present in the heterozygous state, the cell must lose or inactivate the normal APC allele, before its tumor suppressor function is lost [13]. This requirement for loss of heterozygosity contributes to the lag time required for polyp development in ApcMin/+ mice. Other Apc mutant mice have been developed with similar predisposition to developing intestinal malignancies. In addition to the chemically induced mutation resulting in the Apcmin/+ model, genetic knock out approaches have been used to generate the ApcD716 and the Apc1638N models, with truncation mutations at codons 716 and 1638, respectively [15]. Although the mouse strains produced by knockout technology develop intestinal polyps, the ApcD716 develop many more, approximately 300 polyps, and the Apc1638N develops significantly fewer, approximately three polyps, compared to the ApcMin/+, which most commonly develops approximately 100 polyps on the B6 background . While each of these mutant mouse models have been used in different experimental situations, the ApcMin/+ mice have been the most prevalent model used to study exercise and will serve as the focus of this review. The ApcMin/+ mouse is valuable in that the intestinal phenotype recapitulates the progression from early mutation and polyp development to adenocarcinoma of the colon in humans. Heterozygous mice with Min mutation are fertile, have no apparent embryonic defects, and undergo normal development and maturation. Polyp growth in the ApcMin/+ mice can be evaluated for location and size, in terms of length, diameter, area, and volume as an indicator of tumor burden. Because the polyps can be evaluated quantitatively, the ApcMin/+ mouse provides a useful model to study numerous aspects of intestinal neoplasia that otherwise could not be investigated in humans.

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Fig. 4.1 Schematic illustration of theoretical possibilities for alteration of intestinal polyp numbers as a function of time by factors affecting polyp development and numbers in the ApcMin/+ mouse model. No specific polyp numbers or times are indicated since these are theoretical constructs

In addition to enumerating polyp number, the mice can be used to study genetics, biochemistry, molecular biology, histology, immunology, metabolic pathways and alterations of polyp development as well as factors affecting progression and prevention of adenocarcinoma as well as survival. As indicated above, polyp number, size, and location in the ApcMin/+ mouse can be used to evaluate factors affecting colon cancer growth. Figure 4.1 illustrates some of the ways that interventions can potentially affect polyp growth. Curve 1 illustrates the normal course of polyp development in the ApcMin/+ mouse model. Polyps are usually detected after a lag period of 30–60 days from birth. Polyp numbers increase over 30 days to a relatively characteristic number which remain constant in number or increase slowly while they undergo progressive growth leading to death of the animal. Thus, the ApcMin/+ mouse model can be used to study factors affecting tumor initiation as reflected by polyp numbers or tumor progression as reflected by polyp size. Factors affecting polyp development could function in several different ways, each of which may generate different growth curves and have different mechanistic implications. As shown in curve 2, a factor could suppress the total number of polyps that occur without affecting lag time or initial rate of appearance. Curve 3 shows a situation where the rate of polyp appearance is slower but the total number of polyps unaffected. Curve 4 illustrates a condition where polyps develop more slowly and fewer polyps occur. Curve 5 shows a condition where polyp development undergoes a prolonged lag time but then reaches the same characteristic level as in Curve 1. Examination of the theoretical curves presented in Fig. 4.1 demonstrates that different conclusions can be drawn if observations are performed at different times.

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Thus, polyp count at an early time point would indicate significant differences between curve 1, 3, and 5. In contrast, evaluation at an early time point would suggest no difference between curves 1 and 2; however, later examination would show significant differences between these two curves. Similar differences could occur with curves 3 and 4. The potential variation in shape, slope, and plateau in the polyp growth curve indicates that comparative studies should consist of multiple time points, including at least one that reflects rate of appearance and another that reflects steady state or plateau level. This is significant because it suggests differences in mechanism, i.e., the differences between polyp initiation and progression, decreased polyp development, delayed polyp growth, etc. The ApcMin/+ mouse model has been useful to identify and investigate the role of beta-catenin [15], p53 [16], Smads [17], prostaglandins [18], and prostaglandin dehydrogenase pathways [19], the tumor-promoting effects of cytokines, hormones, and growth factors such as insulin, leptin, and IGFs as well as the effects of different dietary components [20–25]. In addition, this mouse model system has also been useful to investigate the chemopreventative effects of agents such as soybeanderived Bowman-Birk Protease Inhibitor [26], Silibinin [27], and NSAIDS including aspirin [28], sulindac [29], and celecoxib [30]. These studies with ApcMin/+ mice have provided important preclinical evidence for the colorectal cancer preventative efficacy of multiple agents. While epidemiologic evidence supports a beneficial effect of physical activity and exercise on colorectal cancer, the availability of the ApcMin/+ mouse model provided an important tool to directly test the benefits and potential mechanisms of action by which exercise may affect colorectal cancer prevention or development. In one of the first applications of the ApcMin/+ mouse to study the effects of exercise in colorectal cancer, Colbert et al. [31] conducted a 7-week exercise regimen, starting 21 days after birth, and administered as treadmill running for 1 h/day, 5 days/week at speeds of 18–21 m/min, for a total of 1.0–1.36 km/day on a 5% grade. After the exercise program was completed, there was no observed exercise associated decrease in polyp number in female mice (38.0 ± 6.3 vs 40.0 ± 6.3). However, exercise in male mice resulted in a trend, although not significant, toward decreased polyps in the exercised compared to control mice (24.8 ± 3.6 vs. 36.8 ± 4.9). The exercise resulted in no effect on body weight or food intake; however, soleus muscle in the exercised mice showed an increased oxidative capacity as reflected by a 1.64-fold increase in citrate synthetase [31]. Thus although the increased physical activity was shown to have a significant effect on skeletal muscle, the effect on polyp formation did not reach statistical significance. Colbert et al. [32] subsequently showed that greater levels of exercise, approximately 3.8 km/day, achieved by providing mice 24 h access to a running wheel along with caloric restriction, the latter achieved by adjusting food intake to equal that consumed by control mice during the previous week, resulted in lower weight in the exercise plus caloric restriction vs. control mice and fewer polyps, 16.9 ± 2.6 in the experimental group vs. 21.6 ± 1.5 in the control mice. Moreover, for individual mice, polyp number was inversely correlated with total running/day. Thus the combination of exercise plus caloric restriction appeared to decrease polyp development

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and showed dose dependency relative to duration of exercise. However, other studies have shown that caloric restriction alone reduces polyp number in the ApcMin/+ mouse model and no internal controls were performed in these experiments to quantitate the effect of caloric restriction alone [33], thus those experiments did not distinguish between an effect of exercise vs. caloric restriction in reducing polyp number [32]. In studies of potential mechanisms, the authors showed that exercised mice had greater serum levels of IGF-1 levels compared to control mice, but there was no correlation with polyp number [32]. However, no assays were performed to quantitate IGF-1-binding protein levels to more appropriately estimate biologically active, unbound or free IGF-1. Notably, even the control mice in this experiment [32] had fewer polyps than the controls in the previous experiment (21.6 ± 1.5 vs. 36.8 ± 4.9) [31]. These differences may be associated with differences in experimental design including different diets, Tekland, in the earlier experiments vs. AIN 76A in the latter, different duration, 10 weeks in the former vs. 17 weeks in the latter. In addition, mice used in the latter experiment were maintained under quarantine conditions for at least 3 weeks with unspecified diet and unknown treatment [32]. Meanwhile, Mehl et al. [34] studied the effect of different exercise regimens in the ApcMin/+ mouse model by comparing treadmill running and voluntary wheel running to non-exercised controls starting at 3.5 weeks. Polyps were evaluated after a 9-week exercise period during which animals were provided with free access to running wheels vs. 1 h of treadmill running at 18 m/min on a 5% grade for 6 days weekly and ad libitum access to the Harland Tekland Diet #8604, 4.7% fat. Despite more exercise by the mice with voluntary access to the running wheel, 4.7 km/day for males and 3.5 km/day for females compared to 1.1 km/day for treadmill runners, there was no difference in body weight among males or females. In these experiments [34], male treadmill runners showed a 29% decrease in intestinal polyp count, whereas voluntary wheel runners, with greater exercise, showed no significant decrease in polyps. Female mice showed no significant difference in polyp count relative to controls with either mode of exercise. Both males and females showed significant reduction in circulating IL6 and wheel runners showed a greater increase in muscle citrate synthetase than treadmill runners compared to controls. Thus this set of experiments did show a protective effect of exercise in males but did not show the expected dose-dependent protection. Rather, they suggest that lesser amounts of exercise in the form of treadmill running are more effective at preventing polyp development than the fourfold exercise increase associated with voluntary wheel running. Moreover, this experiment suggests that exercise is effective for polyp prevention in male but not female mice. Interestingly, control mice in these experiments showed between 90 and 100 polyps compared to the 21.6 in the previously reported experiments. However, as noted in the previous experiment, wheel running was accompanied by caloric restriction which may have contributed to the reduced polyp number [32]. Moreover, control animals in the present experiment were fed the Harland Tekland Diet #8604, whereas in the latter experiment they were fed the AIN 76 A which, although similar in fat content (4.7% vs. 5%) may still contribute to the difference between polyp counts in control animals from the two different experiments.

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While the discrepancy between the mice subjected to treadmill running vs. voluntary wheel running was not resolved, Baltgalvis et al. [35] conducted studies of inflammation, apoptosis, and b-catenin signaling in polyps derived from the experiments reported by Mehl, which showed 29% decrease in polyp counts in males associated with treadmill running [34]. These experiments showed decreased macrophages, decreased TUNEL positive cells, and decreased Bax staining in polyps derived from exercise mice. Exercise had no effect on the number of COX-2 or b-catenin positive cells; however, there was an increase noted in phosphorylation of b-catenin [35]. These observations suggest that exercise impacts multiple pathways affecting polyp growth including reduced immune cell infiltration, apoptosis, and Wnt signaling. Of concern in this report is the fact that the investigators added an additional series of animals including seven controls and eight exercise mice to provide fresh tissue for protein assays; however, there were no reports of the effect of exercise in these additional animals [35]. To further define the combined effects of diet and exercise on polyp growth, Baltgalvis et al. [34] compared treadmill running exercise to control sedentary behavior in ApcMin/+ mice that were fed either the AIN 76A diet containing 5% fat vs. a Western Diet containing 21% fat. The treadmill exercise regimen, 18 m/min, 60 min/day, 6 days/week was the same as noted above [35] and both diet and exercise were started at 4 weeks of age and continued until 10 weeks of age at which time all mice were sacrificed and studied. Control mice fed the western diet tended to be 5% heavier than those fed the AIN 76A diet and showed greater weight of the epididymal fat pad. Neither weight nor epididymal fat pad mass were affected by exercise. Exercise reduced leptin levels in the high-fat Western diet fed mice but not in those fed AIN 76A. The control sedentary mice, on the high-fat Western diet showed 67% increase in intestinal polyps compared to control mice fed AIN 76A (approximately 35 vs. 20). Interestingly, exercise did not decrease polyp number in mice fed the Western diet. In fact, exercise plus high-fat diet actually increased polyp number (approximately 42 compared to 35 in high-fat diet non-exercise mice). The same exercise regimen decreased polyp number by 50% (10 vs. 20) in the mice fed the AIN 76A diet. This decrease was mostly associated with small polyps (less than 1 mm). These studies confirm that moderate intensity treadmill exercise can reduce polyp numbers in ApcMin/+ mice, especially those on a low-fat diet. In contrast, in these experiments, high-fat diets (21%) both increase polyp count in sedentary animals and overcome the beneficial effects of exercise in animals subjected to a moderate intensity exercise regimen. It is noteworthy that in the present study, polyps were counted at 10 weeks of age compared to 13 weeks of age in previous experiments. These differences in experimental duration result in evaluations being performed at different locations along the horizontal axis in Fig. 4.1 and may contribute to differences in experimental results and interpretation. In a series of experiments with female ApcMin/+ mice, Ju et al. [35] evaluated the effect of voluntary wheel running, approximately 2.8–3.9 km/mouse/day on mice fed a normal AIN 93G or high-fat diet, AIN 76A supplemented with 20% fat. Groups of mice on the normal diet (AIN 93G) exposed to the exercise wheel for 6 weeks showed a decrease in omental fat pad mass relative to control mice and

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showed 29–31% decrease in small intestinal polyps. When mice on the high-fat diet and a 9-week exercise program were sacrificed at 14 weeks of age, they showed decreased circulating IGF-1 and increased IGFBP-3 resulting in lower levels of bioactive IGF-1 and decreased polyps associated with exercise vs. control 30.8 ± 3.4 vs. 22.0 ± 3.8. Thus, these experiments indicate that voluntary wheel running reduced polyp development in female ApcMin/+ mice on both normal fat (5%) and high-fat diets (20%) [37]. In additional experiments, these investigators showed that voluntary wheel running in male CF-1 mice maintained on a high-fat diet and treated with a chemical carcinogen, azoxymethane (AOM) plus dextran sulfate sodium (DSS) protocol, resulted in decreased intestinal tumor formation relative to nonexercised controls [37]. In another comparison of a fixed exercise regimen, using treadmill running vs. free access to a running wheel, Basterfield and Mathers [38] found that intestinal polyp numbers showed no significant difference between stationary, treadmill and wheel running mice, although treadmill running mice showed a tendency to lower numbers of larger polyps (>2 mm). In these experiments, female wheel running mice were reported to run approximately twice as far as males; however, both genders were combined for analysis. In addition, mice were analyzed together on an “intention to treat” approach, independent of actual exercise activity, thereby potentially nullifying any exercise associated events by combining animals with variable exercise intensities. Moreover, in these experiments, any potential effects of exercise may have been counteracted by the high-fat western style diet. In addition, since polyps were enumerated at 17 weeks of age (regimens started 5 weeks of age and continued for 12 weeks before sacrifice), polyp growth may have proceeded far enough along the horizontal axis in Fig. 4.1 to a point where polyp numbers equalize and plateau. A further problem with this report relates to the low mean numbers of polyps in all mice ranging from 11.0 in treadmill runners to 14.1 in controls. This is significantly lower than the 30–100 polyps usually found in ApcMin/+ mice on the C57BL/6 background and suggests the presence of polyp suppressors in the diet. Overall, these experiments demonstrate that exercise can reduce the development of intestinal polyps in the ApcMin/+ mouse model. Results, however, remain inconsistent. Different experiments suggest that both treadmill running [31, 33, 36, 37] and voluntary wheel running [32, 37] are effective at preventing polyp development, while other experiments suggest that they are not. Some experiments, but not all, indicate that exercise protects against polyp development in both male and female mice [37], whereas others discriminate between genders [31, 33]. Caloric restriction together with exercise was shown to reduce polyp development, although these experiments did not distinguish the independent contribution of each component [32]. In contrast, high-fat diets were shown to increase polyp count in one experiment and to interfere with exercise prevention of polyp development in male mice [35]. Another report demonstrated that exercise does prevent polyp formation in both female and male mice fed a high-fat diet [37]. At least, one experiment suggested dose dependency of the polyp preventative effects of exercise, polyp count was inversely related to total running/day [32], whereas another experiment suggested the absence of dose dependence, treadmill running mice that ran ~1 km/day

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showed reduced polyp numbers compared to wheel running mice at ~3.8 km/day which showed no reduction in polyp number [37]. At least one report suggested that exercise affects polyp progression but not total number [37]. The ApcMin/+ mouse continues to provide an interesting model system to study the impact of exercise on intestinal neoplasia; however, experimental conditions need to be refined to assure reproducibility and remove inconsistencies. Clarification is needed of the variable response to different types of exercise, treadmill running vs. voluntary wheel running, dose dependency, apparent gender differences, and effects of differential dietary components including quantity and quality of fat and other components such as antioxidants, anti-inflammatory agents and inhibitors of prostaglandin synthesis. Each of the latter have been shown to have profound effects on polyp initiation and/or progression. In addition, time of intervention and evaluation in the animal’s lifespan is important since as suggested in Fig. 4.1, variable timing may have differential effects on polyp latency, development, or plateau. Starting experiments 3, 4, or 5 weeks after birth will result in different stages and numbers of polyps developed before experimental interventions are ever initiated. Moreover, in the experiments reported above, polyp evaluations were carried out at different times including 10, 11, 13, 14, and 17 weeks of age. Since as indicated in Fig. 4.1, these variable ages at time of evaluation occur at different points along the horizontal axis, they may mask some of the differences that would be observed if all evaluations were performed at a uniform time point. Thus, the experimental approach would be improved by sampling both at an early time point to demonstrate differences in polyp development and at a later point to demonstrate differences in plateau levels. Finally, analyzing the effect of the exercise intervention on survival would provide useful information about the effects of exercise on prevention and progression of established tumors. Acknowledgment Support for this work was derived in part from NIH Grants U54 CA116867 and P30 CA043703 to Nathan A. Berger. We thank Stephanie Doerner for assistance with the figure.

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6. Cormier RT, Dove WF (2000) Dnmt1N/+ reduces the net growth rate and multiplicity of intestinal adenomas in C57BL/6-multiple intestinal neoplasia (Min)/+ mice independently of p53 but demonstrates strong synergy with the modifier of Min 1(AKR) resistance allele. Cancer Res 60(14):3965–3970 7. Halberg RB, Chen X, Amos-Landgraf JM, White A, Rasmussen K, Clipson L, Pasch C, Sullivan R, Pitot HC, Dove WF (2008) The pleiotropic phenotype of Apc mutations in the mouse: allele specificity and effects of the genetic background. Genetics 180(1):601–609 8. Luongo C, Gould KA, Su LK, Kinzler KW, Vogelstein B, Dietrich W, Lander ES, Moser AR (1993) Mapping of multiple intestinal neoplasia (Min) to proximal chromosome 18 of the mouse. Genomics 15(1):3–8 9. Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M et al (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66(3):589–600 10. Su LK, Kinzler KW, Vogelstein B, Preisinger AC, Moser AR, Luongo C, Gould KA, Dove WF (1992) Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256(5057):668–670 11. Fodde R (2002) The APC gene in colorectal cancer. Eur J Cancer 38(7):867–871 12. Su LK, Johnson KA, Smith KJ, Hill DE, Vogelstein B, Kinzler KW (1993) Association between wild type and mutant APC gene products. Cancer Res 53(12):2728–2731 13. Shoemaker AR, Luongo C, Moser AR, Marton LJ, Dove WF (1997) Somatic mutational mechanisms involved in intestinal tumor formation in Min mice. Cancer Res 57(10):1999–2006 14. McCart AE, Vickaryous NK, Silver A (2008) Apc mice: models, modifiers and mutants. Pathol Res Pract 204(7):479–490 15. Taketo MM (2006) Wnt signaling and gastrointestinal tumorigenesis in mouse models. Oncogene 25(57):7522–7530 16. Patel AC, Nunez NP, Perkins SN, Barrett JC, Hursting SD (2004) Effects of energy balance on cancer in genetically altered mice. J Nutr 134(12 Suppl):3394S–3398S 17. Sodir NM, Chen X, Park R, Nickel AE, Conti PS, Moats R, Bading JR, Shibata D, Laird PW (2006) Smad3 deficiency promotes tumorigenesis in the distal colon of ApcMin/+ mice. Cancer Res 66(17):8430–8438 18. Wang D, Wang H, Shi Q, Katkuri S, Walhi W, Desvergne B, Das SK, Dey SK, DuBois RN (2004) Prostaglandin E(2) promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor delta. Cancer Cell 3:285–295 19. Myung SJ, Rerko RM, Yan M, Platzer P, Guda K, Dotson A, Lawrence E, Dannenberg AJ, Lovgren AK, Luo G, Pretlow TP, Newman RA, Willis J, Dawson D, Markowitz SD (2006) 15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis. Proc Natl Acad Sci USA 103(32):12098–12102 20. Mai V, Colbert LH, Perkins SN, Schatzkin A, Hursting SD (2007) Intestinal microbiota: a potential diet-responsive prevention target in ApcMin mice. Mol Carcinog 46(1):42–48 21. Wang B, Bobe G, LaPres JJ, Bourquin LD (2009) High sucrose diets promote intestinal epithelial cell proliferation and tumorigenesis in APC(Min) mice by increasing insulin and IGF-I levels. Nutr Cancer 61(1):81–93 22. Hassan AB, Howell JA (2000) Insulin-like growth factor II supply modifies growth of intestinal adenoma in Apc(Min/+) mice. Cancer Res 60(4):1070–1076 23. Fenton JI, Hursting SD, Perkins SN, Hord NG (2006) Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line. Carcinogenesis 27(7):1507–1515 24. Mutanen M, Pajari AM, Oikarinen SI (2000) Beef induces and rye bran prevents the formation of intestinal polyps in Apc(Min) mice: relation to beta-catenin and PKC isozymes. Carcinogenesis 21(6):1167–1173 25. Tammariello AE, Milner JA (2010) Mouse models for unraveling the importance of diet in colon cancer prevention. J Nutr Biochem 21(2):77–88 26. Kennedy AR, Beazer-Barclay Y, Kinzler KW, Newberne PM (1996) Suppression of carcinogenesis in the intestines of Min mice by the soybean-derived Bowman-Birk inhibitor. Cancer Res 56(4):679–682

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27. Rajamanickam S, Kaur M, Velmurugan B, Singh RP, Agarwal R (2009) Silibinin suppresses spontaneous tumorigenesis in APC Min/+ mouse model by modulating beta-catenin pathway. Pharm Res 26(12):2558–2567 28. Barnes CJ, Lee M (1998) Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin. Gastroenterology 114(5):873–877 29. Beazer-Barclay Y, Levy DB, Moser AR, Dove WF, Hamilton SR, Vogelstein B, Kinzler KW (1996) Sulindac suppresses tumorigenesis in the Min mouse. Carcinogenesis 8:1757–1760 30. Jacoby RF, Seibert K, Cole CE, Kelloff G, Lubet RA (2000) The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the Min mouse model of adenomatous polyposis. Cancer Res 60(18):5040–5044 31. Colbert LH, Davis JM, Essig DA, Ghaffar A, Mayer EP (2000) Exercise and tumor development in a mouse predisposed to multiple intestinal adenomas. Med Sci Sports Exerc 32(10):1704–1708 32. Colbert LH, Mai V, Tooze JA, Perkins SN, Berrigan D, Hursting SD (2000) Negative energy balance induced by voluntary wheel running inhibits polyp development in APCMin mice. Carcinogenesis 27(10):2103–2107 33. Mai V, Colbert LH, Berrigan D, Perkins SN, Pfeiffer R, Lavigne JA, Lanza E, Haines DC, Schatzkin A, Hursting SD (2003) Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms. Cancer Res 63(8):1752–1755 34. Mehl KA, Davis JM, Clements JM, Berger FG, Pena MM, Carson JA (2005) Decreased intestinal polyp multiplicity is related to exercise mode and gender in ApcMin/+ mice. J Appl Physiol 98(6):2219–2225 35. Baltgalvis KA, Berger FG, Pena MM, Davis JM, Carson JA (2008) Effect of exercise on biological pathways in ApcMin/+ mouse intestinal polyps. J Appl Physiol 104(4):1137–1143 36. Baltgalvis KA, Berger FG, Pena MM, Davis JM, Carson JA (2009) The interaction of a highfat diet and regular moderate intensity exercise on intestinal polyp development in Apc Min/+ mice. Cancer Prev Res (Phila) 2(7):641–649 37. Ju J, Nolan B, Cheh M, Bose M, Lin Y, Wagner GC, Yang CS (2008) Voluntary exercise inhibits intestinal tumorigenesis in Apc(Min/+) mice and azoxymethane/dextran sulfate sodium-treated mice. BMC Cancer 8:316 38. Basterfield L, Mathers JC (2010) Intestinal tumours, colonic butyrate and sleep in exercised Min mice. Br J Nutr 104(3):355–363

Chapter 5

Obesity and the Pathogenesis of Barrett’s Esophagus Rom Leidner and Amitabh Chak

Abstract Barrett’s esophagus (BE), an intestinal-type metaplasia of normal esophageal squamous epithelium, is the only known precursor of esophageal adenocarcinoma (EAC). This is the protean reason for interest in BE as a clinical entity, as 95% of BE patients die of other causes. EAC has risen at a rate of >350% since the mid1970s, faster than any other cancer in the USA. This has been termed the “EAC epidemic” and has tracked in parallel with rising rates of obesity. Gastroesophageal reflux disease (GERD) is widely accepted as the principle cause of BE. Obesity is the leading modifiable risk factor for BE and GERD. Obesity is also the leading modifiable risk factor for EAC, associated with a threefold increased risk of cancer. Central obesity has consistently correlated with BE and BMI has not. This may explain a significant skew toward white males, but trends are actually rising in all demographic groups.

1

Introduction

1. Barrett’s esophagus (BE), an intestinal-type metaplasia of normal esophageal squamous epithelium, is the only known precursor of esophageal adenocarcinoma (EAC). This is the protean reason for interest in BE as a clinical entity. 95% of BE patients die of other causes. 2. Gastroesophageal reflux disease (GERD) is the leading risk factor for BE. Obesity is the leading modifiable risk factor for BE and is independent of GERD. Obesity is also the leading modifiable risk factor for GERD and EAC, associated with a threefold increased risk of EAC. 3. Central obesity, most often measured by waist-to-hip ratio (WHR), has consistently correlated with BE and body mass index (BMI) has not. This may explain skew in incidence toward white males, but trends are actually on the rise in all groups. R. Leidner , M.D. (*) • A. Chak, M.D. (*) Department of Medicine, Case Western Reserve University, Cleveland, OH, USA e-mail: [email protected]; [email protected] S.D. Markowitz and N.A. Berger (eds.), Energy Balance and Gastrointestinal Cancer, Energy Balance and Cancer 4, DOI 10.1007/978-1-4614-2367-6_5, © Springer Science+Business Media, LLC 2012

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4. EAC has risen at a rate of >350% since the mid-1970s, faster than any other cancer in the USA. This has been termed the “EAC epidemic.” 5. Parallel increases in incidence of EAC and obesity have been observed since the 1980s, and this is also the case for GERD. It is impossible to know, however, if BE is also tracking with obesity because population screening for BE does not exist. 6. The true incidence of BE is unknown, but is believed to be increasing at a rate which might, if known, account for the “EAC epidemic.” 7. A well-recognized cancer progression model exists for EAC which is known as the M-D-A sequence. Unlike progression models in nearly all other organs, the EAC sequence does not begin with hyperplasia. The initial and hallmark event is metaplasia (BE), which subsequently proceeds through grades of dysplasia and then adenocarcinoma. The genetic, epigenetic, and molecular basis of this progression is an area of intense research focus and must be rooted in an understanding of the metaplastic initiating event. 8. Unlike preneoplastic precursors of other cancers (polyps and nevi), BE cannot be readily excised and therefore must be monitored clinically for evidence of progression by interval endoscopy and biopsy. As such, this an ideal in vivo model for the study of tumorigenesis. 9. Roughly 40% of patients with BE or EAC do not report reflux symptoms prior to diagnosis. There is no evidence that endoscopic screening improves early detection of BE prior to EAC diagnosis. Most EAC patients survive less than 1 year after diagnosis. 10. Prevention strategies will be most effective at the earliest stage of this progression e.g., preventing emergence of metaplasia, rather than preventing progression of metaplasia once established.

2

Definition: Barrett’s Esophagus

Barrett’s esophagus (BE) is an acquired metaplastic transformation of the mucosal lining of the distal esophagus from a normal stratified (multilayered) squamous epithelium to a single-layered intestinal-type columnar epithelium (intestinal metaplasia). The microscopic hallmark of BE is the presence of single-layered acid mucin-containing goblet cells (Fig. 5.1), which stain intensely blue with Alcian blue pH 2.5 stain, proximal to the normal gastroesophageal junction [1, 2].

3

GERD and BE

The strongest risk factor for BE is chronic GERD, conferring a fivefold increased risk [3, 4]. GERD is estimated to affect roughly one in five individuals in the Western World [5]. Inflammation resulting from chronic acid reflux in GERD is widely accepted to be the principal cause of BE [6]. A community-based endoscopic study

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Fig. 5.1 Metaplastic intestinal type epithelium with characteristic goblet cells seen in Barrett’s esophagus

from the Portland, Oregon VA observed a dose–response relationship between duration of GERD symptoms and development of BE. In individuals with 1–5 years of symptoms, BE was threefold more common compared with individuals with less than 1 year of symptoms. BE was fivefold more common in individuals with 6–10 years of symptoms and 6.4-fold more common in individuals with >10 years of symptoms (p < 0.001) [7]. A recent meta-analysis of 26 studies concluded that overall, symptomatic GERD is associated with a threefold increase in BE (p = 0.001, 95% CI 1.9–4.5), and a fivefold increase for long-segment BE (LSBE) in particular [3]. However, only 10% of patients with long-standing GERD symptoms will ultimately develop BE, suggesting that cofactors beyond acid reflux are also involved in the pathogenesis of BE [8]. A Swedish study in a random sample of 1,000 individuals who consented to undergo screening endoscopy and biopsy, found 16 cases of incident BE. Seven of these 16 subjects (44%) reported no history of reflux symptoms in a pre-procedure questionnaire [9]. Of the five individuals with LSBE (>3 cm), 80% reported reflux symptoms and 60% had evidence of esophagitis, whereas only 46% of the 11 individuals with short-segment BE reported reflux symptoms and esophagitis was seen in only 9% of these cases. These data suggest that a complex set of biologic interactions is likely involved in what might otherwise appear to be, on the surface, a straightforward epidemiologic risk association between GERD and BE.

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4 The Cancer Progression Model of Esophageal Adenocarcinoma A two phase cancer progression model, composed of an initial sequence from GERD to intestinal metaplasia (BE) and a later, somewhat delayed, sequence from BE to dysplasia to EAC is widely accepted as the predominant model of the natural history of EAC. This is based on the following observations. BE is the only known precursor to EAC and individuals with BE have a 30- to 100-fold increased risk of developing EAC as compared to the general population [10]. Symptomatic GERD, which along with obesity, is intimately involved in the initiating metaplastic transformation of stratified squamous esophageal epithelium to a specialized singlelayered intestinal metaplasia characteristic of BE, was definitively correlated to risk of EAC in the landmark 3-year nationwide population-based case–control Swedish study reported by Lagergren et al. in 1999 [11]. In this study, a 7.7-fold increased overall risk of EAC was determined for individuals with GERD (95% CI 5.3–11.4) and a dose–response relationship was demonstrated, such that for individuals with long standing and severe reflux in the highest tertile, based on a composite score of frequency of heartburn and/or regurgitation during the day and at night, a 43.5-fold increased risk of EAC was observed (95% CI 18.3–103.5). Esophagectomy specimens characteristically reveal a field of intestinal metaplasia within which an EAC tumor arises [12]. A stepwise cancer progression model of EAC has long been recognized histologically, with evidence of sequential development from metaplasia (BE) to dysplasia and ultimately adenocarcinoma. This is pathologically termed the “M-D-A” sequence. It is fundamentally important to note that unlike cancer progression models in nearly every other organ, characterized by hyperplasia as the initiating event, this model starts with metaplasia, itself a genetically regulated transformation, from which subsequent genetic changes are believed to accumulate and ultimately progress to cancer. The key crossroads, for cancer prevention, therefore, may ultimately lie much further upstream and depend on understanding the cofactors which modulate an initial metaplastic committing event. This, in the main, accounts for the intense interest in BE as a clinical entity.

5

Prevalence of BE and EAC

The incidence of EAC has dramatically increased in recent decades in the Western World, rising over >350% in the USA since the 1970s, more rapidly than any other cancer [4, 13]. At the same time, the predominant histology has reversed from squamous cell carcinoma, located in the upper two-thirds of the esophagus, to adenocarcinoma, located in the distal third of the esophagus. The causes of this dramatic change in epidemiology, sometimes termed the “EAC epidemic” are unknown, but it is well recognized that this trend tracks directly with rising obesity rates (Fig. 5.2) [14]. The incidence of GERD has also increased in step with rising obesity rates [15].

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Adenocarcinoma

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Squamous cell carcinoma

Obesity 25

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Fig. 5.2 Ecological study showing the correlation of increasing obesity (yellow curve) with rising incidence of esophageal adenocarcinoma in the USA (purple bars) at a time when the incidence of squamous cell carcinoma of the esophagus (blue bars) is decreasing [14]

It would, therefore, be predicted that the incidence of BE would likewise track with rising rates of obesity. This is generally believed to be the case, but remains elusively difficult to confirm. The true incidence and prevalence of BE remains unknown because this would require random population-based screening endoscopy studies. Such studies are not feasible or justifiable from a medical economics standpoint. There is, therefore, a selection bias in available incidence data aggregated from referral-based endoscopic series. Under current practice, patients are selected for endoscopic evaluation according to severity of reflux symptoms and refractoriness to medical treatment. To our knowledge, the only random population data on the true prevalence of BE comes from a Swedish study involving a random population sample of 1,000 volunteers who consented to endoscopy [9]. Sixteen incident cases of BE were thus identified, representing a population prevalence of 1.6%, with a 95% CI of 0.8–2.4%, leaving the true prevalence a matter of ongoing conjecture. A communitybased study of BE incidence between 1994 and 2006 in the Northern California Kaiser Permanente health system, which included 4,205 eligible new cases in that time period, found an annual incidence of 3.6%, adjusted for the volume of endoscopies performed in 2006, the final year of the study (95% CI 3.3–3.9%) [16]. Temporal trends across the health care organization showed a steady linear increase in the prevalence of BE over the 12-year time course of the study, reaching 131/100,000 member years in the final year of the study. In agreement with other studies, prevalence was significantly higher among men than women, and among whites than, in descending order of prevalence, Hispanics, Asians, and African-Americans.

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Obesity Is the Key Modifiable Risk Factor at Each Stage of Neoplastic Progression

The established risk factors for BE and EAC, such as white race, male gender and advanced age are impossible to modify. Modifiable cofactors represent the logical focus of preventative research efforts. Obesity is far and away the strongest identified modifiable risk factor for each phase of the cancer progression sequence from GERD to BE to EAC. The other identified modifiable risk factors are a diet low in fruits and vegetables and smoking, each of which confers a roughly twofold increased level of independent risk [4, 17].

6.1

GERD, EAC, and Obesity

The National Health and Nutrition Examination Survey (NHANES) data have tracked rising obesity in American adults from 15% in 1980 to 34% in 2008 [18]. Obesity is believed to contribute to GERD through several mechanisms, including reduced lower esophageal sphincter pressure, impaired gastric emptying, increased intragastric pressure, and hiatal hernia [19]. A meta-analysis of eight studies showed a significant and dose–dependent association between obesity and GERD, with odds ratio increasing from 1.5 for BMI 25–30 kg/m2 (95% CI 1.1–2.0) to 2.8 for BMI >30 kg/m2 (95% CI 1.9–4.2) [20]. In the Nurses’ Health Study of 10,545 women, a dose–dependent relationship was observed between increasing BMI and frequent reflux symptoms, which were threefold more common in the upper quartile of BMI (p-trend < 0.001) [21]. In a meta-analysis of 14 studies representing a total of 2,488 EAC cases, Kubo et al. found that EAC was increased 1.9-fold for BMI of 25–30 kg/m2 (95% CI 1.5–2.4) and 2.4-fold for BMI >30 kg/m2 (95% CI 2.0–2.8) [22]. This is consistent with results we have observed associating obesity and earlier age of onset of EAC (Fig. 5.3) [23]. Perhaps most convincing are the findings of Whiteman et al., reporting the combined effects of obesity, GERD, and smoking on EAC risk, in an Australian case– control study which included 367 EAC cases and 1,580 population controls [24]. Obesity, defined as BMI ³30 kg/m2, without reflux symptoms, was associated with a 2.2-fold increased risk of EAC (95% CI 1.1–4.3), while frequent reflux, defined as at least weekly symptoms, without obesity, was associated with a 5.6-fold increased risk of EAC (95% CI 2.8–11.3). The combination of obesity and frequent reflux was associated with a 16.5-fold increased risk of EAC (95% CI 8.9–30.6). These results suggest the interaction of GERD and obesity as comodulators of EAC risk.

7

BE and Obesity

To our knowledge, the first case–control data supporting an association between obesity and BE appeared in a 2002 study of familial aggregation in BE by Chak et al. in Cleveland [25]. This study—which was also the first to systematically demonstrate

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Fig. 5.3 Histograms of age of diagnosis in cancer patients without obesity (left) and those with obesity (right) 1 year before diagnosis. Mean age of cancer diagnosis in those with history of obesity was 58.99 years vs. 63.6 years for those without obesity, p = 0.008 [23]

a significant familial component in BE—collected anthropometric data including BMI at 0, 1, 5, 10, and 20 years prior for the 35 BE cases and 106 matched GERD controls in the report. Obesity was defined as BMI ³27.3 kg/m2 for females and ³27.8 kg/m2 for males. Foreshadowing subsequent reports, obesity, as determined by BMI at time of diagnosis, was not associated with BE. However, duration of obesity was found to be significantly associated with BE with a dose–response relationship, (e.g., for 10 prior years obesity OR = 2.3/p = 0.02 and for 20 prior years obesity OR = 3.2/p = 0.004) (Fig. 5.4). Much of the subsequent data regarding an association between obesity and BE comes from studies conducted through the Veterans Affairs medical system (VA). A cross-sectional study from the Palo Alto VA reported by Gerson et al. in 2002 enrolled 110 asymptomatic primarily white male volunteers over age 50 who were scheduled to undergo routine screening colonoscopy and agreed to also undergo endoscopy with research biopsies [26]. Among 110 participants, 27 incident cases of BE were identified (25%). Obesity, defined as BMI >25 kg/m2, was not significantly associated with BE cases (p = 0.7). However, the 83 participants categorized as non-BE for statistical comparison, included 17/83 (20%) with specialized intestinal metaplasia restricted to the GE junction. Among the 27 incident BE cases, 19/27 were short segment BE (70%) and

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Fig. 5.4 Duration of obesity is associated with Barrett’s esophagus [25]

8/27 (30%) were LSBE. The 7% overall prevalence of LSBE in this asymptomatic group (8/110) was in line with rates previously reported in the symptomatic GERD population, but the prevalence of obesity, given a lenient threshold BMI >25 kg/m2, was surprisingly low at 15 and 12% for BE and non-BE, respectively. A retrospective cross-sectional study from the Southern Arizona VA reported by Stein et al. in 2005 compared 65 BE cases and 385 non-BE among patients undergoing endoscopy over a 6-year period from 1988 to 1994 [27]. BMI of 25–30 kg/m2 was associated with a 2.4-fold higher risk of BE (p = 0.03, 95% CI 1.1–5.3). BMI ³30 kg/m2 was associated with 2.5-fold higher risk of BE (p = 0.03, 95% CI 1.1–5.4). The presence and frequency of reflux symptoms, however, was not included in the analysis. No correlation was seen between length of BE segment (short or long) and BMI at time of diagnosis. A case–control study from Queensland, Australia reported by Smith et al. in 2005, compared 117 BE cases, 50 dysplasia cases, and 261 matched controls enrolled in 2003 [28]. The investigators did not find a significant association between BE and BMI at time of diagnosis. In the unadjusted analysis, a significant association was seen between dysplasia and obesity, defined as BMI ³30 kg/m2, but statistical significance fell out after adjustment for reflux symptoms.

7.1

BMI and BE Meta-analysis

Three meta-analyses involving 10–11 studies each have reached similar conclusions. Between the three meta-analyses, results from 21 separate BE studies are represented which collected sufficient anthropometric data for comparison of the association of BMI to BE cases versus controls. Two of the three meta-analyses found no significant

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association between BMI and BE [29, 30]. The meta-analysis by Kamat el al. in 2009, which included 11 studies, reported a statistically significant 1.4-fold increased risk of BE for BMI ³30 kg/m2 (p < 0.001, 95% CI 1.2–1.6) and 1.5-fold increased risk of BE for BMI ³25 kg/m2 (p < 0.001, 95% CI 1.2–1.8) [31]. However, only 2 of the 11 studies evaluated, included GERD controls, and in a separate analysis of these two studies there was no significant association between BMI and BE.

7.2

Central Obesity and BE

In light of the conflicting data regarding BMI and BE, other studies have undertaken to refine measures of obesity, beyond BMI, in assessing the association between obesity and BE. The first data to support this approach was reported in a Seattle study of NSAIDs, anthropometric parameters and BE genetic biomarkers by Vaughan et al. in 2002 [32]. This cross-sectional study of the Seattle cohort of 429 individuals diagnosed with BE, used a logistic regression model adjusting for age, gender, NSAIDs, smoking and found that increasing WHR was significantly associated with genetic abnormalities previously demonstrated by the same group to increase the risk of neoplastic progression, including aneuploidy on flow cytometry (p trend = 0.01), 9p LOH (p trend = 0.005), and 17p LOH (p trend = 0.007). In an innovative 2005 computed tomography (CT) hospital-based case–control study reported by El-Serag et al., visceral adipose tissue (VAT) surface area at the level of the L4–5 vertebral disk by CT was compared in 36 BE cases and 93 matched controls who underwent upper endoscopy between 2000 and 2003 at the Houston VA [33]. A significant association with BE was noted for the upper tertile of visceral obesity by VAT, with 3.2-fold increased risk (p = 0.03, 95% CI 1.1–9.3). A similar CT-based measure of subcutaneous adipose tissue (SAT) surface area at the same level was not significantly associated with BE. The strongest univariate association with BE was observed for BMI >30 kg/m2 with a fourfold increased risk (p = 0.008, 95% CI 1.4–11.1). However, multivariate logistic regression models suggested that the association of VAT and BE was independent of BMI (p = 0.03), whereas BMI was not independently associated with BE (p = 0.55). A 2007 nested case–control study reported by Corley et al. in San Francisco enrolled 317 randomly selected population controls and 316 GERD controls with negative endoscopy and 320 incident cases of BE diagnosed between 2002 and 2005 through the Northern California Kaiser Permanente health system [34]. Abdominal circumference >80 cm, after adjusting for BMI, was independently associated with a 2.2-fold increased risk of BE compared with population controls (95% CI 1.2–4.2), but this risk was attenuated to 1.5-fold when compared with the GERD control group (95% CI 0.8–2.7). No association was noted between BMI and BE. Probably the most definitive data for this association were reported in landmark study by Edelstein et al. in Seattle [35]. This study identified 193 BE cases diagnosed between 1997 and 2000 by upper endoscopy for refractory GERD with matched population controls. Anthropometric measurements assessed included BMI and three measures of central adiposity: waist circumference (WC), WHR, and waist-to-thigh ratio (WTR). All three measures of central adiposity were significantly associated

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with BE with a 2.3-fold increased risk for elevated WC (p trend = 0.001, 95% CI 1.2–4.4), 2.8-fold for elevated WHR (p trend < 0.001, 95% CI 1.5–5.1), and 4.5-fold for elevated WTR (p trend = 0.002, 95% CI 2.1–9.2). The association with BMI was mixed. BE by standard criteria was not associated with BMI, but a significant association was observed for BMI ³30 kg/m2 and the presence of focal intestinal-type metaplasia on microscopic review with Alcian blue acid stain, with a 2.6-fold increased risk (p = 0.001, 95% CI 1.5–4.4). The frequency of reflux symptoms, as anticipated, was highly associated with BE. Weekly symptoms were associated with an impressive 8.1-fold increased risk (95% CI 4.5–14.5). However, elevated WHR was found to be independently associated with BE in a model which adjusted for reflux symptom frequency, with a 2.9-fold increased risk (95% CI 1.3–6.3). Elevated WHR was also independently associated with BE after adjusting for BMI, with a similar 2.9-fold increased risk (p = 0.002, 95% CI 1.5–5.7). One of the most important conclusions to be drawn from this study was to highlight the significant role of central obesity in BE. Importantly, this suggests a plausible cofactor contributing to the striking discrepancy in BE and EAC incidence between males and females (BE M:F ratio 2.5 to 1 and EAC M:F ratio 7 to 1). An increased visceral distribution of visceral body fat, as opposed to a truncal distribution, may also account for the higher incidence of BE and EAC in whites as compared to Asians and African-Americans. A cross-sectional study of 80,100 patients in the Northern California Kaiser Permanente health systems found that increased abdominal circumference was an independent risk factor for reflux symptoms after adjusting for BMI, with a significant 85% increased risk for whites (95% CI 1.6–2.2) but not for African-Americans (OR 0.95, 95% CI 0.6–1.5) or Asians (OR 0.64, 9% CI 0.2–2.3) [36].

8

Central Obesity and GERD as Comodulators of BE Pathogenesis

It is important to note that in the landmark 2007 study by Edelstein et al., WHR was shown to be independently determinant of BE risk, regardless of reflux symptom frequency [35]. A 2.9-fold increased risk of BE was observed for increased WHR, independent of reflux, which rose to a striking 8.1-fold risk in association with weekly reflux symptoms. The significant conclusion from these findings is that although obesity and GERD cleary overlap in the pathogenesis of BE, the effects of obesity, in particular visceral obesity, are further mediated through factors other than chronic acid reflux, to a significant extent. In the 2005 study by Smith et al., the coexistence of frequent reflux symptoms and obesity was shown to result in a striking combined 30-fold increased risk of BE [28]. The biologic basis of the interaction between these two cofactors is being elucidated by a growing body of research. Adipocytes, in particular visceral adipocytes, produce an excess of bioactive compounds known as adipokines. These include leptin, adiponectin, free fatty acids, and inflammatory cytokines.

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Evidence for Leptin

Serum leptin levels are upregulated in human obesity and associated with several human cancers [37–39]. Keen interest in the action of leptin in esophageal malignancy emerged following in vitro studies demonstrating enhanced proliferation of EAC cell lines through anti-apoptotic (OE33), mitogenic (OE33), and angiogenic mechanisms (OE19 and OE33), mediated through COX-2-dependent prostaglandin E2 activation of EGFR signaling and synergism of leptin and acid to activate AKT signaling through NFkB [40–43]. The truncated leptin receptor was subsequently shown to be expressed on esophageal epithelium in BE [44]. The association of serum leptin levels and BE has been investigated in two epidemiologic studies. Kendall et al. in 2008 reported a case–control study design utilizing a pilot cohort of 51 BE cases and 67 population controls, followed by validation cohort of 306 BE cases and 309 controls [45]. A significant 3.3-fold increased risk of BE was observed for men in the highest quartile of serum leptin levels independent of BMI (95% CI 1.7–6.6). After adjusting for GERD symptoms, the risk association was attenuated but remained significant at 2.4-fold (95% CI 1.1–5.2). A significant association was not observed for women, despite significant inclusion (25 pilot cases and 98 validation cases). Thompson et al. in 2010 reported a study of 177 intestinal metaplasia cases and 173 population controls, in which serum leptin levels in the upper tertile were associated with a twofold increased risk for both genders (95% CI 1.1–3.4), which was no longer significant following adjustment for WHR [46]. Of the 177 intestinal metaplasia cases, 90 had endoscopically visible changes which would qualify for BE diagnosis. A subset analysis using these 90 BE cases did not show a significant association between increased serum leptin and risk of BE, however.

8.2

Evidence for Adiponectin

Adiponectin, unlike leptin, is inversely correlated with obesity and has insulin sensitizing and anti-inflammatory effects [47]. Reduced adiponectin levels are associated with several cancers including breast, endometrial, and colorectal [48]. Adiponectin inhibits humoral production of IL6 and TNFa while stimulating anti-inflammatory IL10 production. Adiponectin binds circulating growth factors involved in proliferation and angiogenesis signaling pathways, such that reduced circulating adiponectin levels are thought to confer a proproliferative milieu [49]. Adiponectin has been shown to activate proapoptotic signaling in vitro through cell surface receptor interactions and inhibit leptin-induced proliferation in EAC cell lines (OE19 and OE33) [43]. Reduced expression at the mRNA level of adiponectin receptors has been demonstrated in mucosal BE biopsies [50]. Rubenstein et al. in 2009 examined the association between reduced serum adiponectin and risk of BE by comparing 112 BE cases and 1999 GERD controls [51]. Reduced levels of low molecular weight adiponectin multimer, in particular, was associated with threefold increased risk of

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BE (95% CI 0.2–0.7). Thompson et al. in 2010 reported a case–control study of 177 BE cases and 173 population controls, finding a twofold increased risk of BE for serum adiponectin in the lower tertile (95% CI 0.3–0.8) [46].

8.3

Evidence for Free Fatty Acids

Excess free fatty acid synthesis by visceral adipocytes contributes to insulin resistance [52, 53]. The resulting hyperinsulinemia is a cardinal manifestation of metabolic syndrome and can promote proliferation and inhibit apoptosis through decreased IGFBP levels and increased bioavailability of IGF1, as well as contributing to increased IL6 and TNFa levels. A cross-sectional study of metabolic syndrome and BE by Ryan et al. in 2008 enrolled 102 BE cases in Ireland [54]. Anthropomorphic measurements were recorded and serum analysis was performed to evaluate levels of various adipocytokines including CRP, leptin, adiponectin, VEGF, IL1-10, and INFg. Significant associations favoring LSBE, over short-segment, included abdominal circumference, hyperinsulinemia, increased IL6 levels, and metabolic syndrome diagnosis.

9

Future Directions: Physical Activity as a Modifiable Risk Factor

Prospective interventions targeting the modifiable factors which modulate the initial metaplastic transformation in the distal esophageal epithelium may prove to be the most effective strategy to attenuate the rising incidence of EAC. This is an active focus of ongoing research. Three studies are briefly reviewed. The NIH-AARP Diet and Health Study is a longitudinal cohort study, which enrolled 487,732 individuals, aged 50–71, from eight sites in the USA who returned a mail-in baseline questionnaire between 1995 and 1996 [55]. Incident cases of esophageal or gastric carcinoma between 1995 and 2003 were ascertained from state cancer registries in the eight states of origin, as well as TX, AZ, and NV, and classified by histology and anatomic site according to ICD codes. The AARP questionnaire included self-reporting of average frequency of physical activity, defined as lasting at least 20 min and resulting in increased heart rate, breathing, or working up a sweat. Participants were divided into five categories according to physical activity frequency per week (0, <1, 1–2, 3–4, and ³5 times). Over 3.5 million person-years of follow-up were represented in the 8-year period of this study, with 523 cases of esophageal cancer (374 adenocarcinoma and 149 squamous) and 642 cases of gastric cancer (all adenocarcinoma, 313 cardia, and 329 noncardia) ascertained. Multivariate analysis included age, gender race, education level, marital status, smoking, alcohol, red meat, fruit and vegetable intake, and BMI. Perhaps not surprisingly, participants who reported higher physical

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activity levels tended to be leaner, married, smoke less, graduated college, have lower red meat intake and higher fruit and vegetable intake. The aggregate risk of adenocarcinoma anywhere along the upper GI tract was reduced by 27% with any level of physical activity above “0” after multivariate adjustment including BMI (95% CI 0.6–0.9). However, a dose–response relationship could not be demonstrated for increasing levels of physical activity. Equal risk reduction was seen regardless of level of physical activity, ranging from every day to less than once per week. An association was not observed for squamous cell carcinoma and when upper GI adenocarcinomas were further stratified by anatomic location (esophageal vs. gastric adenocarcinoma), a significant protective effect was only demonstrated for gastric adenocarcinoma. A dose-dependent protective relationship between increasing physical activity level and gastric adenocarcinoma was observed, ranging from 23% reduced risk (
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25. Chak A et al (2002) Familial aggregation of Barrett’s oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults. Gut 51(3):323–328 26. Gerson LB, Shetler K, Triadafilopoulos G (2002) Prevalence of Barrett’s esophagus in asymptomatic individuals. Gastroenterology 123(2):461–467 27. Stein DJ et al (2005) The association of body mass index with Barrett’s oesophagus. Aliment Pharmacol Ther 22(10):1005–1010 28. Smith KJ et al (2005) Interactions among smoking, obesity, and symptoms of acid reflux in Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev 14(11 Pt 1):2481–2486 29. Cook MB et al (2008) A systematic review and meta-analysis of the risk of increasing adiposity on Barrett’s esophagus. Am J Gastroenterol 103(2):292–300 30. Seidel D et al (2009) The association between body mass index and Barrett’s esophagus: a systematic review. Dis Esophagus 22(7):564–570 31. Kamat P et al (2009) Exploring the association between elevated body mass index and Barrett’s esophagus: a systematic review and meta-analysis. Ann Thorac Surg 87(2):655–662 32. Vaughan TL et al (2002) Nonsteroidal anti-inflammatory drug use, body mass index, and anthropometry in relation to genetic and flow cytometric abnormalities in Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev 11(8):745–752 33. El-Serag HB et al (2005) Abdominal obesity and the risk of Barrett’s esophagus. Am J Gastroenterol 100(10):2151–2156 34. Corley DA et al (2007) Abdominal obesity and body mass index as risk factors for Barrett’s esophagus. Gastroenterology 133(1):34–41, quiz 311 35. Edelstein ZR et al (2007) Central adiposity and risk of Barrett’s esophagus. Gastroenterology 133(2):403–411 36. Corley DA, Kubo A, Zhao W (2007) Abdominal obesity, ethnicity and gastro-oesophageal reflux symptoms. Gut 56(6):756–762 37. Zhang Y et al (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432 38. Considine RV et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334(5):292–295 39. Garofalo C, Surmacz E (2006) Leptin and cancer. J Cell Physiol 207(1):12–22 40. Beales IL et al (2007) Activation of Akt is increased in the dysplasia-carcinoma sequence in Barrett’s oesophagus and contributes to increased proliferation and inhibition of apoptosis: a histopathological and functional study. BMC Cancer 7:97 41. Beales IL, Ogunwobi OO (2007) Leptin synergistically enhances the anti-apoptotic and growth-promoting effects of acid in OE33 oesophageal adenocarcinoma cells in culture. Mol Cell Endocrinol 274(1–2):60–68 42. Ogunwobi O, Mutungi G, Beales IL (2006) Leptin stimulates proliferation and inhibits apoptosis in Barrett’s esophageal adenocarcinoma cells by cyclooxygenase-2-dependent, prostaglandin-E2-mediated transactivation of the epidermal growth factor receptor and c-Jun NH2-terminal kinase activation. Endocrinology 147(9):4505–4516 43. Ogunwobi OO, Beales IL (2008) Glycine-extended gastrin stimulates proliferation via JAK2and Akt-dependent NF-kappaB activation in Barrett’s oesophageal adenocarcinoma cells. Mol Cell Endocrinol 296(1–2):94–102 44. Francois F et al (2008) The association of gastric leptin with oesophageal inflammation and metaplasia. Gut 57(1):16–24 45. Kendall BJ et al (2008) Leptin and the risk of Barrett’s oesophagus. Gut 57(4):448–454 46. Thompson OM et al (2010) Serum leptin and adiponectin levels and risk of Barrett’s esophagus and intestinal metaplasia of the gastroesophageal junction. Obesity (Silver Spring) 18(11):2204–2211 47. Weyer C et al (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86(5):1930–1935 48. Kelesidis I, Kelesidis T, Mantzoros CS (2006) Adiponectin and cancer: a systematic review. Br J Cancer 94(9):1221–1225

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49. Wang Y et al (2005) Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner. J Biol Chem 280(18):18341–18347 50. Konturek PC et al (2008) Effect of adiponectin and ghrelin on apoptosis of Barrett adenocarcinoma cell line. Dig Dis Sci 53(3):597–605 51. Rubenstein JH et al (2009) Association of adiponectin multimers with Barrett’s oesophagus. Gut 58(12):1583–1589 52. Xu H et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112(12):1821–1830 53. Wajchenberg BL (2000) Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 21(6):697–738 54. Ryan AM et al (2008) Barrett esophagus: prevalence of central adiposity, metabolic syndrome, and a proinflammatory state. Ann Surg 247(6):909–915 55. Leitzmann MF et al (2009) Physical activity and esophageal and gastric carcinoma in a large prospective study. Am J Prev Med 36(2):112–119 56. Huerta JM et al (2010) Prospective study of physical activity and risk of primary adenocarcinomas of the oesophagus and stomach in the EPIC (European Prospective Investigation into Cancer and nutrition) cohort. Cancer Causes Control, http://www.springerlink.com/content /5n272700m7008225/ 21(5):657–669 57. Winzer BM et al (2010) Exercise and the Prevention of Oesophageal Cancer (EPOC) study protocol: a randomized controlled trial of exercise versus stretching in males with Barrett’s oesophagus. BMC Cancer 10:292

Chapter 6

Obesity and Pancreatic Cancer Donghui Li

Abstract Pancreatic cancer is the fourth leading cause of cancer death for both men and women in the United States. It is a highly fatal disease with a 5-year survival rate of approximately 6%. Obesity, in addition to cigarette smoking and diabetes, is one of the few modifiable risk factors that have been associated with increased risk of pancreatic cancer. Obesity has also been associated with an early onset and reduced survival of pancreatic cancer. Insulin resistance and inflammation are two most anticipated biological mechanisms that link obesity and pancreatic cancer. Because of the high prevalence of overweight or obesity in the U.S. population, a better understanding of the complex association between obesity and pancreatic cancer may provide opportunities for the development of novel strategies in prevention and treatment of this deadly disease. The current epidemiological evidence and potential biological mechanisms involved in the obesity-pancreatic cancer association are reviewed.

1

Pancreatic Cancer

Pancreatic cancer ranks tenth in incidence of all cancers and second among the gastrointestinal (GI) cancers [1]. In 2010, more than 43,000 new cases and about 36,800 deaths of pancreatic cancer occurred in the USA [2]. Worldwide, an estimated 227,000 people die of pancreatic cancer each year [3]. Pancreatic cancer ranks fourth in death rate among all malignancies, and it accounts for a quarter of GI cancer deaths [2]. The high mortality rate of this malignancy has been explained by the facts that most patients are diagnosed with advanced disease and that the tumor is highly

D. Li, Ph.D. (*) Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Unit 426,1515 Holcombe Boulevard, Houston, TX 77030, USA e-mail: [email protected] S.D. Markowitz and N.A. Berger (eds.), Energy Balance and Gastrointestinal Cancer, Energy Balance and Cancer 4, DOI 10.1007/978-1-4614-2367-6_6, © Springer Science+Business Media, LLC 2012

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aggressive and resistant to most cancer therapies. It is such a dismal disease that 75% of patients die within 1 year of diagnosis and the 5-year survival rate is estimated to be only 6% [1]. Surgical resection offers the best prognosis, but <10% patients are eligible for resection at diagnosis. Even for patients who undergo tumor resection, the long-term survival rate is <20% because most patients will have recurrence or metastatic disease shortly after the procedure. The median survival time for patients who undergo resection ranges between 16 and 23 months. Patients with locally advanced pancreatic cancer have a median survival of 10–12 months. Patients with metastatic disease have a median overall survival duration of only 3–4 months without active therapy; treatment typically extends survival by only a few months [4]. Known risk factors for pancreatic cancer include cigarette smoking, excessive alcohol consumption, increasing age, family history, obesity, and diabetes [5]. Germ-line mutations of genes associated with several rare cancer syndromes or in association with hereditary pancreatitis or cystic fibrosis contribute to 5–10% of known cases of pancreatic cancer. Other exposures and conditions—such as dietary factors, occupation, use of non-cigarette tobacco products, pancreatitis, Helicobacter pylori or hepatitis B virus infection, and use of aspirin and statins— have been less consistently associated with the risk for pancreatic cancer [6]. Recent genome-wide association studies also have identified several chromosome regions harboring the ABO blood group [7], the nuclear receptor subfamily 5A2 (NR5A2) and the cleft lip and palate transmembrane 1-like (CLPTM1L)-telomerase reverse transcriptase (TERT) gene [8] in association with risk of pancreatic cancer.

2

Obesity and Risk of Pancreatic Cancer

There is increasing evidence that risk of pancreatic cancer is elevated among individuals who are obese or have high body mass index (BMI; weight in kilograms divided by height in meters squared). On the basis of findings from 23 cohort and 15 case–control studies, the World Cancer Research Fund Panel concluded that there is a “convincing increased risk” of pancreatic cancer related to body fatness and a “probable increased risk” with abdominal fatness [9]. One prospective study estimated that obesity could contribute to as much as a fourth of pancreatic cancer cases [10]. Given the fact that 70% of US adults are overweight or obese [11], the elucidation of an association between pancreatic cancer and obesity may provide an opportunity for the primary prevention of this deadly disease by encouraging a healthy body weight.

2.1

Body Mass Index

The high and rapid fatality of pancreatic cancer makes it a difficult cancer to study because the most severely ill patients often die before recruitment to a case–control

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study and their information has to be collected by proxy interviews, which generates selection bias and information bias. Further, pancreatic cancer is often accompanied by substantial weight loss even before diagnosis [12], which may bias any association between body weight and cancer risk when the body weight at recruitment is used in the studies. On the other hand, prospective studies need to follow up large numbers of individuals for long periods to accrue a sufficient number of incident pancreatic cancer cases to achieve appropriate power for meaningful analyses. Epidemiological studies of pancreatic cancer frequently use the self-reported weight 2 years before interview or at specific ages or the self-reported usual adult weight and height data to calculate BMI [13–26]. Several studies have compared selfreported data with measured height and weight to address concerns on recall and reporting biases associated with self-reported weight and height and have found good consistency [22, 27–29]. Overall, the associations between a high BMI and the risk of pancreatic cancer are more consistent in cross-prospective studies than in case–control studies. At least 19 of 29 prospective studies, 3 large pooled analyses [30–32] and 2 of 3 meta-analyses [33–35] have reported a positive association between a high BMI and an increased risk of pancreatic cancer. In general, the pooled and meta-analyses have reported a 10% or greater increased risk for a 5 kg/m2 unit increase in BMI or a 20–50% increased risk among obese relative to normal BMI participants. In the earliest meta-analysis, which was published in 2003, the authors analyzed data for 6,391 cases from six case–control and eight cohort studies from North America and Europe [33]. The summary relative risk (RR) per unit increase in BMI was 1.02 (95% confidence interval [CI]: 1.01–1.03), which translates into an RR of 1.19 (95% CI: 1.10–1.29) for obese people (>30 kg/m2) compared with people with a normal body weight (<22 kg/m2). The second meta-analysis, published in 2007, included 21 prospective cohort studies involving nearly 3.5 million individuals and 8,062 cases of pancreatic cancer [34]. The estimated summary RR of pancreatic cancer per 5 kg/m2 increase in BMI was 1.12 (95% CI: 1.06–1.17) for men and women combined, 1.16 (95% CI: 1.05–1.28) for men alone, and 1.10 (95% CI: 1.02–1.19) for women alone. Additional analyses showed significantly greater RRs based on self-reported weight and height (RR = 1.17) compared with measured data (RR = 1.05) and for diabetes-adjusted estimates (RR = 1.15) compared with estimates from studies that did not adjust for diabetes (RR = 1.06). The most recent meta-analysis, published in 2008, was from a large systematic review and meta-analysis of observational studies that had investigated the risk of multiple cancers associated with obesity [35]. A weak association between increased BMI and pancreatic cancer risk was found in 4,443 cases from 16 pancreatic cancer studies included in the review. The summary RR was 1.07 (95% CI: 0.93–1.23) for men and 1.12 (95% CI: 1.02–1.22) for women [35]. Three prospective cohort studies that pooled projects published from April 2010 to November 2010 examined the association of anthropometric factors with the risk of pancreatic cancer and the interaction of BMI with other known risk factors for pancreatic cancer [30–32]. The first of these projects included seven

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prospective cohort studies (2,454 cases) and assessed whether the association between obesity and pancreatic cancer risk was modified by age, sex, smoking status, physical activity, or history of diabetes [32]. The summary RR was similar to those published in previous meta-analyses but was significantly different by sex (RR = 1.06 for men and 1.12 for women). The association between obesity and pancreatic cancer risk also differed by smoking history, i.e., a positive association was found in never smokers and former smokers but not in current smokers (Pinteraction = 0.08). The second pooled nested case–control analysis included data from 13 studies (12 cohort and 1 case–control) included in the National Cancer Institute’s Pancreatic Cancer Cohort Consortium (PanScan) for a total of 2,170 cases and 2,209 controls [30]. A positive association between increasing BMI and increasing risk of pancreatic cancer was observed. The adjusted odds ratio (OR) for the highest versus lowest BMI quartile was 1.33 (95% CI: 1.12–1.58) for all participants, 1.33 (95% CI: 1.04–1.69) for men, and 1.34 (95% CI: 1.05–1.70) for women. Overall, for a 5 kg/m2 increase in BMI, the odds of pancreatic cancer increased 1.13-fold. The third pooled analysis used primary data from 14 cohort studies (846,340 individuals and 2,135 cases) included in The Pooling Project of Prospective Studies of Diet and Cancer, an international consortium [31]. The analysis assessed pancreatic cancer risk in association with BMI at young ages and change in BMI as an adult. A positive association was observed for BMI in early adulthood (pooled multivariate RR = 1.30, 95% CI: 1.09–1.56 comparing BMI >25 kg/m2 to a BMI of 21.0–22.9 kg/m2). Compared with individuals who were not overweight or obese, the risk was 54% higher (95% CI: 24–93%) for those who were overweight in early adulthood and obese at baseline. A 40% higher risk was observed among individuals whose BMI increased >10 kg/m2 between baseline and younger ages compared with individuals whose BMI remained stable.

2.2

Central Adiposity

Abdominal fatness is a possible risk factor for pancreatic cancer. Central adiposity is associated with glucose intolerance and increased risk of diabetes; consequently, the increased circulating level of insulin may promote tumor development. Because BMI does not reflect the distribution of body fat, a number of studies have collected data for other measures of adiposity, such as waist circumference and waist-to-hip ratio (WHR) [20, 24, 26, 30, 31, 36–38]. In the American Cancer Society Cancer Prevention Study II Nutrition Cohort, men and women who reported “central” weight gain (i.e., in the chest, shoulder, and waist) had an RR of pancreatic cancer of 1.45 (95% CI: 1.02–2.07) compared with men and women who reported peripheral weight gain (i.e., in the hips and thighs or equally all over) independent of BMI [24]. In the European Prospective Investigation into Cancer and Nutrition (EPIC) study, larger WHR and greater waist circumference were both associated with an increased risk of developing pancreatic cancer (RR per 0.1 = 1.24; 95% CI: 1.04–1.48;

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Ptrend = 0.02 and RR per 10 cm = 1.13; 95% CI: 1.01–1.26; Ptrend = 0.03, respectively) [37]. Some studies have found positive associations with WHR but not with waist circumference [30, 31, 38]. In the NIH-AARP Diet and Health study [26] and a pooled analysis of 12 cohort studies [30], increased WHR was associated with increased risk of pancreatic cancer in women but not in men. In the Women’s Health Initiative study [38], after adjustment for potential confounders women in the highest quintile of WHR had 70% (95% CI: 10–160%) excess risk compared with women in the lowest quintile. When WHR was analyzed as a continuous variable, the risk increased by 27% (95% CI: 7–50%) per 0.1 increase. One recent pooled analysis of 14 cohort studies found a positive association between WHR and pancreatic cancer risk in both men and women (pooled multivariate RR = 1.35, comparing the highest versus lowest quartile, 95% CI: 1.03–1.78) [31]. In the Swedish Mammography Cohort and the Cohort of Swedish Men, Larsson et al. reported that for a difference of 20 cm (about two standard deviations) in waist circumference, the multivariate RR was 1.32 (95% CI: 0.73–2.37) among women and 1.74 (95% CI: 1.00–3.01) among men [20]. Waist circumference was significantly associated with increased risk of pancreatic cancer in men in a pooled analysis of 30 cohort studies involving 519,643 Asian-Pacific participants and 324 deaths from pancreatic cancer; the RR was 1.08 (95% CI: 1.02–1.14) for every 2-cm increase in waist circumference [36].

2.3

Physical Activity

Physical activity has been associated with glucose metabolism and insulin sensitivity, independent of its effects on body weight [39]. Chronic moderate physical activity has also been associated with increased anti-inflammatory cytokines, increased natural killer cell activity, increase DNA repair activity, and reduced angiogenesis [40]. Investigating the association between physical activity and cancer in epidemiologic studies is difficult because of the challenges in accurately measuring the amount and intensity of physical activity. For this reason physical activity is prone to misclassification bias. Studies on physical activity and the risk of pancreatic cancer have resulted in mixed findings, including no associations, positive associations, and negative associations, as summarized in a recent review [41]. In a meta-analysis of 22 prospective and 6 retrospective studies, a reduction in pancreatic cancer risk with higher levels of total activity (five prospective studies, RR: 0.72, 95% CI: 0.52–0.99) and occupational activity (four prospective studies, RR: 0.75, 95% CI: 0.59–0.96) was found [41]. Nonsignificant inverse associations were detected between risk and recreational and transport physical activities. These data suggest a weak inverse association between overall physical activity and pancreatic cancer risk. However, because physical activity directly impacts obesity and obesity-related carcinogenesis, improved methods for elucidating the role of physical activity in pancreatic cancer risk are needed.

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Obesity and Age of Onset and Survival of Pancreatic Cancer Age of Onset

In a large-scale hospital-based case–control study conducted at The University of Texas MD Anderson Cancer Center, it was found that individuals who were overweight (BMI >25 but <30 kg/m2) or obese (BMI >30 kg/m2) from the ages of 20–49 years had an earlier onset of pancreatic cancer than individuals with normal BMI by 2–6 years [21]. For example, the median age of cancer diagnosis was 64 years for those with normal BMI but 61 years for overweight patients and 59 years for obese patients [21]. The association between obesity and time of diagnosis was also reported in a pooled analysis of 12 cohort studies, in which obese participants were diagnosed on average 1 year earlier than those of normal weight [30].

3.2

Survival

The reported results from studies on the association of obesity and pancreatic cancer survival are inconsistent. Three clinical studies on patients who had undergone surgical resection [42–44] and three case–control studies [21, 45, 46] have reported positive associations between obesity and reduced overall survival of patients with pancreatic cancer. On the other hand, two clinical studies found no association between BMI and survival, and one study found a negative association between BMI and survival in patients who had undergone pancreatectomy [47, 48]. The clinical studies on surgical patients usually used BMI at the time of diagnosis. Because weight loss is a common symptom of pancreatic cancer, BMI at the time of diagnosis or surgery may not be an appropriate measurement for examining the role of obesity in patient survival. Interestingly, one study measured the amount of fat in the pancreas by using immunohistochemical analysis [49] and another study measured the intraabdominal fat with the use of computed tomography [42], and both found a positive association between a larger amount of fat and reduced overall survival. The single study that found better survival in association with higher BMI was conducted in a relatively large series (795 cases) of surgical patients in which both overweight (hazard ratio = 0.68) and obese patients (hazard ratio = 0.72) had improved survival relative to patients with normal BMI [50].

3.3

Mortality

Data on obesity or high BMI and pancreatic cancer mortality are also inconsistent. Obesity and high BMI was not associated with pancreatic cancer mortality in three large prospective cohorts: the Whitehall cohort study, the College Alumni Health

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study, and a study conducted in Japan [51–53]. On the other hand, obesity and high BMI was associated with increased mortality in the Million Women study, which is a large cohort of middle-aged women [54], in a large cohort of US adults [55], and in a prospective cohort of men in US area of Chicago [56]. A pooled analysis of data from 30 cohort studies in the Asia Pacific showed an increase in pancreatic cancer mortality with increase in waist circumference [36]. The inconsistent data on the association between obesity and survival or mortality of pancreatic cancer could be partially explained by differences in study designs, study populations, and measures and classifications of obesity. Because clinical studies usually use BMI at the time of cancer diagnosis or surgery, weight loss may be a confounder in the risk analysis. In addition, data obtained from the patients with resected tumor may not be generalizable to the majority of pancreatic cancer patients, who have more advanced disease. Variations in adjuvant treatment and other clinical practices between studies may also affect the clinical outcome, which make data interpretation more challenging. Continued research is needed to clarify the role of obesity in pancreatic cancer survival and mortality.

4

Mechanism of Obesity-Related Pancreatic Cancer

In obesity, the adipose tissue not only serves the purpose of fat storage but also actively functions as an endocrine organ. Adipose tissue is made up of adipocytes, pre-adipocytes, fibroblasts, macrophages, other cell types, and blood vessels. It produces numerous adipokines, such as leptin, adiponectin, resistin, interleukin (IL)-6, tumor necrosis factor-alpha (TNF-a), monocyte chemoattractant protein-1 (MCP-1; also known as CCL2), plasminogen activator inhibitor-1, and vascular endothelial growth factor [57]. These adipokines are perhaps the major mediators of obesity-related carcinogenesis. Although obesity could contribute to cancer via different mechanisms in different types of cancer, e.g., female hormones in breast and endometrial cancers and insulin in colon cancer, insulin resistance [58], and inflammation [59] are the most likely mechanisms in pancreatic cancer.

4.1

Adipokines

Leptin and adiponectin are the most abundant adipokines. Obese individuals usually have a higher level of leptin, as a consequence of leptin resistance, and a reduced level of adiponectin. Leptin plays a pivotal role in regulating the energy balance by decreasing appetite and increasing metabolism. Leptin has a mitogenic effect in colon, breast, and endometrial cancer cells but inhibits the growth of pancreatic cancer cells [60]. Adiponectin has significant anti-inflammatory and insulin-sensitizing effects. Adiponectin also has direct anti-carcinogenic effects, many of which are

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mediated through the AMP-activated protein kinase (AMPK) system via the receptors AdipoR1 and AdipoR2 [61]. Activated AMPK regulates growth arrest and apoptosis by inhibiting mTOR and stimulating p53 and p21 signaling [62]. AMPK is the molecular target of metformin, a common anti-diabetic drug that has been associated with reduced risk of pancreatic cancer in diabetics [63]. Experimental studies have shown that leptin is not associated with cell proliferation or tumor progression in obese mice inoculated with human pancreatic cancer cells, whereas circulating adiponectin is inversely associated with tumor progression [64]. A few clinical and epidemiological studies have examined the association of the circulating levels of leptin and adiponectin and the risk of pancreatic cancer. In four small clinical studies (sample size ranging from 64 to 81 patients), a higher level of adiponectin [65–67] and a lower level of leptin [66–68] were detected in patients with pancreatic cancer compared with healthy controls or patients with chronic pancreatitis or diabetes. In contrast, a higher level of prediagnostic circulating adiponectin was associated with a reduced risk of pancreatic cancer in a prospective study of male smokers [69]. These inconsistent data underscore the need for additional research to clarify the role of leptin and adiponectin in the association between obesity and pancreatic cancer.

4.2

Insulin Resistance

Although obesity and diabetes have been found to be independent risk factors for pancreatic cancer [21, 70], insulin resistance and compensatory hyperinsulinemia and also elevated levels of circulating insulin-like growth factors (IGF) are perhaps the common mechanisms shared by obesity and type II diabetes in promoting the development of pancreatic cancer [71]. A number of prospective studies have shown that elevated levels of post-load plasma glucose [51, 56], serum and plasma glucose [72], insulin [73, 74], and plasma C-peptide [75] are associated with an increased risk of pancreatic cancer. Even though epidemiological investigations have found no significant association between pancreatic cancer risk and prediagnostic plasma levels of IGF1 and IGF2 [76, 77], a reduced level of IGFBP1 was found to be predictive for an increased risk of pancreatic cancer [78]. Interestingly, a recent study that used immunohistochemical evaluation of Ki67 in autopsy samples of human pancreatic tissue showed that obesity and type II diabetes were associated with a tenfold and fourfold higher level, respectively, of pancreatic ductal replication [79]. This finding is consistent with observations in animal studies that human pancreatic cancer cells grow faster and metastasize to a greater extent in obese mice than in lean mice [64]. Data from animal studies suggest that islet cell turnover, which is associated with insulin resistance, is critical to pancreatic carcinogenesis. For example, in hamsters, the stimulation of islet cell proliferation enhances pancreatic ductal carcinogenesis [80], and the destruction of islet cells by streptozotocin or alloxan inhibits cancer induction [81, 82]. Furthermore, metformin inhibited chemical carcinogen- and

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high-fat-induced pancreatic tumors in hamsters by normalizing the rate of islet cell turnover [83]. Pancreatic b-cell hyperactivity, which is characterized by increased b-cell mass in the pancreas, contributes to insulin oversecretion in response to insulin resistance. The exocrine pancreatic tissue may be chronically exposed to local insulin concentrations much higher than the circulating insulin levels seen in hyperinsulinemic patients. Experimental evidence suggests that insulin is a growth-promoting hormone with mitogenic effects. Insulin promotes cell proliferation and increases glucose utilization [84], both of which are important to tumor development and progression. Furthermore, insulin upregulates the bioavailability of IGFs by reducing the hepatic production of IGF binding proteins [85, 86]. IGF1 has more potent mitogenic and anti-apoptotic activities than insulin does and could act as a growth stimulus in cells expressing insulin and IGF1 receptor (IGF1R). IGF1 and IGF1R are highly expressed in pancreatic cancer cells [87], and IGF1-mediated signaling transduction leads to increased proliferation and invasion, the expression of angiogenesis mediators, and decreased apoptosis in pancreatic cancer cells [88–90]. Because insulin receptor (IR) and IGF1R show >50% overall sequence homology and 84% homology in tyrosine kinase domain of the b-subunit, insulin, and IGF1 can interact either with IR or IGF1R. The IR/IGF1R-mediated initiation of signal transduction activates important intracellular signal pathways, including the Ras/Raf/MEK/ERK and phosphoinositide-3 kinase/Akt/mTORE pathways. Genetic variants of the IGF axis genes have been associated with both the risk and survival of pancreatic cancer [91, 92]. The IGF1R-mediated signaling pathway has been recognized as a therapeutic target in the treatment of pancreatic cancer.

4.3

Inflammation

Obesity reflects a state of chronic low-grade inflammation and is associated with an increased number of macrophages in adipose tissue [57]. Accumulation of lipids in the adipocytes and enlarged adipose tissues lead to a relative hypoxia state, which induces hypoxia-inducible factor-1a and IL-6 and decreases the expression of adiponectin [93, 94]. Hypoxia-inducible factor-1a is involved in the overexpression of leptin in tumors and in mediating the attraction of macrophages into adipose tissue, which initiate the inflammatory response [95]. In a well-established animal model of pancreatic cancer, a high-fat diet predisposes mice with oncogenic K-ras activation to enhanced pancreatic intraepithelial neoplasm (PanIN) development [96]. In this model, tumor promotion is closely associated with increased inflammation without the presence of insulin resistance, and abrogation of TNF-a receptor signaling significantly blocks PanIN development, which underlines a central role for TNF-a in obesity-mediated enhancement of PanIN lesions. An increased level of TNF-a stimulates the production of MCP-1 and activates the IKKb and nuclear factor (NF)-kB axis, the master regulator of innate and adaptive immunity. IKKbmediated suppression of tuberous sclerosis (TSC1), a growth inhibitory protein,

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activates the mTOR pathway, enhances angiogenesis, and promotes tumor development [97]. NF-kB is constitutively activated in pancreatic cancer [98], and increased NF-kB activity can inhibit apoptosis and promote growth, tumorigenesis, angiogenesis, invasion, and metastasis in pancreatic cancer [99]. In addition to the IKKb/ NF-kB signaling pathway, other transcription factor-signaling pathways involved in the pro-inflammatory effect of obesity are the c-Jun NH2-terminal kinase (JNK) pathway [100] and the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway [101], both are critical for cell survival, proliferation, and differentiation. The obesity-related proinflammatory cytokines such as TNF-a, IL-6, resistin, MCP-1, and plasminogen activator inhibitor-1 not only contribute to insulin resistance but also affect the endothelium function leading to upregulated adhesion molecule synthesis and increased vascular permeability. Other obesity-related inflammatory components that could contribute to the development of cancer include the matrix metalloproteinases, which are associated with cancer cell invasion and metastasis, and vascular endothelial growth factor, an angiogenic factor [102]. Non-alcoholic fatty pancreas disease (NAFPD) has been proposed as another link between obesity and pancreatic cancer. NAFPD is a disease with a pancreatic phenotype ranging from deposition of fat in the pancreas through fat deposition with inflammation, resultant pancreatic fibrosis, and possibly pancreatic cancer. This pancreatic phenotype is similar to that of obesity-induced liver disease, non-alcoholic fatty liver disease, which describes a spectrum from hepatic steatosis through steatohepatitis to cirrhosis, and primary hepatocellular cancer [103, 104]. In an animal study, pancreata from leptin-deficient obese mice fed a 15% high-fat diet had greater amounts of triglycerides, free fatty acids, cholesterol, and total fat as well as a higher levels of the cytokines IL-1b and TNF-a compared with those from control lean mice [103]. These data suggest that obesity leads to NAFPD. Another experiment showed that maternal obesity led to significant increases in body weight, pancreatic triglyceride content, TGF-b expression (a marker for the pancreatic stellate cell), and collagen gene expression in offspring, indicating a dysmetabolic and NAFPD phenotype [105]. As discussed above, fat is a dynamic endocrine organ and central adiposity is possibly associated with an increased risk of pancreatic cancer. Central adiposity leads to organ steatosis and altered serum adipokines, including a reduced adiponectin level and markedly elevated levels of leptin and proinflammatory cytokines. This abnormal adipokine milieu results in increased tissue infiltration of the monocytes and macrophages which produce the chronic inflammation state. Over many years, the combination of steatosis and local inflammation leads to fibrosis and eventually to cancer [104]. Pancreatic cancer exhibits extensive proliferation of stromal fibroblasts and deposition of extracellular matrix components (desmoplasia) [106]. The stromal interaction, or tumor microenvironment, plays an important role in tumor growth and invasion as well as in drug resistance [107]. The molecular basis of this phenotype is not well defined. The role of adipose stromal cells and adipose endothelial cells in tumorigenesis is intriguing. A recent animal study [108] demonstrated the recruitment of cells from the white adipose tissue to the tumor and went on to

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demonstrate that adipose stromal and epithelial cells migrate to and become engrafted into tumor compartments. These data support the hypothesis that the expanded white adipose tissue in obesity results in increased levels of adipose stromal cells, which are mobilized from the white adipose tissue by obesity-associated inflammation to contribute to tumor development.

4.4

Genetic Susceptibility

Genetic factors that predispose to obesity might also predispose to the development of pancreatic cancer. In a case–control study, we observed that two FTO (fat mass and obesity associated) gene variants and one adiponectin gene variant were differentially associated with the risk of pancreatic cancer by BMI level (Pinteraction = 0.0001, 0.0015, and 0.03, respectively). For example, the adjusted OR for the FTO IVS12777 AC/AA genotype was 0.72 (95% CI: 0.55–0.96) in participants with a BMI <25 kg/m2 but was 1.54 (95% CI: 1.14–2.09) in those with a BMI ³25 kg/m2 [109]. Recent genome-wide association studies have identified NR5A2 as one of the susceptibility genes for pancreatic cancer. A direct target of the pancreatic duodenal homeobox (PDX-1) gene during pancreatic differentiation and development [110], NR5A2 controls the expression of a number of developmental genes, such as those for the transcription factors hepatocyte nuclear factor-3b, -4a, and -1b. NR5A2 also regulates the metabolism of cholesterol and steroid hormones. Interestingly, the adiponectin gene promoter contains a NR5A2 response element, and NR5A2 plays an important role in transcriptional activation of the adiponectin gene [111]. NR5A2 gene variants have been associated with BMI in the Framingham Heart study [112]. Although the functional significance of the NR5A2 gene variants has not been elucidated, the dual associations of this gene with BMI and risk of pancreatic cancer suggest that these two diseases have a common mechanism. Intensive research on the biological significance of the NR5A2 gene in pancreatic cancer and on additional gene traits that modify the risk of obesity-related pancreatic cancer is under way.

5

Conclusion

Obese individuals are at increased risk of pancreatic cancer, which may contribute to poor prognosis and survival compared with persons of normal weight. The adipose tissue in obesity plays an important role in pancreatic carcinogenesis by regulating the synthesis and release of hormones, cytokines, and chemokines. These adipokines contribute to the state of insulin resistance and chronic inflammation, two major biological mechanisms that underlie obesity-related pancreatic cancer. The combined effect of fat accumulation and local inflammation in the pancreas may result in fibrosis and eventually the development of cancer. Although the incidence and prognosis of pancreatic cancer can be improved by reducing the prevalence of obesity in

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the population and by promoting energy balance through prevention and intervention, identifying the key biologic pathways in obesity-associated pancreatic cancer will offer an opportunity for developing novel therapeutic strategies.

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Chapter 7

Obesity, Insulin Resistance Pathway Factors, and Colon Cancer Li Li

Abstract Obesity, central adiposity in particular, is considered a “probable” cause for colon and many other cancers. Insulin resistance resulting from long-term energy imbalance is believed to be one of the key mechanisms underpinning the obesity–colon cancer link. This chapter synthesizes existing evidence that supports this hypothesis and discusses molecular pathways through which adipose tissue dysfunction in the state of obesity and insulin resistance may promote colon carcinogenesis. From a public health perspective, lifestyle and behavioral modification to maintain energy balance is clearly the most effective measure to reduce the burden of obesity and colon cancer. Elucidation of the molecular/genetic pathways underlying the connection between obesity-associated insulin resistance and colon cancer may lead to the identification of novel targets upon which interventions can be developed to disrupt the causal link between obesity and colon carcinogenesis.

1

Introduction

Obesity has reached epidemic proportion in most developed nations and shows no sign of abating. In the USA, it is estimated that approximately 34.1% of the adult population is overweight [25.0 kg/m2 £ body mass index (BMI) £ 29.9 kg/m2] and 32.2% is obese (BMI ³ 30.0 kg/m2), and there is a clear upward trend in the mean BMI across all states over the past two decades [1–3]. The rates of overweight and obesity are also rapidly rising in much of the developing world [4]. It has long been

L. Li, M.D., Ph.D. (*) Department of Family Medicine—Research Division, Case Western Reserve University, 11000 Cedar Avenue, Suite 402, Cleveland, OH 44106, USA e-mail: [email protected] S.D. Markowitz and N.A. Berger (eds.), Energy Balance and Gastrointestinal Cancer, Energy Balance and Cancer 4, DOI 10.1007/978-1-4614-2367-6_7, © Springer Science+Business Media, LLC 2012

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recognized that excess adiposity increases risks of cardiovascular disease and type 2 diabetes mellitus. A plethora of evidence accumulated in the past decade strongly suggests that obesity may also play an etiological role in a number of malignancies. Notably, the International Agency for Research on Cancer (IARC) expert panel concluded that sufficient evidence exists for a “probable” causal link between obesity and colon cancer, adenocarcinoma of esophagus, endometrial cancer, renal cell carcinoma, and postmenopausal breast cancer [5]. There is also increasing evidence for association of obesity with cancers of the pancreas, gallbladder, and hepatocellular carcinoma. Although the underlying pathophysiology of obesity-related carcinogenesis is still largely unclear, evidence accumulated to date suggests that several biological mechanisms and their complex interplay are likely to be involved, including insulin resistance and compensatory hyperinsulinemia, oxidative stress, inflammation, heightened production of insulin-like growth factors (IGFs), and increased bioavailability of sex steroids [6]. In colon carcinogenesis, evidence supporting the insulin resistance hypothesis is particularly strong [7]. Increasing data also suggest that adipose tissue dysfunction in obese persons also plays an important role in the development of systematic inflammation, insulin resistance, and colon cancer [8, 9]. This chapter synthesizes evidence supporting a central role of insulin resistance and adipose tissue dysfunction in colon tumorigenesis and discusses the key molecular/ genetic signaling pathways linking obesity-associated insulin resistance to colon neoplasia. Given the escalating obesity epidemic worldwide, it is a pressing public health priority to fully dissect these pathways to guide intervention strategies targeted at disrupting the obesity–colon carcinogenesis processes.

2

Energy Imbalance and Colon Cancer

Insulin resistance resulting from long-term energy imbalance and subsequently exaggerated insulin, growth factor, and adipokine responses and downstream signaling are believed to be at the core mediating the causative connection between obesity and colon carcinogenesis [6, 10–12]. The concept of insulin resistance is not restricted to changes in carbohydrate, lipid, or protein metabolisms, but encompasses other biological actions of insulin, growth factors, and adipokines in the state of chronic low-grade inflammation associated with being overweight and obesity, which affects growth, differentiation, DNA synthesis, and regulation of gene expression [10, 13, 14]. Altogether, these metabolic and cellular changes create an environment in which a number of risk factors accumulate and interact synergistically to drive the development of colon neoplasia. Figure 7.1 gives an overview of the obesity-associated insulin resistance/inflammation pathways in colon carcinogenesis.

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Energy Imbalance

Obesity

Insulin, IGFs Adipokines Oxidative stress

Insulin Resistance / Inflammation MAP Kinase Pathway

AMP Kinase Pathway

PI3K/AKT Pathway

PPARs NF-kB

Colon Carcinogenesis

Fig. 7.1 Overview: Obesity-associated insulin resistance/inflammation colon carcinogenesis pathway

2.1

Excess Energy Consumption

Excess energy consumption in relation to energy expenditure, typical of a Western lifestyle, is believed to drive the development of obesity and insulin resistance [15, 16]. Data accumulated from model systems have provided strong support for an important impact of excess energy intake on colon carcinogenesis [17, 18]. In feeding experiments, caloric restriction has been consistently documented across multiple animal models to reduce the risks of numerous tumor types, including colon neoplasia, and the number of advanced aberrant crypt foci (AFC) of the colon [18–21]. Conversely, animals with excess total energy intake were significantly more likely to develop colon tumors or preneoplastic lesions. The effects of energy restriction are often profound: a 30% restriction in energy intake can reduce mammary tumors as much as 80% [22]. In humans, energy restriction inhibits colonic proliferation in obese persons [23]. In epidemiologic studies, disentangling the effect of total energy intake and the specific caloric-producing macronutrient, such as fat or carbohydrate, is difficult because of the generally high intercorrelations among these nutrients. More importantly, under reporting bias of dietary intakes is known to be related to the degree of obesity, distorting the true relationship [24]. Nevertheless, total energy intake has been consistently associated with an increased risk of colon cancer even after adjustment for fat intake [22, 25, 26]. Particularly noteworthy, a recent large cohort study reported an inverse, albeit weak, association between energy restriction early in life and subsequent colon cancer risk for both men and women [27].

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Taken together, these data support the hypothesis that excess energy intake rather than fat intake per se may, at least partially, account for the difference in colon cancer risk observed in ecologic comparison across populations. This notion is further supported by feeding experiments showing that rats given carcinogens to induce mammary or colon cancer and fed high fat diets that were restricted in total energy were significantly less likely to develop tumors [28, 29].

2.2

Physical Inactivity

Physical activity is a key determinant of energy imbalance and insulin resistance. Excess energy intake can be compensated for by an increase in physical activity to maintain energy balance. Indeed, the relationship between physical activity and a reduced risk of colon cancer is among the most consistent findings in the epidemiologic literature [30–32]. Increased physical activity has also been associated with a reduced risk of colon adenoma, particularly large polyps [33–35]. In aggregate, studies suggest a dose–response relationship with risk reduction across a wide range of activity levels and intensities. An extensive review reported an up to 50% reduction in incidence of colon cancer among the most active individuals [36]. The consistency and strength of the evidence indicate that physical activity–colon cancer association is causal [37]. This is further supported by biological plausibility. Physical activity appears to result in preferential loss of visceral adipose tissue relative to subcutaneous adipose tissue [38, 39]. Moreover, independent of its effect on adiposity, physical activity directly increases insulin sensitivity and reduces plasma insulin levels [40–42]. Consistent with its profound effects on insulin resistance and its complex interplay with excess energy intake and obesity, physical activity has been shown in epidemiologic studies to modify the observed association of both energy intake and obesity with colon cancer risk [25, 32, 43, 44].

2.3

Obesity

In free-living populations, energy imbalance is best approximated by level of obesity and associated insulin resistance. Visceral adiposity is a particularly critical determinant of insulin resistance [45, 46]. A positive association between obesity and risk of colon cancer is compelling, especially in men. Although BMI, a surrogate measure of adiposity, has been widely used in epidemiological studies, it does not discriminate between fat and lean body (muscle and bone) mass and provides limited information about the distribution of fat [47]. The well-documented weaker association of BMI with risk of colon cancer in women as compared to that in men is believed in part due to different distribution of body fat between men and women for a given state of adiposity [48]. Studies have shown that adipose tissue in visceral regions (central obesity) confers greater risks of insulin resistance and metabolic

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and cardiovascular diseases than peripheral subcutaneous adipose tissue [49–51]. Thus, BMI may not accurately reflect visceral fat accumulation and colon carcinogenic processes associated with obesity, particularly in women. In supporting of this hypothesis, the European Prospective Investigation into Cancer and Nutrition (EPIC) study has recently shown that waist circumference or waist-to-hip ratio is associated with risk of colon cancer, equally strong in both men and women, whereas BMI is only associated with risk of colon cancer in men but not in women [52]. To date, very few studies have comprehensively examined the relationship between body fat distribution and risk of colon adenoma. Such information may provide new insight into obesity-associated colon carcinogenesis, allowing for risk stratification and intervention based on adiposity phenotypes to prevent colon neoplasia. A systematic review concluded that obesity contributed to as many as 11% of colon cancers [37]. Evidence from several recent meta-analyses further supported this observation [48, 53, 54]. Data from the largest cohort study to date also support that obesity is associated with increased risk of death from all major cancers, including colorectal cancer for both men and women [55]. It is estimated that current patterns of obesity in USA adults could account for up to 14.2% of all deaths from cancer in men and up to 19.8% in women. Conversely, corroborating data exist to suggest that intentional weight loss lowered colon cancer risk by 9% [56].

2.4

Adult Weight Gain

Weight gain during adulthood depends mostly on the accumulation of adipose tissue, and therefore changes in body size may better reflect fatness rather than adult attained weight itself, which is more dependent on lean mass [5]. A number of epidemiologic studies have demonstrated that adult weight gain is significantly associated with an increased risk of postmenopausal breast cancer in women not using hormonal replacement therapy (HRT) [57, 58]. Although how adult weight gain affects colon cancer risk has not been well explored, a few studies have shown an independent association of large body weight gain with increased risk of developing adenomatous polyps [34, 59, 60]. We have recently shown in a case–control study of 438 cases and 491 controls that adult weight gain since the age of 20 or 30 is associated with increased risks of colon cancer in a dose–response manner, particularly among women [61]. These results suggest that large adult weight gain may be an important and independent risk factor for colon cancer, particularly among women, possibly because weight gain as compared to BMI is a better indicator of intra-abdominal adiposity in women. These data emphasize the importance of considering changes in body size over time in assessment of colon cancer risk. More recently, two large studies showed that bariatric surgery for severe obesity led to sustained weight loss and a decrease in incidence and mortality from cancer [62, 63], providing important data supporting a potentially causal effect of obesity and cancer, including that of colorectum. However, proof of causality ultimately relies on confirming evidence from randomized controlled trials.

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Diabetes Mellitus

Colon cancer and type 2 diabetes mellitus share a remarkably similar risk profile, including obesity, physical inactivity, a Western diet characterized by high red meat and processed food intakes. This observation has led to the insulin–colon cancer hypothesis that insulin resistance with resultant metabolic perturbations may be the underling mechanism linking long-term energy imbalance and colon cancer. The insulin–colon cancer hypothesis has spawned a wealth of epidemiologic studies examining the association of type 2 diabetes and risk of colorectal cancer and adenoma, a well-established precursor lesion of colorectal cancer. Overall, studies support a statistically significant positive association independent of many of the known risk factors for colon cancer. A comprehensive meta-analysis of nine cohort and six case–control studies reported a combined risk estimate of 1.39 for colorectal cancer [95% confidence interval (CI) = 1.20–1.40] [64]. The association was remarkably consistent across diverse study populations and study designs. In the Nurses’ Health Study (NHS) with 18 years of follow-up, a history of diabetes was significantly positively associated with colorectal cancer (RR = 1.43, 95% CI = 1.10–1.87) [65]. The association was stronger for colon carcinomas than for rectum carcinomas and for fatal colorectal cancer (RR = 2.39, 95% CI = 1.46–3.92). Interestingly, the RR was reduced to nonsignificance among women with diabetes diagnosed over 15 years. As the authors argued, this could reflect progress of diabetes and depletion of b islet cell insulin reserve, resulting in relative hypoinsulinemia, hence diminished risk of colorectal cancer. This, in turn, could support that compensatory hyperinsulinemia to insulin resistance contributes to colon carcinogenesis. This notion is further supported by a large retrospective study of 24,918 patients with type 2 diabetes from the General Practice Research Database of the UK, showing that patients receiving insulin treatment had a hazard ratio (HR) of 2.1 (95% CI = 1.2–3.4) for developing colorectal cancer [66].

2.6

Metabolic Syndrome

The syndrome of insulin resistance, commonly known as the metabolic syndrome, is a concurrence of disturbed glucose and insulin metabolism, overweight and visceral adiposity, dyslipidemia, and hypertension. Although there is still debate as to whether the metabolic syndrome is a conglomerate of interdependent risk factors, or a distinct entity with a common denominator underlying its variable manifestations, the syndrome is widely accepted as an integral clinical entity by both the World Health Organization (WHO) and the American National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) [67, 68]. The third National Health and Nutrition Survey revealed that 22% of American adults had metabolic syndrome and the prevalence rose to approximately 44% among those over the age of 60 [69]. The metabolic syndrome is commonly believed to be driven by insulin resistance resulting from a Western lifestyle (high energy intake, physical inactivity

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and obesity) [15, 16, 70]. A recent critical review of the ATP III definition broadened the etiological basis of the syndrome to also include obesity-associated adipose tissue dysfunction [71]. Epidemiological studies of the major biochemical components [elevated triglycerides, hyperglycemia, and low high density lipoproteins (HDL)] of the metabolic syndrome overall support a significant association of each of these factors with risks of colorectal cancer or adenoma (reviewed by Giovannucci [7]). More recently, an increasing number of studies have examined the association of the metabolic syndrome as an integral entity with colon cancer or adenomas [72–78]. Although results from these studies are not entirely consistent, most studies are compatible with a positive association. Furthermore, the components of metabolic syndrome appear to have an additive effect on colon cancer development as the risk tends to increase with the number of the metabolic syndrome defining domains.

3

3.1

Biomarkers: Insulin Resistance, Insulin-Like Growth Factors, Adipokines and Inflammatory Cytokines Insulin Resistance

Insulin resistance is defined as impaired biological response to the action of insulin in insulin responsive tissues such as muscle, liver, and adipose tissue. It is characterized by compensatory hyperinsulinemia to maintain glucose homeostasis. Epidemiological studies examining the association of circulating levels of insulin with risk of colon cancer have yielded inconsistent results. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, smokers in the top quartiles of baseline insulin were at significantly increased risk colon cancer (HR = 1.84, 95% CI = 1.03–3.30) when compared with those in the lowest quartile of serum insulin [79]. In a nested case–control study from North Sweden, non-fasting insulin levels were associated with a slightly elevated risk of colon cancer, but were statistically nonsignificant (OR = 1.22, 95% CI = 0.64–2.31) comparing the highest to the lowest quartiles [80]. Measurement of circulating levels of insulin is highly influenced by state of fasting and assay characteristics, which may partly explain the inconsistency across studies of serum insulin levels and risk of colon cancer. C-peptide, which is cleaved from proinsulin and secreted in equimolar amounts as insulin into the circulatory system, has a relatively long half-life and may be a better biomarker for overall endogenous insulin exposure. Indeed, several cohort studies have examined the associations of C-peptide with risks of colon cancer and provide evidence for a consistent positive association. In the New York University Women’s Health Study, compared to those in the lowest quintile of C-peptide, women in the highest quintile had an approximately threefold increased risk of colorectal cancer (OR = 2.92, 95% CI = 1.26–6.75) and an almost fourfold increased risk of colon cancer alone (OR = 3.96, 95% CI = 1.49–10.50) [81].

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Similarly, in the Physicians’ Health Study, compared to men in the lowest quartile of plasma concentration of C-peptide, those in the highest quartile had an approximately threefold increased risk of colorectal cancer (RR = 2.7, 95% CI = 1.2–6.2) [82]. The same group also showed in the Nurses’ Health Study with 10 years of follow-up that C-peptide was positively, albeit weakly, associated with risk of colorectal cancer in women (RR = 1.76, 95% CI = 0.85–3.63) [83]. Interestingly, simultaneously adjustment for BMI or factors related to insulin resistance appeared to further strengthen the association of C-peptide and risk of colorectal cancer. More recently, the EPIC study shows that circulating levels of C-peptide are equally strongly associated with risk of colon cancer in men and women [84]. Insulin resistance commonly precedes hyperinsulinemia. The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was developed to quantitatively assess b-cell function and insulin resistance from basal glucose and insulin or C-peptide concentration [85]. Studies examining the association of HOMA-IR and risk of colorectal cancer or adenomas, however, have yielded inconsistent results [79, 86–89].

3.2

Insulin-Like Growth Factors

The IGF family consists of the peptide ligands (IGF-I and IGF-II), the IGF receptors (IGF-IR and IGF-IIR), the six IGF-binding proteins (IGFBPs), and the IGFBP proteases. The IGF system plays a critical role in regulation of cell growth, proliferation, transformation, and apoptosis. There is compelling evidence that the effects of insulin and growth hormone (GH) on metabolism and growth are at least partially mediated by the IGF system [90]. GH provides the key stimulus for synthesis of IGF-I and IGFBP-3, the most abundant binding proteins for IGF-I. Insulin, on the other hand, enhances the GH-stimulated synthesis of IGF-I and IGFBP-3 by increasing the levels of GH receptors [91]. In addition, insulin increases the bioactivity of IGF-I by inhibiting the synthesis of IGFBP-1 and IGFBP-2. IGF-I exerts potent mitogenic and anti-apoptotic effects on colonic epithelial cells and promotes their proliferation [90, 92]. IGF receptors are overexpressed in colon cancer cells. IGFBPs prevent IGF-I or IGF-II from binding to IGF receptors and activating the signal pathways for cell proliferation [93]. IGFBP-3 also independently induces apoptosis and inhibits cell growth, and mediates the growth inhibitory effects of transforming growth factor-b (TGF-b) [92]. The complex interactions among insulin, GH, IGFs, and IGFBPs determine the effects of the insulin–GH–IGF axis on colon carcinogenesis. Epidemiological studies of the relationship between IGF-I or IGF-I to IGFBP-3 molar ratio (a surrogate of the bioavailable free fraction of IGF-I) and risk of colorectal cancer are fairly consistent in showing a positive association [80, 81, 83, 94–96]. Meta-analyses showed that results regarding IGFBP-3 and IGFBP-1, however, are inconsistent [97, 98].

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Adipokines and Inflammatory Cytokines

Obesity, characterized by an excess accumulation of adipose tissue, is considered a state of chronic inflammation and oxidative stress [99, 100]. Adipose tissue is a highly active endocrine and metabolic organ, producing numerous adipokines and inflammatory cytokines that affect homeostasis, metabolism, and gene expression. Increased production of adipokines (such as leptin, resistin, visfatin, and ghrelin) and inflammatory cytokines (such as interleukin (IL)-6, IL-8, IL-10, and TNF-a), decreased production of adiponectin, and the diminished capacity of the adipose tissue to store excessive free fatty acids in the state of obesity are characteristic of adipose tissue dysfunction [9]. Obesity-associated adipose tissue dysfunction is believed to play a crucial role in the development of insulin resistance, systematic inflammation, and obesity-related chronic diseases, including colon neoplasia [9]. In contrast to other adipokines, levels of circulating adiponectin correlate negatively with obesity. Lower levels of adiponectin have been associated with increased waist circumference, insulin resistance, and increased risk of colorectal cancer in men [101–103]. In mouse models, adiponectin deficiency enhances colorectal carcinogenesis induced by azoxymethane [104]. Several studies have reported a positive association between leptin levels and risk of colon cancer and adenomas [105–108]. However, these associations appeared to be more consistent in men than in women [106, 108]. Data on the associations between resistin and visfatin levels and risk of colorectal cancer are emerging, albeit the sample sizes of these studies are relatively small [109–111]. Several studies have reported associations between high levels of TNF-a, IL-6, C-reactive proteins (CRP), and increased risk of colon cancer and adenomas [112–114]. A Greek study further demonstrated that serum levels of TNF-a, IL-6, and CRP are positively correlated with the size of colorectal tumors, suggesting that large tumors may trigger a more potent immunological response manifested by the circulation of proinflammatory cytokines [115].

4

Possible Mechanisms Linking Obesity, Insulin Resistance to Colon Cancer

Obesity-induced insulin resistance and inflammation, key features of adipose tissue dysfunction, are believed to be key mechanisms linking obesity to colon carcinogenesis. Insulin resistance may potentially cause colon cancer through at least three mechanisms [8, 10, 12, 116]. First, hyperinsulinemia leads to increased insulin exposure of colonocytes that are known to express insulin receptors. Upon binding to its receptor, insulin increases colonocyte proliferation and decreases apoptosis via the MAPK and PI3K pathways, respectively [117]. Thus, elevated insulin signaling

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in the colonocyte may lead to an enhanced proliferative state with tumorigenic consequences. Second, increased concentrations of available energy substrates such as glucose, triglycerides, and nonesterified fatty acids (NEFA) may provide increased energy for transformed colonocytes as well as induce changes in cell signaling pathways, such as activating the protein kinase-C and MAP Kinase pathways with potential mitogenic and carcinogenic effects, affecting the activity of PPARs which play key roles in lipid, glucose, and energy homeostasis and adipogenesis [118, 119]. PPARs have anti-proliferative, pro-apoptotic, and anti-inflammatory effects [120]. PPAR-g is expressed in colonocytes and inhibits the growth and increases the differentiation of colonic tumors, and plays a key role in insulin sensitization. Increased energy availability also stimulates reactive oxygen species synthesis, and increases oxidative stress, causing DNA damage [121, 122]. Furthermore, increases in cellular energy state, as reflected by a decrease in the AMP:ATP ratio, deactivate AMPK, an intracellular energy sensor and a cell growth checkpoint, which in turn activates the mTOR and MAPK pathways [123, 124]. Third, insulin resistance causes alterations in the IGF system, most notably, the reduction of IGFBPs, hence increasing of free fraction of IGF-I [90, 125]. Following activation of IGF binding to IGF receptors expressed on colonocytes, colonocyte apoptosis is inhibited and cell cycle progression ensues. Elevated levels of IGF may, therefore, provide a selective growth

Fig. 7.2 Obesity-associated insulin resistance signaling pathways: Obesity and adipose tissue dysfunction with insulin resistance and chronic low-grade inflammation lead to heightened insulin/ IGF, and adipokine signaling through IGF1R, IR, and adipokine receptors, deactivating AMP kinase and activating PI3K/AKT and MAP kinase signaling and downstream pathways. Increased adiposity may also inhibit PPARs, activating NF-kB, and JAK2/STAT3 pathways. Collectively, these perturbed pathways lead to increased colon carcinogenesis

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stimulus, causing clonal expansion of colon epithelial cells with abnormal growth regulation. In addition, obesity perturbs the bioavailability of endogenous sex hormones, inhibits hepatic sex binding protein synthesis leading to increased levels of circulating sex hormones. Alteration in sex hormone levels is believed to at least in part account for the gender difference in the relationship between body size and colon cancer [6]. Figure 7.2 summarizes the obesity-associated insulin resistance signaling pathways and their potential involvement in colon carcinogenesis.

5

Future Directions

5.1

Emerging New Risk Factors for Colon Cancer

5.1.1

Gut Microbiota

Emerging evidence suggests that the gut microbiota affects nutrient acquisition and energy regulation [126]. An adult’s gut microbiota is remarkably constant with two groups of beneficial bacteria, the Bacteroidetes and the Firmicutes, accounting for more than 90% of all phylotypes of bacteria, suggesting that host genetic background is important in determining the composition of the gut microbiota [127, 128]. A comparative 16S-rRNV-gene-sequence-based survey of the distal gut microbiomes of genetically obese (ob/ob) mice and their lean (ob/+ and +/+) littermates revealed that obesity is associated with changes in the relative abundance of the dominant divisions, with the Bacteroidetes 50% lower and the Fermicutes 50% higher in ob/ ob mice [129]. An elegant series of experiments showed that the composition of gut microbiota in mice affects the efficiency of dietary energy extraction [130, 131]. Normal mice have a 40% higher body fat than germ-free mice, and transplantation of the distal gut microbiota from the normal mice into germ-free mice resulted in a 60% increase in body fat without any increase in food consumption. The increase in body fat was accompanied by insulin resistance and increased levels of circulating leptin and glucose. Studies in humans show similar changes of relative abundance of Bacteroidetes and Fermicutes with weight loss. In a 1-year follow-up study of 12 obese subjects participating in a low-calorie diet weight-loss program, obese people were found to have fewer Bacteroidetes (p < 0.001) and more Fermicutes (p = 0.002) before dietary interventions than did lean controls. After weight loss via dietary intervention, the relative abundance of Bacteroidetes increased (p < 0.001) and that of Fermicutes decreased (p = 0.002). Moreover, the increased abundance of Bacteroidetes correlated with percentage of weight loss of body weight [129]. A recent study of APCmin mice provided direct evidence linking diet-induced changes in intestinal microbiota to the formation of intestinal polyps [132]. APCmin mice fed on a high olive oil-containing diet supplemented with a freeze-dried fruit and vegetables extract (OFV) had a reduced formation of intestinal adenomas which correlated to composition changes in the intestinal microbiota. Various mechanisms through which gut microbiota may

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promote colon carcinogenesis have been proposed [133, 134]. The recent development of powerful molecular microbiota analyses methods and the National Institutes of Health’s recent roadmap Human Microbiome Project (HMP) will greatly facilitate our understanding of the complex gut microbiota in the etiology of obesity and colon carcinogenesis.

5.1.2

Sleep Disturbance

Sufficient sleep on a daily basis is an important correlate of healthy living. Acute sleep deficits have been associated with negative health outcomes, such as impaired glucose tolerance, higher levels of evening cortisol and other endocrine factors, elevated markers of systemic inflammation, increased blood pressure, and daytime cognitive dysfunction [135–139]. Although less studied, long-term chronic sleep deficits have been associated with all causes of mortality, incident coronary heart disease, incident diabetes, and weight gain [140–144]. A recent systematic review revealed that short duration of sleep is monotonically associated with weight gain. Emerging evidence suggests that disruption in the circadian rhythm may also increase risks of several types of cancer. In particular, night shift work has been associated with increased risks of cancer in the breast, endometrium, prostate, and colorectum [145–149]. While published work suggests a link between circadian rhythm and tumorigenesis, the relationship of sleep quality and duration with colon neoplasia development has been understudied, and most studies reported thus far were limited to breast cancer or cancer survivors. We have recently shown that sleep disturbance may be a component of the metabolic syndrome, and we have further shown that short duration of sleep is associated with 50% increased risk of colorectal adenomas [150]. The exact mechanism through which short duration of sleep and sleep disturbance may promote colon carcinogenesis is largely unknown, investigation of the mechanistic link between short duration of sleep and colon carcinogenesis represents a new avenue that may lead to new strategies for the prevention of colon neoplasia.

5.2

Chemoprevention of Colon Cancer Targeting Insulin Resistance Pathways

Mounting evidence supports the hypothesis that insulin resistance resulting from long-term energy imbalance plays a critical role in the mechanistic link between obesity and development of colon neoplasia. From a public health perspective, lifestyle and behavioral modifications to maintain energy balance shall clearly be the focus in our effort to reduce obesity, metabolic syndrome, and the incidence of colon cancer. The insulin resistance–colon neoplasia hypothesis also suggests that targeted interventions that disrupt the obesity-associated insulin resistance signaling pathways may also be an effective approach to the prevention of this deadly disease.

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To this end, a number of recent epidemiologic studies have shown that metformin, an antidiabetic drug acting mainly through activation of the AMP kinase, which deactivates the downstream mTOR pathway, is associated with reduced risk of colorectal cancer among patients treated for diabetes [151–153]. Laboratory studies indicate that metformin suppresses tumorigenesis and cancer cell growth [154–156]. Furthermore, a small randomized trial from Japan recently showed that 1-month trial with low dose of metformin dramatically reduced rectal AFC [157]. A largescale randomized trial to assess the optimal dose and duration of metformin in the prevention of colon neoplasia is clearly warranted and represents a promising new avenue for the prevention of colon cancer. Acknowledgment Support for this work was derived in part from NIH Grants R01CA136726 and U54 CA116867

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Chapter 8

Ras/Raf and Their Influence in Glycolysis in Colon Cancer Fred Bunz and Nickolas Papadopoulos

Abstract Genetic alterations that cause the constitutive activation of Ras/Raf signaling are highly prevalent in colorectal cancers and contribute significantly to critical stages of tumor growth and invasion. While genetic analyses have firmly established the importance of this pathway in cancer, the many contributions of dysregulated Ras/Raf signaling to cancer cell phenotypes remain a topic of intensive investigation. This review will focus on recent insights into the role of Ras/Raf signaling on glucose uptake, and the consequences of altered glucose metabolism on the evolution of neoplastic cell clones. Tumor-promoting metabolic defects have suggested new strategies for anticancer therapy.

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Introduction

Normal epithelial tissues generate ATP primarily via oxidative phosphorylation, while tumor cells also activate glycolytic pathways and therefore metabolize increased amounts of glucose to lactate. First recognized in the 1920s by Otto Warburg, the increased glycolytic capacity that is acquired during tumorigenesis represents a fundamental difference between cancer cells and their normal neighbors [1, 2]. Glycolysis produces less energy per glucose molecule than does oxidative phosphorylation, but the ability of neoplastic clones to use an anaerobic pathway F. Bunz, M.D, Ph.D. Department of Radiation Oncology and Molecular Radiation Sciences, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA e-mail: [email protected] N. Papadopoulos, Ph.D. (*) The Ludwig Center for Cancer Genetics and Therapeutics, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA e-mail: [email protected] S.D. Markowitz and N.A. Berger (eds.), Energy Balance and Gastrointestinal Cancer, Energy Balance and Cancer 4, DOI 10.1007/978-1-4614-2367-6_8, © Springer Science+Business Media, LLC 2012

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renders them increasingly adaptable to alternative niches that may be poorly oxygenated. In the past several years, genetic and biochemical studies have provided new insights into how growth-regulatory intracellular pathways—recurrently altered during tumorigenesis—function to control the cellular uptake of glucose and to determine the rate of glucose metabolism. This chapter focuses on the Ras/Raf pathway, an evolutionarily conserved signal transduction mechanism that transmits proliferative signals from the cell surface to the nucleus. Genetic alterations that cause the constitutive activation of Ras/Raf signaling were among the first oncogenic mutations to be identified, and alterations of the Ras/Raf pathway are now known to contribute to a wide range of human cancers. Genetic alterations affecting the Ras/Raf pathway are present in approximately 50% of colorectal cancers [3]. Recently, this signaling pathway has been shown to increase glucose transport, thereby allowing cells to bypass a critical selective barrier to malignant growth [4]. This new insight adds to our understanding of the biochemical changes that occur during colorectal tumorigenesis, and also suggest potential new targets for therapeutic intervention.

2 The Ras/Raf Pathway The RAS gene family encodes small guanine nucleotide-binding proteins that are activated by growth signals from the cell surface, predominantly originating from receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR). Like other structurally related GTPases, Ras proteins bind GTP and catalyze its hydrolysis to GDP [5]. The cycle of GTP binding and hydrolysis by Ras proteins is tightly controlled by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs), respectively. In their GTP-bound form, Ras proteins trigger the activation of several downstream effectors that are important to cancer cell growth. Oncogenic mutations in RAS genes occur most frequently in codons 12, 13, and 61 [6]. These alterations affect a Ras domain that is required for the Ras–GAP interaction. Tumor cells harboring mutated forms of RAS, therefore, exhibit higher levels of GTP-bound Ras and correspondingly decreased hydrolysis of GDP. Ras oncoproteins exhibit resistance to GAPs and have impaired GTPase activity [7]. Thus, cancer cells harboring RAS oncogenes have constitutively active Ras signaling. GTP-bound Ras proteins positively regulate several downstream signaling pathways that control cell proliferation; survival and cell migration (Fig. 8.1). Upon activation by Ras, the serine/threonine kinases in the Raf family phosphorylate substrates in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK–ERK) pathway. Thus activated, ERK proteins phosphorylate cytosolic and nuclear substrates that increase transcription and promote cell cycle transitions. While the Raf–MEK–ERK pathway is the best characterized pathway downstream of Ras, activated Ras proteins also stimulate growth signaling via the phosphatidylinositol 3-kinase (PI3K) pathway. GTP-bound Ras directly binds the PI3K catalytic subunit. Ras binding causes translocation of PI3K to the plasma membrane and activation of downstream growth-stimulatory kinases, most prominently Akt.

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Fig. 8.1 The RAS–RAF pathway. The activation of the Ras pathway is initiated by a transmembrane receptor tyrosine kinase, such as EGFR. The membrane-associated Ras GTPase is promoted by the activities of guanine nucleotide exchange factors, such as GRB2/SOS. Once activated by bound GTP, Ras turns on the Raf–MEK–ERK pathway which activates genes that contribute to cancer cell phenotypes. Similarly, Ras promotes activation of oncogenic PI3K/AKT signaling, and other pathways that remain incompletely defined

3 Activation of Ras/Raf Signaling During Colorectal Tumorigenesis The majority of colorectal cancers harbor genetic alterations that cause constitutive Ras/Raf signaling. Of the three genes in the RAS family (KRAS, NRAS, HRAS), the KRAS gene is mutated in about one-half of invasive colorectal cancers; NRAS mutations are found less frequently [3]. RAS mutations occur relatively early in the process of colorectal tumorigenesis, prior to local invasion. A similar proportion of large adenomas (>1 cm) and invasive cancers harbor activated RAS oncogenes, implying that constitutive activation of Ras is important for the outgrowth of malignant cell clones. Raf kinase activity is also directly targeted by driver mutations. Mutations in the RAF kinase family member BRAF occur in about 10% of colorectal cancers, and arise at a similar stage of tumor development as RAS mutations [8]. The most frequent BRAF alteration is a missense mutation (V600E) that increases the basal kinase activity of the encoded protein approximately 500-fold [9]. The BRAF V600E mutation and a mutant RAS gene are never found together in the same tumor, suggesting that both mutations confer a similar selective advantage during tumorigenesis [10]. Interestingly, BRAF mutations occur disproportionately in tumors with deficient mismatch repair [8]. The frequency of genetic alterations that affect the Ras/Raf pathway and the timing of these alterations in developing colorectal neoplasia suggest that dysregulated

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Ras/Raf signaling is required at a critical transition point, at which point tumors acquire the ability to invade neighboring tissues. As large tumors grow beyond the normal confines of their tissue compartment and attendant vasculature, hypoxia, acidosis and hypoglycemia increasingly represent barriers to further growth and invasion. From an evolutionary perspective, constitutive Ras/Raf signaling must provide neoplastic clones with a selective advantage during this transitional interval. Presumably, the unique microenvironment of a large colorectal adenoma creates selective pressure that favors cells harboring oncogenic RAS or RAF genes. Studies in the past several years have begun to reveal how the activation of common oncogenes and frequent losses of tumor suppressor genes can provide selective advantages as tumors outgrow their blood supply. For example, the hypoxic conditions that are found in poorly vascularized cancers have been found to favor the selection of cells that have activated PIK3CA or CMYC oncogenes, or loss of the p53 tumor suppressor [11, 12].

4

Upregulation of GLUT1 in Cells with Constitutive Ras/Raf Signaling

Despite the detailed level of understanding of RAS biochemical interactions and the numerous paths that a RAS-mediated signal can presumably take, it is not yet clear how activated Ras/Raf signaling results in the selective growth of colorectal cancer cells. There is even less information about the precise microenvironmental conditions surrounding colorectal cancer cells that specifically favor the selection and expansion of cells with KRAS or BRAF mutations over those with wild-type KRAS and BRAF. As it is the case with other oncogene- and tumor suppressor gene-encoded proteins, RAS proteins have been implicated in the regulation of metabolism and energy balance in cancer cells. For example, transformation of rodent cells with HRAS can result in the upregulation of the facilitative glucose transporter encoded by GLUT1 (SLC2A) [13, 14]. However, this upregulation of GLUT-1 in rodent cells had also been ascribed to HIF1A and linked to hypoxia [15– 17]. The patterns and timing of KRAS and BRAF mutations during colorectal tumorigenesis indicate that they provide a redundant survival advantage to cancer cells growing in a microenvironment that would otherwise not be conducive to neoplastic growth. Important clues as to how constitutive Ras/Raf signaling confers this survival advantage have been obtained from rigorous studies of human somatic cell knockouts. In isogenic human colorectal cancer cell lines that differ only on the genetic status of KRAS or BRAF, GLUT1 was only one of the three genes consistently upregulated in all cell lines with either a KRAS or BRAF mutation, providing an unbiased link between Ras/Raf activation in colon cancer and increased glucose uptake. Isogenic cell lines with altered PIK3CA and HINF1A, derived from the same maternal cell lines, did not result in the consistent upregulation of GLUT1 under normoxic conditions, suggesting that this effect was highly specific for activated Ras/Raf [4] (Fig. 8.2).

Ras/Raf and Their Influence in Glycolysis in Colon Cancer

Low glucose microenvironment

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Fig. 8.2 Mutations in the KRAS–BRAF pathway in colon cancer promote cell survival by increasing glucose uptake. In the low glucose microenvironment of a developing colorectal neoplasm, mutant KRAS promotes activation of downstream Raf–MEK–ERK signaling, which increases the expression of the glucose transporter GLUT-1 (left panel). A similar upregulation of GLUT-1 occurs in cancers harboring a BRAF mutation (right panel), demonstrating the importance of downstream signaling pathways to the control of glucose transport

The growth of cell lines with either a KRAS or a BRAF mutation was equivalent to that of cells with wild-type KRAS/BRAF when all were maintained under numerous microenvironmental conditions, including hypoxia. There was one significant exception; under low glucose conditions, the cell lines with mutant KRAS or BRAF exhibited increased survival compared with the isogenic wild-type controls. Consistent with this phenotype and the upregulation of GLUT1, glucose uptake and lactate production was increased in the Ras/Raf activated cell lines, indicating an increase in glycolysis. When wild-type KRAS cell lines were forced to grow under glucose deprivation most cells died. However, clones resistant to low glucose environment emerged. These clones had GLUT1 upregulated and, a fraction of them, also had KRAS mutations in most cases different than the KRAS mutation of the maternal cell line. These results suggest that the microenvironment facilitates adaptation of the cells to the low glucose state by causing increased expression of GLUT1, and resultant uptake of glucose, through oncogenic mutations in the Ras/ Raf pathway. Furthermore, the adaptation of the colorectal cancer cells to anaerobic glycolysis apparently occurs independently of hypoxia. This finding runs contrary to previous models of clonal selection, in which hypoxia has been proposed to be the primary selective pressure that favors adaptation to glycolysis [18]. Indeed, as Warburg originally observed, cancer cells use glycolytic metabolism even in normoxic environments. For example, leukemic cells are highly glycolytic, yet they are present in an environment with high oxygen, the blood stream [19, 20]. Similarly,

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lung cancers growing in the airways are highly glycolytic, despite the presence of abundant oxygen [21]. Clinical data also provide support for the idea that limiting glucose provides a selective barrier during colorectal tumorigenesis. F-18-Fluoro-deoxyglucose (FDG)—positron emission tomography (PET) scans routinely used to scan cancers allow the visualization in tumors of increased glucose transporter expression and glucose uptake [22]. It is tantalizing that these abnormal FDG-signals are observed in pre-malignant colorectal neoplasms congruent with the stage during tumorigenesis in which KRAS or BRAF mutations appear [23, 24]. Not surprisingly, both KRAS mutations and increased FDG-PET signal are markers for poor prognosis in colon cancer [25, 26].

5

Clinical Implications

The link between KRAS or BRAF mutations and the upregulation of GLUT1 suggests that blocking either, glucose uptake and/or KRAS and BRAF signaling would be effective therapeutic approaches. In a proof of principle experiment, the growth of xenografts with KRAS or BRAF mutations was retarded by 3-bromo-pyruvate, an alkylation agent that blocks glycolysis [4]. This experiment provides new evidence that colorectal cancers with KRAS or BRAF mutations can be treated with agents that block glucose transport or interfere with glycolysis, but the development of such therapeutic agents has not been successful thus far. Unfortunately, the development of direct KRAS inhibitors has fallen short of expectations, too. The development of anticancer agents that target BRAF have been more promising. New strategies in medical chemistry, innovative approaches to drug design and greater selectivity for the mutated protein have contributed to the development of a new generation of BRAF inhibitors [27]. In vitro, PLX4032/RG7204 (Plexxicon/ Roche) selectively inhibits all three RAF kinases at nanomolar concentrations [27–29]. In preclinical studies, PLX4032 inhibits the MAP kinase pathway in cells with BRAF V600E mutations. However, in the cells with wild-type BRAF, including the cells with KRAS mutations, not only it does not block the downstream MAP pathway, it actually stimulates it [30–32]. In cells with KRAS mutations, and therefore increased Kras activity, RAF proteins form dimers; binding of the drug to one Raf molecule in the dimer thereby activates the other. In cells with BRAF mutations and low Kras activity, BRAF kinase is active, dimerization is not promoted and binding of the drug inhibits Braf activity. In clinical trials, metastatic melanomas harboring the BRAF V600E mutation showed remarkable PLX4032 sensitivity resulting in complete or partial regression in the vast majority of the patients [33]. This success has prompted optimism for the treatment of patients with colorectal cancers harboring BRAF mutations; additional trials are under way. As is the case in many targeted therapies, cancers can acquire resistance to PLX4032 treatment. Recently, it was shown that the mechanism of resistance involves Braf bypass and restoration of activity of MEK activation of the MAP

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kinase pathway downstream of BRAF [34, 35]. That the resistance mechanism to BRAF inhibitor involves the reactivation of the MAP kinase pathway underscores the ongoing dependence of cancer cells to this pathway, either because it still provides the necessary survival advantage or because the cells were “hard coded” during their selection to use this pathway even when it does not provide a selective advantage anymore. While the development of BRAF inhibitors provides hope for the patients with colorectal cancer that carry BRAF mutations, such drugs would unfortunately not be useful for patients that have KRAS mutations. This is not the only time that KRAS mutations have been a negative indicator for the administration of a targeted anticancer therapy. KRAS mutations also predict a lack of response in patients with colorectal cancer to EGFR inhibitors cetuximab and panitumumab, either as single agents or in combination with chemotherapy [36– 39]. For this reason, companion diagnostics for the detection of KRAS mutations have become a must for the stratification of colorectal patients for treatment with EGFR inhibitors.

6

Conclusion

Mutations that activate Ras/Raf signaling are pivotal for the development of colon cancer. They appear right at the cusp of the transition to more aggressive disease. KRAS is one of the most studied oncogenes. Nonetheless, our understanding of the signaling pathway has not been sufficient for the development of effective therapeutic interventions. Borrowing from the studies described in this chapter and through the use of appropriate experimental models, advances in pharmacology and genetics, new insights into the mechanisms by which these genes promote cancer will continue to emerge. The hope is that new opportunities for the development of therapies will emerge too.

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Chapter 9

Energy Balance and Other Modifiable Host Factors on Colorectal Cancer Prognosis Jeffrey Meyerhardt

Abstract Epidemiologic and scientific research indicates that host factors that influence energy balance have a significant influence on the risk of developing colorectal cancer. Obesity and certain diets increase one’s risk of developing colorectal cancer, while physical activity decreases this risk. Until recently, it was largely unknown if any of these modifiable factors influence the outcomes of patients already diagnosed with colorectal cancer. However, data are emerging of factors that may influence disease recurrences and mortality for colorectal cancer survivors. Prospective observational studies have shown that increased exercise after diagnosis and avoidance of a Western pattern diet are associated with reduced risk of cancer recurrence and improved overall survival in early stage colorectal cancer after standard therapy. Patients with class II and III obesity (BMI ³ 35 kg/m2) have a modestly increased risk of recurrence. In contrast, change of weight after diagnosis is not associated with outcomes after diagnosis. The data supporting these observations will be reviewed and potential mechanisms of actions will be discussed.

1

Colorectal Cancer Statistics

Colorectal cancer afflicts 1.2 million people globally each year and results in over 600,000 deaths [1]. The highest incidence rates of colorectal cancer are found in countries associated with unfavorable energy balance host factors, including obesity,

J. Meyerhardt, M.D., MPH. (*) Division of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Department of Medicine, Harvard Medical School, 450 Brookline Ave, Boston, MA 02215-5450, USA e-mail: [email protected] S.D. Markowitz and N.A. Berger (eds.), Energy Balance and Gastrointestinal Cancer, Energy Balance and Cancer 4, DOI 10.1007/978-1-4614-2367-6_9, © Springer Science+Business Media, LLC 2012

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lack of physical activity, and Western pattern diets. Rates of colorectal cancer are lowest in Africa and South-East Asia, regions with populations that maintain a more favorable energy balance profile. In the USA, an estimated 142,570 individuals will be diagnosed with colorectal cancer and 51,370 will die from the disease in the USA annually [2]. The incidence of colorectal cancer has decreased over the past several decades, despite growing adiposity rates in the USA. Screening and removal of precancerous precursors (adenomas) has been associated with this decline.

2

Colorectal Cancer Staging and Standard Treatments

Upon diagnosis of colorectal cancer, pathologic stage (including depth of invasion in the bowel, involvement of regional lymph nodes, and distant metastasis) is considered critical in determining relative prognosis and in deciding the modalities of therapy [3]. Surgery is the primary modality of management for colorectal cancer, and a “curative intent” resection occurs in 80–85% of patients with non-metastatic disease (stages I–III) [4]. For patients with metastatic (stage IV) cancer, 5-year survival is less than 5% [4]. In contrast, for patients with stage I cancer (no lymph nodes involved, tumor limited to the muscular layer of the bowel wall), 5-year overall survival exceeds 90%, similar to the survival for an otherwise healthy agematched population [3]. Stage I patients do not receive adjuvant therapy and the absolute benefit of any additional intervention will be minimal at best. For patients with stage II cancer (no lymph nodes involved, but extension of the tumor beyond the muscle layer), surgery alone conveys a 5-year survival of 80% [5]. The use of adjuvant therapy after surgery is controversial in stage II disease; an expert panel convened by the American Society of Clinical Oncology determined that the absolute benefit from chemotherapy would not exceed 5% [5]. In contrast, 35–40% of patients with stage III colon cancer (regional lymph nodes involved but no evidence of metastatic spread of disease) will develop cancer recurrence despite “curative” surgery and postoperative adjuvant chemotherapy [6]. Overall, 38% of colorectal cancer patients have stage III disease at diagnosis (~56,500 people in the USA annually). Although many patients with stage III disease may be cured with standard therapy, there remains a critical need to improve the outcome for these patients.

3

Risk Factors for Colorectal Cancer: Energy Balance

As with many cancers, the risk of developing colorectal cancer increases with age [7]. Colorectal cancer has been associated with various genetic syndromes, including adenomatous polyposis coli and hereditary nonpolyposis colorectal cancer syndrome, as well as nonsyndromic family history. In addition, colorectal cancer has been consistently associated with a variety of potentially modifiable host factors, including various energy balance factors.

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Prospective cohort studies support the relationship between adiposity and the risk of developing colon cancer [8–21]. In a report of over 360,000 men and women in Europe, higher body mass index (BMI), waist-to-hip ratio, and waist circumference were associated with increased rates of colon cancer; the estimated absolute risk of developing colon cancer within 5 years of follow-up was 203 and 131 cases per 100,000 men and 129 and 86 cases per 100,000 women in the highest and lowest quintiles of waist-to-hip ratio, respectively [22]. Physically active people have a reduced risk of developing colon cancer [11, 14, 16, 21, 23–29]. A meta-analysis of 52 observational studies found an inverse association between physical activity and colon cancer development, with an overall relative risk of 0.76 (95% confidence interval, 0.72–0.81) [30]. When physical activity and BMI are assessed jointly, the highest risk of colon cancer occurs among those both physically inactive and with high BMI levels [31, 32]. Epidemiologic and scientific research indicates that diet may have a significant influence on the risk of developing colon cancer. Consumption of red meat [17, 33–36], alcohol [37, 38], calcium [5, 13, 39–42], vitamin D [26, 29, 30, 43–45], vitamin E [1, 12, 46], and folic acid [38, 43, 47–49] are among factors that appear to influence the risk of developing the disease. Specific dietary patterns have been associated with the development of colorectal cancer in case–control and cohort studies [27, 50–54]. In two large prospective cohort studies, increasing consumption of a Western diet (characterized by higher intakes of red and processed meats, sweets and desserts, French fries, and refined grains) was associated with a significantly increased risk of colon cancer, whereas a prudent diet (higher intakes of fruits, vegetables, legumes, fish, poultry, and whole grains) was nonsignificantly associated with a reduced risk [27, 54]. Recent hypotheses have linked physical activity, obesity, dietary patterns, and adipose distribution to circulating insulin and free insulin-like growth factor-1 (IGF-1) [55–57], which accounts for the integrated actions of circulating IGF-1 and IGF binding proteins (BPs) [56]. In observational studies, colon cancer risk is elevated in individuals with higher circulating levels of insulin or C-peptide (a marker of insulin secretion) [58–60] and IGF-1 or IGF-1/IGFBP-3 ratio [61–65]. Preclinically, insulin stimulates pathways that increase levels of free IGF-1, and both insulin and IGF-1 promote cell proliferation and inhibit apoptosis in colon cancer cells [9, 66–69]. In the Physicians’ Health Study, obesity and physical inactivity influenced colon cancer risk primarily through the insulin axis, but non-hyperinsulinemic (and nonoverweight, physically active) men were still at elevated risk if they had high-IGF-1 levels. Thus, high circulating IGF-1 (or IGF-1/IGFBP-3 ratio) and hyperinsulinemia may represent two different axes that influence colorectal neoplasia risk [70].

4

Risk Factors Influencing Outcomes

Despite advances in therapy, patients and oncologists continually seek further ways to improve outcomes [71–73]. Patients will utilize complementary therapies, either with advice and support of their oncologist or without consultation with their oncologist.

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Until recently, there was a lack of data for such adjunctive therapies in patients with colorectal cancer. However, in the past decade, there are increasing data that certain modifiable factors related to physical activity, adiposity, and diet may impact on the outcomes of subpopulations of colorectal cancer patients [74–82]. The mechanism that are believed in part to underline how these host factors influence tumorigenesis may be influential in the progression and metastases of established disease.

5

Obesity and Colorectal Cancer Prognosis

Studies on the impact of adiposity on outcomes colorectal cancer have led to mixed results (Table 9.1) [24, 76, 79, 80, 87]. An early analysis by Tartter and colleagues reported a significant difference in recurrence-free rates by Quetelet’s index (defined in the study as weight × 100/height2) in female patients with stage II and III colon cancer but not male patients [88]. However, the study was performed prior to the standard initiation of adjuvant chemotherapy, and residual confounding by other known predictors of cancer recurrence could not be excluded in that analysis. After excluding underweight patients, Slattery and colleagues found that increasing baseline BMI was associated with a nonsignificant increase in overall mortality in a cohort of colorectal cancer patients identified through the Utah Cancer Registry [89]. However, that study was limited by the heterogeneous patient population and stage of disease, and an inability to adjust for cancer treatment and other potential clinical predictors of colorectal cancer outcome. In a large randomized trial of adjuvant chemotherapy for stage II and III colon cancer (INT 0089), obesity (BMI ³ 30 kg/m2) was associated a 24% nonstatistically significant worse disease-free survival compared with normal weight women (BMI 21–24.9 kg/m2) [76]. Among patients enrolled in two National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant chemotherapy trials for colon cancer, very obese patients (BMI ³ 35 kg/m2) experienced a 27% statistically significant increase in cancer recurrence or death compared with normal weight participants [24]. Both studies were limited by a single anthropometric data point at the time of initiation of adjuvant therapy. Using data from a randomized phase III study of adjuvant therapy in stage III colon cancer patients (CALGB 89803) in which BMI measurements were collected at the time of initiation of adjuvant therapy and approximately 6 months are the completion of adjuvant therapy (14 months after surgery), Meyerhardt and colleagues reported that patients with class II and III obesity (BMI > 35 mg/m2) had a nonsignificant 20% worse disease-free survival compared with normal weight patients [79]. Only one study has observed the influence of change in weight after diagnosis on cancer recurrences and survival [79]. In breast cancer survivors, gain in weight has been associated with increased risk of cancer in some [16, 90] but not all studies [14, 15]. Increasing weight after diagnosis (between time on adjuvant therapy and 6 months after completion of adjuvant therapy) was not associated with disease-free survival or overall survival in the CALGB 89803 cohort.

1976–1981

1988–1992

1990–1992

1989–1994

1999–2001

1981–2001

Slattery [49]

Meyerhardt [84]

Meyerhardt [85]

Dignam [24]

Meyerhardt [86]

Hines [68]

496

1053

4288

1792

3759

411

Sample size 279

TNM tumor, node, metastases staging, CI confidence interval

Year of diagnosis 1976–1979

Author Tartter [83]

TNM stage I–IV colon cancer

TNM stage III colon cancer

Duke B and C colon cancer

Duke B2, B3, C colon cancer TNM stage II and III rectal cancer

Stages of disease Duke B2, C1, C2 colon cancer All stages

Table 9.1 Summary of studies of body mass index in colorectal cancer survivors

Overall survival

Recurrence-free survival Overall survival

Disease-free survival

Colon cancer events

Disease-free survival Overall survival Disease-free survival Overall survival Local recurrences Disease-free survival

Overall survival

Outcome measure Recurrence rate

p > 0.05 for trend with increasing BMI quintile 1.11 (0.94–1.30) BMI ³ 30 kg/m2 1.11 (0.96–1.29) BMI ³ 30 kg/m 1.10 (0.91–1.32) BMI ³ 30 kg/m2 1.09 (0.90–1.33) BMI ³ 30 kg/m2 1.31 (0.91–1.88) BMI ³ 30 kg/m2 1.06 (0.93–1.21) BMI 30–34.9 kg/m2 1.27 (1.05–1.53) BMI ³ 35 kg/m2 1.04 (0.88–1.24) BMI 30–34.9 kg/m2 1.38 (1.10–1.73) BMI ³ 35 kg/m2 1.00 (0.72–1.40) BMI 30–34.9 kg/m2 1.24 (0.84–1.83) BMI ³ 35 kg/m2 0.97 (0.69–1.37) BMI 30–34.9 kg/m2 1.27 (0.85–1.89) BMI ³ 35 kg/m2 0.90 (0.61–1.34) BMI 30–34.9 kg/m2 0.87 (0.54–1.42) BMI ³ 35 kg/m2 0.77 (0.61–0.97) BMI ³ 25 all stages 0.92 (0.65–1.30) stage I and II 0.92 (0.59–1.45) stage III 0.58 (0.37–0.90) stage IV

Hazard ratio (95% CI) or p value (compared to normal weight) p = 0.003 for above median weight

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Obesity can lead to additional complications in patients with rectal cancer. Obesity has been associated with increased perioperative complications, including anastomotic leakage and blood transfusion requirements from rectal cancer [6, 91]. Using data from a large, adjuvant chemoradiotherapy trial of patients with stage II and stage III rectal cancer (INT 0114), Meyerhardt and colleagues reported that a higher baseline BMI was associated with an increased rate of abdominoperineal resections and, consequently, permanent colostomy [80]. In a study from a specialty cancer center, operative time was longer in obese than nonobese patients (4.3 h vs. 3.7 h, p < 0.01) and length of stay was longer in obese than nonobese patients (8 days vs. 7 days, p < 0.01) [18]. Obesity was also predictive of an increased risk of local recurrence among male, though not female, patients. The influence of adiposity in patients with metastatic colorectal cancer is largely unknown. In one study of 120 patients with metastatic colorectal cancer who received combination chemotherapy, higher BMI and higher visceral fat adiposity (VFA) was associated with shorter time to progression to second-line therapy and higher VFA was associated with shorter survival [44].

6

Physical Activity and Colorectal Cancer Prognosis

Observational studies have shown that higher physical activity levels and/or meeting physical activity guidelines is associated with better patient-reported quality of life, physical functioning, and fatigue [10, 21, 22, 92–94]. Only one randomized trial has investigated the effects of an exercise intervention in colorectal cancer survivors [23]. Conclusions from the study are limited due to greater than anticipated contamination in the comparison group that undermined the intention-to-treat analyses. In a secondary analysis, participants whose fitness increased over the course of the intervention, regardless of group assignment, reported significantly improved quality of life, physical functioning, and psychosocial distress compared with participants whose fitness decreased. Data are emerging for the potential influence of exercise in colorectal cancer survivors with stage I to III disease. Haydon and colleagues identified 526 colorectal cancer survivors from a prospective observational cohort of 41,528 Australians who completed pre-diagnosis questionnaires, including assessment of physical activity [45]. Increased exercise was associated with improved disease-specific survival [adjusted hazard ratio (HR) = 0.73; 95% CI: 0.54–1.00]. In subgroup analyses, the association seemed restricted to stage II and III tumors (HR = 0.49; 95% CI: 0.30– 0.79). In efforts to correlate these findings with molecular markers, the investigators reported that physically active colorectal cancer survivors had higher insulin-like growth factor binding protein-3 (IGFBP-3), which was associated with a significant reduction in disease-specific death (HR = 0.52; 95% CI: 0.33–0.83) [45]. These data suggest that the association between physical activity and disease-specific survival in colorectal cancer survivors may be through the IGF axis particularly IGFBP-3. Three studies have examined the association between post-diagnosis physical activity and disease outcomes in colorectal cancer survivors (Table 9.2) [77, 95, 96].

0.01

0.002

0.01

CALGB Cancer and Leukemia Group B, HR hazard ratio, CRC colorectal cancer

0.0003

Referent 1.00 (0.68–1.48) 1.12 (0.74–1.70) 0.74 (0.46–1.20) 0.59 (0.41–0.86)

P trend

Referent 0.77 (0.48–1.23) 0.50 (0.28–0.90) 0.43 (0.25–0.74) for >18 MET-hours/ week 0.003

Referent 1.06 (0.55–2.08) 1.30 (0.65–2.59) 0.76 (0.33–1.77) 0.47 (0.24–0.92)

Referent 0.92 (0.50–1.69) 0.57 (0.27–1.20) 0.39 (0.18–0.82) for >18 MET-hours/ week 0.008

Referent 0.87 (0.58–1.29) 0.90 (0.57–1.40) 0.51 (0.26–0.97) 0.55 (0.33–0.91)

<3 3–8.9 9–17.9 18–26.9 ³27

Referent 0.85 (0.49–1.49) 0.71 (0.36–1.41) 0.71 (0.32–1.59) 0.37 (0.16–0.82)

Health Professionals Follow-up Study Adjusted HR for Adjusted HR for CRC-specific mortality overall mortality (95% CI) (95% CI)

Table 9.2 Association between physical activity and outcome in colorectal cancer survivors CALGB 89803 Nurse’s Health Study Adjusted HR Adjusted HR for Adjusted HR for MET-hours/ disease-free survival Adjusted HR overall CRC-specific overall mortality week (95% CI) survival (95% CI) mortality (95% CI) (95% CI)

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A prospective, observational study of 832 patients who participated in an adjuvant study comparing 5-fluorouracil (5-FU) and leucovorin to irinotecan, 5-FU and leucovorin (IFL) for stage III colon cancer (CALGB 89803) found that higher levels of self-reported physical activity [at least 18 metabolic equivalent task (MET)-hours/ week] approximately 6 months after completion of chemotherapy were associated with superior disease-free, recurrence-free, and overall survival, adjusted for known prognostic factors, including BMI [96]. For reference, 3 MET-hours is equivalent to 1 h average pace walking. In a second study, a cohort of 573 women diagnosed with stages I–III colorectal cancer who participate in the Nurses’ Health Study and self-reported leisure-time physical activity before diagnosis and 1–4 years after diagnosis was utilized to test the association between exercise before diagnosis and after diagnosis and survival outcomes [77]. Women who were most physically active experienced 61% reduced colorectal cancer-specific mortality and 57% reduced overall mortality compared to inactive women, adjusted for other prognostic factors. Level of physical activity prior to diagnosis was not associated with mortality. Similarly, a cohort male colorectal cancer survivors from the Health Professionals Follow-up Study also demonstrated an association between physical activity and survival [95]. Among 668 men with stage I–III colorectal cancer, more than 27 MET-hours/week of exercise had an adjusted HR for colorectal cancer-specific mortality of 0.47 (95% CI: 0.24– 0.92) compared with men who engaged in 3 or less MET-hours/week. Based on these data, the Colon Health and Life-Long Exercise Change (CHALLENGE) trial was developed as a multinational collaboration between Canada and Australia to determine the effects of a 3-year structured physical activity intervention on disease outcomes in 962 high-risk stage II and III colon cancer survivors who have completed adjuvant chemotherapy within the previous 2–6 months [20]. Within 2 and 6 months after completion of all standard treatments, patients will be randomized to intensive physical activity intervention or control arm with general health education materials only. The intervention will include behavior support sessions and supervised physical activity sessions. Within the first 6 months, the goal will be to gradually increase recreational physical activity by 10 MET-hours weekly over baseline. Over the next 6 months, the investigators aim to have participants reach 20–27 total MET-hours weekly and during year 2 and 3, up to 27 total MET-hours weekly. The primary endpoint is disease-free survival and secondary endpoints include patient-reported outcomes, health-related fitness, biologic correlative markers, and an economic analysis. The trial opened to accrual in 2010 with the goal of accruing all patients within 3 years of trial activation and an additional 4.7 years of follow-up from enrollment of the last patient.

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Diet and Colon Cancer Outcomes

Diet has been extensively studied as a risk factor for the development of colorectal cancer [11, 63, 97–99]. In contrast, few studies have examined the association between diet and outcomes in colorectal cancer survivors [25, 78, 89]. Slattery and colleagues

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4.5 Western Pattern Diet 4

Prudent Pattern Diet

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Quintile Fig. 9.1 Dietary patterns and disease-free survival in stage III colon cancer patients

studied 411 colon cancer patients from two population-based case–control studies and observed an improved survival with increasing consumption of calories, fat, and protein [89]. Among 148 patients with colorectal cancer, Dray et al. reported improved survival with increasing consumption of calories based on dietary information prior to diagnosis [25]. These two studies were limited by their heterogeneous patient population that included all stages of disease, small sample size, lack of data on cancer treatment, and limited capacity to adjust for other prognostic factors. To address these concerns, a prospective observational study on diet in 1,009 colon cancer survivors from CALGB 89803 was reported in which participants completed a food frequency questionnaire during adjuvant therapy and 6 months after the completion of adjuvant therapy [78]. Using factor analysis, two major dietary patterns were identified: prudent and Western patterns. The prudent pattern was characterized by high fruit and vegetable, poultry and fish intakes; the Western pattern was characterized by high meat, fat, refined grains, and dessert intakes. All patients were assigned a relative value along the spectrum of both dietary patterns. The two patterns were not correlated with each other (Spearman correlation coefficient = 0.02). Western pattern diet was associated with disease-free and overall survival (Fig. 9.1). When compared with patients in the lowest quintile of Western pattern diet, those in the highest quintile experienced worse disease-free survival, with an adjusted HR of 3.25 (95% CI: 2.04–5.19; p for trend <0.0001). In that patient cohort, patients in the highest quintile of Western pattern diet

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consumed a mean intake of 6 servings of red meat per week, 5.6 servings of processed meat per week, 5.8 servings of refined grains daily, and 2.5 servings of sugary desserts daily [100]. In comparison, those in the lowest quintile of Western pattern diet reported a mean intake of 2.3 servings of red meat and 1.8 servings of processed meats per week and 2.0 servings of refined grains and less than 1 serving of sugary desserts daily. Degree of prudent pattern diet was not significantly associated to cancer recurrence or mortality (Fig. 9.1). Since these patterns are mutually exclusive, the data would suggest an avoidance or reduction of foods associated with a Western pattern diet but not necessarily an increase in foods associated with the prudent pattern diet.

8

Potential Mechanisms of Energy Balance Factors and Outcomes in Colorectal Cancer Survivors

Physical activity, adiposity, and diet influence energy balance within individuals. Molecular pathways associated with alterations in energy balance are a leading potential mechanism for the association between these host factors and outcomes in colorectal cancer survivors. Shifts in energy balance may lead to changes in insulin and IGFs levels as well as sensitivity to insulin [55–57]. In observational studies, colon cancer risk is elevated in individuals with higher circulating levels of insulin or C-peptide (a marker of insulin secretion) [58–60] and IGF-1 or IGF-1/IGFBP-3 ratio [61, 62, 85, 101, 102]. Preclinically, insulin stimulates pathways that increase levels of free IGF-1, and both insulin and IGF-1 promote cell proliferation and inhibit apoptosis in colon cancer cells [9, 41, 76, 77, 100]. In one study, obesity and physical inactivity influenced colon cancer risk primarily through the insulin axis, but non-hyperinsulinemic (i.e., non-overweight and physically active) men were still at elevated risk if they had high IGF-1 levels, suggesting that high circulating IGF-1 (or IGF-1/IGFBP-3 ratio) and hyperinsulinemia may represent two different axes that influence colorectal neoplasia risk [70]. The presumed cause of disease recurrence and colorectal cancer-specific mortality in patients initially diagnosed with non-metastatic colorectal cancer is the growth of micrometastatic cells in distant organs. Physical activity, obesity, and a Western pattern diet may influence insulin and IGFs, which subsequently stimulate growth and inhibit apotosis of micrometastases. Among 373 patients diagnosed with nonmetastatic colorectal cancer in two prospective observational cohort studies, those in the top quartile of plasma C-peptide had an age-adjusted HR for death of 1.87 (95% CI: 1.04–3.36; p = 0.03 for trend), whereas those in the top quartile of circulating IGFBP-1 had a significant reduction in mortality (HR = 0.48; 95% CI: 0.28– 0.84; p = 0.02 for trend), both compared to patients in respective bottom quartiles. Other potential mechanisms for the influence of physical activity, adiposity, and diet are alterations in vitamin D (as these host factors influence vitamin D levels), changes in hormones (particularly estrogen), inflammation, and immune modulation.

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Conclusions

To date, studies in colorectal cancer on energy balance as a host factor in tumor progression are primarily limited to preclinical and observational studies in nonmetastatic disease. There are very few data addressing these host factors with metastatic disease. Patients with metastatic disease also seek adjunctive treatments to their care and frequently engage in integrative treatments. It is imperative to address the role of alterations in energy balance in the metastatic population as well. While efforts are made to account for reverse causality, biases, and residual confounding, in the previously reported observational studies, ultimately randomized controlled trials are needed to provide definitive evidence on the causal effects of energy balance on disease outcomes in these patient populations. A limited number of these studies are developing and hopefully others will achieve funding and reach their accrual goal to further define the role of energetics in colorectal cancer. Nonetheless, colorectal cancer is typically diagnosed in older individuals where cardiovascular disease, type II diabetes, and hypertension are common comorbidities. Maintaining a healthy body weight, exercising and controlling obesity-related metabolic risk factors may reduce not only cancer-specific mortality but also total mortality in cancer survivors.

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Chapter 10

Cyclooxygenase-2 and Chronic Inflammation: Drivers of Colorectal Tumorigenesis Monica M. Bertagnolli

Abstract A common feature of the relationship between abnormal energy balance, altered hormonal regulation, and cancer is the presence of increased inflammation. In individuals with obesity-associated metabolic disorder, an increased inflammatory response can be identified on both systemic and tissue-specific levels. This chapter details the relationship between cyclooxygenase-2 (COX-2), a key mediator of local inflammatory response, and the development of colorectal cancer. It also describes the modulation of COX-2 activity as a means of preventing and treating colorectal tumors. Finally, this chapter addresses new data concerning the role of COX-2 activity in obesity and metabolic syndrome.

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Historical Perspective

Our understanding of the nature of the mucosal inflammatory response began in the 1970s with the recognition by many researchers that prostaglandins and leukotrienes modulated the activity of resident mucosal immune effector cells, such as macrophages, T cells, NK cells, and dendritic cells. In cell culture, glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibited the activation of immune cells in response to phorbol esters or mitogens. Administration of glucocorticoids and NSAIDs in vivo was effective for the treatment of arthritis because it dramatically attenuated the tissue inflammatory response, and it was generally held that the inhibition of hematopoietic immune effector cell activity was responsible for this

M.M. Bertagnolli, M.D. (*) Division of Surgical Oncology, Dana Farber Cancer Institute, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA e-mail: [email protected] S.D. Markowitz and N.A. Berger (eds.), Energy Balance and Gastrointestinal Cancer, Energy Balance and Cancer 4, DOI 10.1007/978-1-4614-2367-6_10, © Springer Science+Business Media, LLC 2012

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activity. Over the next four decades, it became clear that inflammation at a tissue level involved a network of reactions that altered proliferation, apoptosis, differentiation, and migration of both epithelial cells and stromal tissue components. Inflammatory cells of hematopoietic origin were recognized as only one component of this process. By focusing upon arachidonic acid metabolism as a central feature of inflammation, researchers uncovered a signaling network that coordinated the processes of wound healing and inflammation throughout the cellular constituents of complex tissues. In doing so, links between mucosal inflammation and tumorigenesis were also established. The first solid clinical data linking inflammation to the modulation of human colorectal neoplasia was reported in 1983 by a gastrointestinal surgeon, William Waddell [1]. Dr. Waddell was treating a female patient with familial adenomatous polyposis (FAP) who was suffering from a large desmoid tumor of the mesentery. These mesenchymal tumors, which are now known to be myofibroblastic in origin, demonstrate many histological features of a chronic inflammatory response. Predicting that an inflammatory response was promoting the growth of the patient’s desmoid, Dr. Waddell administered the nonspecific NSAID, sulindac. Consistent with the phenotype of FAP, this patient also had numerous adenomas of the rectum. The sulindac treatment did not significantly affect the patient’s desmoid tumor; however, the drug induced a near total regression of her rectal adenomas. Dr. Waddell then administered sulindac to two of the patient’s affected family members, with the same effect upon the rectal disease (W. Waddell, 2001, personal communication). Since that time, prospective randomized trials confirmed that NSAIDs induce regression of established adenomas in patients with FAP [2–7]. In addition, both observational data and clinical trials showed that NSAIDs prevent the development of sporadic colorectal adenomas and colorectal cancer in patients at risk for this disease [8–19]. Finally, emerging preclinical and clinical data suggested that NSAIDs may demonstrate antitumor activity in patients with established colorectal cancer [20–22].

2 The Inflammatory Response in Gastrointestinal Tissue The inflammatory response is a reactive program that is essential for survival, and as such, the ability to mount an inflammatory response is present in every tissue of the body. In response to injury or infection, a cascade of biochemical events is initiated, beginning with arachidonic acid, a central component of the cell membrane. Upon initiation of an inflammatory response, arachidonic acid is liberated from the cell membrane and metabolized through a series of reactions that produce inflammatory effector molecules known as eicosanoids. Eicosanoids are “rapid response” effector molecules that trigger and promote a diverse range of processes, including fever, pain, activation of immune inflammatory cells, vasoconstriction, vasodilatation, renin release by the kidney, and platelet activation [23]. The prefix, eicosa(from the Greek for 20) denotes the number of carbon atoms in arachidonic acid.

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Fig. 10.1 Arachidonic acid metabolism in the colorectal mucosa

The reactions generated by eicosanoids are context specific, a property conveyed by the presence of tissue-specific enzymes and receptors. As a result, the exact nature of the inflammatory response and the type of eicosanoids produced varies among different organs, epithelial tissues, and cells. In this way, the nature of an inflammatory response is specifically tailored to the type of injury or infection that is commonly encountered by an individual tissue type. Epithelial tissues, such as that lining the gastrointestinal tract, are particularly dependent upon the presence of a properly regulated inflammatory response. These tissues are prone to injury and, therefore, must be able to heal wounds rapidly. In the upper gastrointestinal tract, the mucosa is in regular contact with caustic substances such as gastric acids and pancreatic enzymes. As a result, this mucosa requires the continual presence of cytoprotective mechanisms, produced via activity of eicosanoids, to protect against injury. In addition, epithelial tissues must form a barrier against the microbe-rich outside environment. The inflammatory response of the gastrointestinal tract must, therefore, both suppress inflammation in the presence of commensal bacteria and recognize and react to trauma and pathogenic organisms [24]. A diagram of the arachidonic acid metabolism cascade in the intestinal mucosa is presented in Fig. 10.1. The primary product of arachidonic acid in the colorectal epithelium is prostaglandin-E2 (PGE2). This prostanoid is produced through the activity of rate-limiting cyclooxygenase enzymes, which catalyze the reaction of arachidonate to a short-lived intermediate, PGH2, followed by conversion via a tissue-specific isomerase to PGE2. PGE2 produces its signaling effects by binding to a family of four PGE2-specific G-protein-linked receptors. These receptors are present on a number of different constituents of the colorectal mucosa, including epithelial cells, stromal fibroblasts, stromal endothelial cells, and inflammatory cells of hematopoietic origin. Like all eicosanoids, PGE2 is an autocoid, meaning that it activates membrane receptors that are very close to its site of formation. PGE2 is rapidly produced upon activation of arachidonic acid metabolism by cytokines, growth factors, viruses, bacterial lipopolysaccharides, or other cellular stressors. It is also rapidly eliminated through activity of a tissue-specific degradation enzyme, 15-prostaglandin dehydrogenase (15-PGDH). In this manner, the gastrointestinal tissue can efficiently produce a tissue-localized response to an insult, but it can

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also promptly eliminate the driver of the inflammatory response once the activating stimuli are removed. This important feature of all eicosanoids is essential for preventing excessive collateral tissue damage. Chronic inflammatory diseases of the intestine, such as inflammatory bowel disease or colorectal cancer, are characterized by failure to properly limit the activity of acute inflammatory mediators, particularly PGE2. This condition can occur as a result of increased inflammatory eicosanoid production, or possibly by reduced availability of degradation enzymes such as 15-PGDH. The G-protein-coupled receptors responsive to PGE2 include four subtypes, designated as EP1 to EP4 [25]. The four EP receptors are defined by linkage to different Ga subunits. EP1 regulates Ca2+ channel gating, and its activation raises the intracellular levels of inositol 1,4,5-triphosphate and activated protein kinase C (PKC). EP1 signaling plays a prominent role in the sensation of pain resulting from inflammation and trauma. EP2 and EP4 are predominantly coupled to Gs and mediate increases in cAMP concentrations. EP3 is linked to Gi and G12, and its major signaling effect is inhibition of adenylate cyclase. Highly complex mechanisms link specific EP receptor activation to the cellular response to PGE2. For example, although their dominant connections are described above, the EP receptors can couple to more than one G protein and signal transduction pathway. Within tissues, each EP receptor subtype shows a distinct cellular location and expression level, providing yet another level at which responses to inflammation yield signaling that is context- and tissue-specific.

3

Chronic Inflammation, COX-2 and Colorectal Neoplasia

Studies conducted in the 1980s found that epithelial tumors contained increased levels of PGE2 compared to normal adjacent tissues [26, 27]. A crucial mechanistic link between the inflammatory response and tumor formation was identified in the early 1990s, when researchers discovered a cyclooxygenase-related gene product that was induced in response to pro-inflammatory agents. This gene was inhibited by glucocorticoids, suggesting that it was also modulated by metabolic factors regulating the inflammatory response [28, 29]. This discovery revealed that the cyclooxygenase enzyme exists in two forms, COX-1 and COX-2. The cyclooxygenase isoforms share similar activities and substrate, but have distinct tissue expression patterns [30, 31]. COX-1 is constitutively expressed in the gastrointestinal mucosa, kidney, vascular endothelium, and platelets. This isoform is responsible for maintenance of tissue homeostasis, including protection of the upper gastrointestinal mucosa against injury. In contrast, COX-2 is constitutively expressed in a narrow range of tissues, and its dominant nature is that of a short-lived, inducible enzyme rapidly upregulated in response to cellular stressors. Under non-stimulated conditions, COX-2 is present in small amounts in stromal cells of normal gastrointestinal mucosa; however, it is quickly induced in response to growth factors, cytokines and cellular mitogens [32, 33]. In virtually all states of chronic inflammation, such as rheumatoid arthritis, inflammatory bowel disease, and tumorigenesis, COX-2 protein is present at increased levels compared with normal tissues.

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Fig. 10.2 Activated fibroblast and inflammatory response mediators

The cell of origin for COX-2 protein varies in complex tissues, and tissue expression depends upon the particular state of inflammatory response. Acute inflammation is characterized by COX-2 production from resident tissue inflammatory cells of hematopoietic origin, particularly tissue macrophages [34]. Under conditions of chronic inflammation, COX-2 expression is greatly upregulated in stromal fibroblasts. Recent evidence suggests that activated stromal cells expressing COX-2 originate from bone marrow precursors. For example, upon initiation of a tissue inflammatory response, fibrocytes migrate from the bone marrow to sites of inflammation, where they differentiate into activated myofibroblasts. These cells are a source of many components of the tissue inflammatory response, including COX-2, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), matrix metalloproteinases, and extracellular matrix (ECM) proteins (Fig. 10.2). Driven by chronic PGE2 activity, activated myofibroblasts are the source of tissue fibrosis and drivers of angiogenesis found in chronic inflammatory conditions [35]. COX-2 protein overexpression and the resulting increases in PGE2 can be found across the spectrum of carcinogenesis, from early neoplasia to metastatic disease. Human tissue studies document from 2- to 50-fold increases in COX-2 mRNA and protein levels in ~40% of colorectal adenomas and 80–90% of colorectal cancers [36]. In tumors, COX-2 protein is most often observed in the tumor-associated stroma, specifically the stromal myofibroblasts, but can also be found in epithelial tumor cells. The mechanism by which epithelial cells acquire the ability to express COX-2 is unclear; however, this feature suggests evolution of a tumor cell into one capable of driving inflammation in a stromaindependent fashion. This feature may indicate increased tumor aggressiveness, a conclusion supported by data showing that the presence of COX-2 overexpression in colorectal tumor cells indicates a poor disease prognosis [37–39]. A direct relationship between COX-2 expression and intestinal neoplasia was provided by targeted deletion of the murine COX-2 gene (Ptgs2) in mice with intestinal adenomas as a result of germ-line truncation of the Apc gene (ApcD716) [40]. The ApcD716 mice typically develop hundreds of microadenomas and numerous

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Fig. 10.3 COX-2 promoter

macroscopic tumors of the small intestine. Loss of COX-2 produced a striking decrease in the size and number of adenomatous polyps present in the intestine of ApcD716 mice, with 68% fewer adenomas in ApcD716 Ptgs2+/− animals and 86% fewer adenomas in ApcD716 Ptgs2−/− mice. This effect was reproduced by dietary administration of a selective inhibitor of COX-2 to ApcD716 animals [40]. The structure of the COX-2 gene promoter illustrates the highly responsive nature of its expression, and its role in regulating cellular activation in response to tissue injury or infection. COX-2 gene expression is driven by a wide variety of inflammatory mediators and tumor promoters, including the cytokines transforming growth factor-b1 (TGFb1), tumor necrosis factor-a (TNFa), interferon-g, and interleukins 1 and 6, and the oncogene products H-ras, v-src, Her-2/neu, and wnt1 [33, 41–47] (Fig. 10.3). The COX-2 promoter also contains multiple transcription binding factor sites, including those for cAMP, c-Myb, nuclear factor-IL6 (NF-IL6), CCAAT/ enhancer binding proteins (C/EBPs), NF-kB, and activator protein-1 (AP-1) [22]. PPARd, HIFa, and the intracellular domain of Notch receptor also transactivate the COX-2 promoter [48–50]. The cAMP response element of COX-2 is responsible for transcription in response to activators of the ERK and JNK MAP kinase cellular signaling pathways, while its upregulation by TNFa is mediated through the NF-IL6 and NF-kB sites [51–53]. COX-2 protein expression is regulated by posttranscriptional and posttranslational events that are active during inflammatory states and tumor promotion. Translation of COX-2 is dynamic, and under normal conditions related to inflammatory stimuli. In some CRCs, COX-2 expression may be elevated because the turnover rate of COX-2 mRNA is low. An AU-rich element (ARE) in the 3¢-untranslated region of COX-2 mRNA permits its binding to the RNA stabilization factor HuR, prolonging

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the mRNA half-life [54, 55]. HuR levels are increased in colon cancer, suggesting a mechanism for upregulation of PGE2 levels in these tumors. Interestingly, in vitro studies also shows that increased binding of HuR to the ARE of COX-2 contributes to tumor cell overexpression of VEGF and IL-8, and increased expression of these factors correlates with low COX-2 mRNA turnover in CRCs [55]. COX-2 protein expression is also regulated by an miRNA, miR-101, which is present at increased levels in human colon cancer [56]. An inverse relationship between miR-101 and COX-2 expression has been identified in human colorectal cancers, and in colon cancer cell lines, human miR-101 downregulated COX-2 expression [56].

4 The Role of COX-2 in Obesity and Metabolic Syndrome It is clear that obesity and metabolic syndrome are associated with increased systemic and tissue inflammation. In addition, virtually all available observational studies indicate a positive association between obesity and the development of CRC [57, 58]. A small study of 20 resected colon cancers and paired non-tumor colonic mucosa found increased COX-2 expression in the normal mucosa from overweight patients (body mass index ³25) compared to age- and sex-matched subjects with a healthy weight [59]. Animal models of obesity, however, yielded conflicting results. As compared with wild-type controls, animals with targeted deletion of the murine COX-2 gene (Ptgs2) had significantly reduced body weight and adiposity, and increased metabolic activity [60]. Adipose tissue from these COX-2 deficient mice showed reduced expression of markers for differentiated adipocytes, reduced presence of the peroxisone proliferator-activated receptor g (PPARg) ligand, 15d-PGJ [2], and reduced macrophage-dependent inflammation [60]. Upregulation of COX-2 expression in epithelial cells, however, yielded a similar effect. Transgenic mice overexpressing Ptgs2 under the control of the promoter for the keratin 5 gene displayed a 20% reduction in body weight, which was accounted for by severe reduction in body fat [61]. These animals showed increased energy expenditure, and a significant elevation of the resting metabolic rate. Unlike wild-type mice, the high COX-2 expressing animals failed to gain weight on a high-fat diet and were protected against diet-induced fasting hyperglycemia, hyperinsulinemia, and glucose intolerance. These conflicting results may result from the tissue specificity of COX-2 activity, with opposite effects in mesenchymal adipocytes and intestinal epithelial cells.

5

Protumorigenic Effects of PGE2

The tumorigenic effects of COX-2 activity in the intestinal mucosa are related to the ability of this enzyme to produce the primary inflammatory effector molecule, PGE2. The earliest work on the link between prostaglandins and tumor formation

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focused upon the relationship between PGE2 and immune function. PGE2 exhibits immunosuppressive effects, including the ability to induce loss of surface HLA antigens [62] and to enhance production of immunomodulatory cytokines including IL-4, IL-5, and IL-10 [63]. PGE2 decreases the production of IL-2 and IFN-g, thereby enhancing a pro-inflammatory T-helper 2 (TH2) response and inhibiting a suppressive T-helper 1 (TH1) response. More recent work shows that PGE2 promotes the production of inflammatory T-helper 17 (TH17) cells, thereby amplifying tissue inflammatory stimuli [64, 65]. In addition to modulating stromal responses, PGE2 exerts direct effects upon epithelial cells. In epithelial cell lines, PGE2 suppresses apoptosis by increasing expression of Bcl-2. PGE2 also increases the expression of activated MAP kinase, promotes cell migration/invasiveness, and activates epidermal growth factor receptor (EGFR) in epithelial cells [41, 66–68]. PGE2 induces cell proliferation by activating Ras-Erk and glycogen synthase kinase-3b (GSK3b)-b-catenin signaling in colon cancer cells [69, 70], as well as by upregulating signaling via PI3K-Akt [71]. Direct evidence that PGE2 promotes epithelial tumor formation comes from studies showing that PGE2 increases intestinal tumors in both Apc-deficient mice and mice with azoxymethane (AOM)-induced tumors [71, 72]. ApcMin/+ mice develop multiple intestinal tumors as a result of germ-line mutation of the Apc tumor suppressor [73]. When ApcMin/+ mice were treated with PGE2, intestinal tumor formation increased significantly [71]. In addition, genetic deletion of the PGE2 metabolizing enzyme, 15-PGDH also increased intestinal tumors in ApcMin/+ and AOM-treated mice [74]. Animal models have been used to study the role of EP receptors in mediating the tumorigenic effects of PGE2 in the intestinal mucosa. In vitro assays showed that ligand engagement of EP1, EP2, and EP4 receptors transactivated EGFR [ 75– 77]. Treatment with EP1 and EP4 selective antagonists significantly reduced tumors in Apc Min/+ mice and other animal tumor models [ 78– 80 ] . Deletion of EP2 completely inhibited VEGF production in the ApcD716 mouse model of APC-associated tumorigenesis [80]. PGE2 induced expression of a pro-angiogenic chemokine, CXCL1, in human CRC cells, and this chemokine stimulated endothelial cell migration and microvascular tube formation in vitro [81]. In cornea assays, PGE2 induced angiogenesis, thereby providing a mechanism for growth of both primary and metastatic disease [82, 83]. Other studies showed that EP3 may mediate angiogenesis in response to PGE2 [84]. Finally, the ability of PGE2 to stimulate production of TH17 in an animal model of chronic inflammation was dependent upon engagement of the EP4 receptor [65]. Studies of specific receptor blockade by pharmacological compounds and animal models of targeted disruption of EP receptors provided additional clues to their role in intestinal tumor formation. For example, oral administration of an EP1 antagonist reduced AOM-induced colon tumors in rodents [85], and the same result was observed in EP1-deficient mice [86]. Inhibition of AOM-induced aberrant crypt foci in C57BL/6Cr mice and intestinal adenomas in ApcMin/+ mice was achieved by ONO-AE2-227, a selective EP4 antagonist [78].

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Mechanistic Insights from the Intestinal Inflammatory Response

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In the setting of chronic inflammation, interactions between stromal and epithelial tissue elements promote tumor formation. Under normal conditions, COX-2 expression in the intestine is restricted to the stromal compartment, with expression by fibroblasts, endothelial cells, or macrophages [87]. Myofibroblasts reside subjacent to the basement membrane and interact with enterocytes to regulate epithelial cell positioning and differentiation [88]. Myofibroblasts participate in innate immune responses via signaling from surface pattern recognition receptors (TLRs) that bind microbial products [89]. As a result of inflammatory conditions, myofibroblasts increase in number and produce greater amounts of PGE2. PGE2 works in concert with the cytokine, TGFb, during both normal wound healing and inflammationassociated tumorigenesis [90]. TGFb-mediated signaling is required for the differentiation of precursor cells into myofibroblasts, and it also promotes their acquisition of muscle-like contractility and ECM-remodeling capabilities. Crosstalk between critical signaling pathways occurs in response to stress conditions and is a likely basis for tumorigenic stimuli induced by chronic inflammation. Only a few of many examples are provided here. The key pathway necessary for enterocyte proliferation, Wnt signaling, is codependent on PGE2 to effect tissue regeneration [91]. PGE2 also stimulates enterocyte growth and survival in ApcMin/+ mice via transactivation of EGFR, and crosstalk exists between PGE2 and TGFb pathways in the intestine [90, 92]. For instance, mesenchymal loss of LKB1, the upstream regulator of TGFb-dependent myofibroblast differentiation, caused adenoma formation in mice [93], and COX-2-PGE2 and TGFb signaling pathways both activated the transcriptional pro-inflammatory and anti-apoptotic programs of NF-kB. TLR4 signals with the adaptor myeloid differentiation factor (MyD88) to activate NF-kB pro-inflammatory signaling, increasing COX-2 expression. Suppressing this signaling pathway inhibited intestinal tumor growth, since MyD88−/−ApcMin/+ mice survived longer and bore slower growing tumors with lower COX-2 expression [94]. At sites of inflammation, or in tumors where concentrations of inflammatory cytokines and TGFb ligands are high, a dose-dependent crossregulation of TGFb and NF-kB gene expression was shown [95]. This signaling reciprocity, in turn, dictates biological outcome, including drug sensitivity or resistance [96]. Consistent with this view, a selective IKKb inhibitor, designed to inhibit NF-kB signaling, exacerbated intestinal inflammation upon prolonged administration by increasing cytokine IL-1b secretion [97].

7

Pharmacological Agents Inhibiting Tissue Inflammation

Derivatives of aspirin have been extracted from willow bark and other deciduous plants and used for centuries to treat pain and fever. In the 1930s, a new aspirinlike class of drugs was developed for the treatment of arthritis. These drugs were

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called “nonsteroidal” anti-inflammatory drugs, or NSAIDs, to distinguish them from the glucocorticoids that were the dominant treatment for arthritis at the time. Aspirin exerts its therapeutic effects through an irreversible acetylating reaction at a serine residue located in the arachidonic acid binding channel of cyclooxygenase, thereby inhibiting enzyme-substrate binding. Unlike aspirin, non-aspirin NSAIDs do not covalently alter the arachidonic acid binding channel of cyclooxygenase, and therefore exert a transient blockade of enzyme activity. Although aspirin acetylates both COX-1 and COX-2, its inhibitory activity is 10–100 times more potent against COX-1 than COX-2 [98]. This feature of differential selectivity against the two COX isoforms characterizes all NSAIDs. An NSAID is said to be “selective” when its inhibitory activity against one particular cyclooxygenase isoform is vastly greater than the other, such that the clinical effects against one isoform are dominant. Nonselective NSAIDs are those able to inhibit both isoforms to a clinically relevant extent. Examples of nonselective NSAIDs include the commonly used agents ibuprofen, piroxicam, naproxyn, indomethacin, and sulindac. COX-1 is the cyclooxygenase isoform responsible for platelet activation and for protecting the gastrointestinal mucosa. As a result, NSAIDs that inhibit COX-1 activity to a significant degree increase the incidence of clinically significant bleeding and gastrointestinal ulceration. Following the recognition that COX-2 was primarily responsible for the detrimental consequences of inflammation, COX-2 selective inhibitors were synthesized to preferentially target this inducible isoform. Examples of drugs of this class include celecoxib, currently available for the treatment of pain and arthritis, and rofecoxib, an agent that is presently unavailable for clinical use due to toxicity concerns. Because selective COX-2 agents produce minimal COX-1 inhibition, these drugs reduce tissue inflammation without harmful gastrointestinal side effects. This feature is particularly important for patients who require long-term NSAID use, such as those with severe arthritis. Unfortunately, placebo-controlled studies of selective COX-2 inhibitors for the prevention of colorectal adenomas uncovered a detrimental effect of these drugs in patients with preexisting cardiovascular disease. In the Adenoma Prevention with Celecoxib (APC) Trial, patients using celecoxib who entered the study with significant cardiovascular risk factors were approximately three times as likely to experience a serious cardiovascular complication, such as stroke, myocardial infarction, or congestive heart failure, compared to patients with risk factors who were treated with a placebo [99]. This effect is hypothesized to result from the inhibition of COX-2-regulated prostacyclin (PGI2), an eisocanoid responsible for protection from inflammation-associated vascular thrombosis [23]. It is unclear whether this cardiovascular risk extends to the nonselective NSAIDs. A number of case–control and cohort studies suggest that increased cardiovascular risk is associated with nonselective NSAID use; however, there are no placebo-controlled randomized clinical trials of these agents that adequately address this issue [100, 101].

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8 COX-2-Dependent Effects of NSAIDs in Colorectal Neoplasia Colorectal tumors are commonly initiated by loss of function of the APC tumor suppressor, leading to increased levels of intracellular b-catenin and its subsequent nuclear translocation. In the nucleus, b-catenin associates with Tcf-4 to create a factor that mediates transcription of key genes responsible for cellular growth and migration. These include c-myc, cyclin D1, PPARd, phospholipase D, and MMP-7 [102]. In tumors for which APC protein expression is intact, additional mutations that stabilize b-catenin and prevent its normal degradation are commonly found, providing strong evidence that loss of regulatory control over b-catenin is the primary driver of the vast majority of sporadic CRCs. In the ApcMin/+ mouse model of CRC, initial neoplastic transformation results from loss of APC function in intestinal stem cells, including the population known as crypt base columnar cells (CBCs) [103–105]. These abnormal stem cells give rise to tumors through a process driven by oncogenic activity of activated b-catenin as well as by inflammatory stimuli in the tissue microenvironment. NSAIDs clearly reduce inflammation in target tissues; however, it is also possible that these drugs exert a direct effect upon the stem cells that initiate and maintain tumor growth. One of the earliest antitumor activities found for NSAIDs was the ability to induce apoptosis of intestinal tumor cells in vitro [41, 106]. It is possible that NSAIDs promote apoptosis by reducing PGE2 levels, but data also suggest that certain NSAIDs directly affect the concentrations of proteins that regulate apoptosis, such as Bax and Bcl-XL. In human CRC cell lines, COX-2 inhibitors promote tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Treatment of these cells with COX-2 inhibitors causes clustering of death-inducing signaling complex components, including DR5, FADD, and procaspase-8, together with the activation of acid sphingomyelinase and generation of ceramide within the outer plasma membrane [107]. In other CRC cell culture assays, NSAIDs induced mitochondria- and Bax-dependent apoptosis, a response that requires the downstream mediator of Bax, SMAC (second mitochondria-derived activator of caspase) [108]. This activity has recently been placed in a tissue context by work showing that dietary administration of the NSAID, sulindac, reduced the number of intestinal CBCs containing nuclear b-catenin by 75%, with the majority of the remaining stem cells demonstrating apoptosis as evidenced by positive TUNEL staining [109]. When ApcMin/+ mice were crossed with animals lacking SMAC, (SMAC−/− ApcMin/+), the antitumor effect of sulindac was reduced, and this was associated with reduced apoptosis and preservation of intestinal stem cells expressing activated or nuclear b-catenin [109]. These results suggest that sulindac chemoprevention is achieved by apoptotic elimination of cells with nuclear b-catenin, which include normal CBCs as well as cells with aberrant b-catenin regulation due to APC loss. Angiogenesis is a necessary feature of tumor progression and also a prominent component of tissue inflammatory processes, including wound healing. In human CRC, COX-2 expression correlates with angiogenesis markers, such as microvascular

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density (MVD) and VEGF expression [38, 110]. Patients whose tumors demonstrated elevated COX-2 and MVD experienced a shorter survival time than those with COX-2 negative tumors [38]. In cell culture, NSAIDs induce a variety of antiangiogenic effects, including suppression of tumor VEGF and bFGF secretion [111], and blockade of aVb3-dependent activation of Cdc42 and Rac, resulting in the inhibition of endothelial cell spreading and migration [112]. NSAIDs also demonstrate antiangiogenic effects in whole tissues. For example, selective COX-2 inhibitors blocked bFGF-induced corneal neoangiogenesis [113]. In the ApcMin/+ mouse, administration of tumor-suppressive doses of celecoxib also decreased endothelial cell density in target intestinal mucosa [96]. NSAIDs may counteract the alteration of growth factor signaling that is a characteristic of many epithelial tumors. In CRC, signaling via EGFR is a prominent feature of disease promotion and progression. Activation of PGE2 signaling via engagement of EP1, EP2, and EP4 receptors leads to the transactivation of signaling via EGFR, which, in turn, increases cell proliferation in the intestinal epithelium [75–77]. In addition, PGE2 together with TGFa or activated K-ras synergistically induces expression of the EGFR ligand, amphiregulin in CRC cells [114]. EGFR signaling involves activation of both Ras/Raf/MEK/ERK and PI3K/Akt pathways. PGE2-mediated transactivation of EGFR is inhibited by both selective and nonselective NSAIDs and resulting downstream effects include suppression of survival signaling via activated MAP kinase and the PI3K/Akt pathway [115]. Studies in CRC cell lines also show that the selective COX-2 inhibitor, celecoxib, inhibits Akt signaling directly by blocking Akt phosporylation and that overexpression of constitutively active Akt protects CRC cells from celecoxib-induced apoptosis [116]. EGFR activation also diminishes cadherin-mediated cell–cell adhesion, a property associated with cytoskeletal changes favoring focal adhesion formation and cell contraction [117]. In the ApcMin/+ mouse model, all of these effects were reversed upon treatment with either NSAIDs or EGFR inhibitors [91, 115, 117]. A few NSAID effects contribute to epithelial tumor inhibition through cyclooxygenase-independent mechanisms. For example, NSAID-induced antitumor activity may be related to the ability of these drugs to target peroxisome proliferatoractivated receptors (PPARs). PPARs are ligand-activated transcription factors that are members of the nuclear hormone receptor superfamily. Activation of PPARg signaling inhibits tumor formation in animal models, and in tumor cell cultures, PPARg activity induces apoptosis and anti-proliferative effects [118]. Some NSAIDs are also weak PPARg agonists and receptor ligands [119]. In contrast, PPARd is a product of activated signaling via b-catenin-Tcf4, and its expression is associated with myofibroblast activation and promotion of epithelial cell stem cell division, proliferation, and migration. Under certain conditions, PGE2 can indirectly activate PPARd, and activation of PPARd increases tumor formation in ApcMin/+ mice [71]. In addition, PPARd may be a direct target of sulindac activity, as sulindac blocked the DNA binding activity of PPARd and PPARd overexpression prevented sulindacinduced apoptosis of CRC cells [119]. Finally, certain NSAIDs, including aspirin and sulindac, may directly block signaling via NF-kB. A marker of chronic inflammation in tumor epithelial and stromal elements, NF-kB controls the expression of

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genes important for cellular survival and proliferation. Among its many activities, constitutive activation of NF-kB increases the expression of anti-apoptotic proteins. Aspirin and other nonselective NSAIDs inhibit IkB kinase-b [120, 121], an enzyme that phosphorylates NF-kB and targets it for degradation. Not all NSAIDs, however, are able to alter NF-kB signaling. For example, although sulindac inhibits NF-kB activation, indomethacin does not, yet it has similar antitumor activity in animal CRC models.

9 Activity of Anti-inflammatory Drugs Against Colorectal Neoplasia Dr. Waddell’s key discovery of the antitumor activity of NSAIDs in the colorectum has been confirmed by human observational and clinical trials data. Strikingly consistent results from observational studies of human cancer incidence show that regular use of aspirin and other NSAIDs is associated with a reduced risk of colorectal neoplasia, with reductions in premalignant adenomas, invasive carcinomas, and deaths due to CRC. A large case–control study from Australia was the first to show a protective effect against CRC among individuals who used aspirin, reporting a relative risk (RR) of 0.60 (95% CI = 0.44–0.82) for aspirin users [122]. In a prospective cohort study from the American Cancer Society involving more than 630,000 subjects, aspirin use was associated with a significant decrease in colon cancer mortality (RR = 0.63; 95% CI = 0.44–0.89) [19, 123]. Numerous other prospective cohort studies confirmed these results, with reported relative risks ranging from 0.51 to 0.68, and a dose dependence based upon frequency of use [30, 83, 124]. The most striking evidence for this effect comes from long-duration randomized clinical trials of aspirin for the prevention of cardiovascular disease. A recent report by Rothwell et al. summarized 20-year follow-up data from four randomized trials of aspirin versus control (Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial, Thrombosis Prevention Trial, and the British Doctors Aspirin Trial) and one trial of aspirin at different doses (Dutch TIA Aspirin Trial) [125]. In the four trials of aspirin versus control, 14,033 patients were randomized with a median scheduled treatment duration of 6 years and a median follow-up of 18.3 years. Aspirin treatment reduced the 20-year risk of colon cancer incidence (hazard ratio 0.76; 95% confidence interval 0.60–0.96; p = 0.02) and colon cancer mortality (hazard ratio 0.65; 95% confidence interval 0.48–0.88; p = 0.005). The tumor-suppressive benefit increased with the duration of treatment, and participants randomized to the treatment of 5 years or longer demonstrated a 70% reduction in cancer incidence. In addition, this analysis found no additional benefit to aspirin doses in excess of 75 mg daily [125]. The efficacy of NSAIDs against colorectal neoplasia may be related to metabolic state. In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO Trial), 4.017 cases with a polypoid lesion detected in the left colon were compared to 38,395 controls without these lesions, recruited during the period from September 1993 to September 2000, with follow-up data analyzed as of March 2003 [126].

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Overall, the PLCO Trial showed that frequent NSAID users (aspirin and ibuprofen) developed fewer adenomatous, hyperplastic, and malignant lesions during follow-up than NSAID nonusers (OR for advanced adenomas 0.8; 95% CI 0.7–1.0). In keeping with the hypothesis that higher BMI is associated with both increased adenoma risk and increased tissue inflammatory response, the PLCO found more pronounced protection against adenomas when NSAID users were of healthy weight (BMI < 25 = OR 0.6; 95% CI 0.4–0.8) than overweight (BMI > 25 = OR 0.9; 95% CI 0.7–1.0) [126].

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Prevention Clinical Trials

The ability of nonselective NSAIDs, such as sulindac, to regress established colorectal adenomas in patients with FAP was confirmed by a number of randomized controlled trials in this high-risk population [2–7]. In these studies, patients with FAP who had numerous adenomas of the colorectum demonstrated significant reductions in adenoma size and number following treatment with sulindac for 4–12 months. Independent case series also reported adenoma regression following treatment with sulindac sulfone, a metabolite of sulindac with no anti-prostaglandin activity [127] and with intrarectal indomethacin treatment [128]. A randomized trial of the selective COX-2 inhibitor, celecoxib, also produced regression of established rectal adenomas in patients with FAP [129]. In addition, this study examined the effect of celecoxib upon duodenal neoplasia in FAP patients, showing a positive but not statistically significant reduction in disease extent for the upper gastrointestinal tract. Several important randomized trials examined the effect of aspirin for prevention of sporadic colorectal adenomas. Because many case–control and cohort studies showed a strong association between routine aspirin use and CRC prevention, the expectation for successful outcome for these trials was high. Interestingly, these trials yielded mixed results. A study reported by Baron et al. examined treatment with aspirin at either 81 or 325 mg daily, compared to placebo, in a randomized trial of 1,121 patients at moderate risk for CRC based upon a history of prior adenoma formation [9]. Patients were treated for 48 months, with interval colonoscopies to detect new adenoma development. A perplexing inverse dose–response was observed, with a 40% reduction in advanced adenoma formation for patients using low-dose aspirin, but only a 19% reduction for those using high-dose aspirin [9]. Another trial enrolled patients with a history of successfully treated CRC, randomizing them to either placebo or 325 mg of aspirin daily. This study showed a 35% reduction in adenoma detection over a median posttreatment observation period of 12.8 months [130]. A study by Benamouzig et al. reported results from a 4-year study that randomized adenoma patients to either placebo or lysine acetylsalicylate, a form of aspirin with increased solubility. Early results following 1 year of treatment indicated a 37% reduction in recurrent adenomas among those taking aspirin compared to placebo [10]. However, long-term follow-up at 4 years of treatment demonstrated only a reduction in adenoma multiplicity [131]. Finally, the relationship between

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aspirin, folate, and adenoma recurrence was examined in a placebo-controlled 2 × 2 factorial trial, using 300 mg enteric-coated aspirin daily with or without 0.5 mg folate. The advanced adenoma detection rate over 3 years in this cohort of 945 patients was reduced by 41% [132]. As already mentioned, significant long-term reductions in CRC incidence and mortality were observed in cohorts followed after randomization to aspirin versus placebo for cardiovascular disease prevention [125]. Although these data are weaker than those from the adenoma prevention trials due to their observational nature, the results against a cancer endpoint make a compelling argument for adopting low-dose aspirin for CRC chemoprevention. Selective COX-2 inhibitors have also been tested in randomized controlled trials for prevention of sporadic colorectal neoplasia. In the APC Trial, 2,035 patients with a high risk for adenoma recurrence based upon prior adenoma history were randomized to receive twice daily treatment with either 200 mg celecoxib, 400 mg celecoxib, or placebo. Following a screening interval of 3 years, the trial found a 57% reduction in advanced adenoma detection for the low-dose celecoxib arm and a 66% reduction for the high-dose arm [11]. Unfortunately, this study also found that celecoxib use was associated with increased cardiovascular toxicity. For a combined serious cardiovascular endpoint that included myocardial infarction, stroke, congestive heart failure, and death due to cardiovascular disease, the relative risk of an event was 2.3 for the 200 mg bid celecoxib arm and 3.4 for the 400 mg bid celecoxib arm [99]. A second trial, the Prevention of Recurrent Adenomatous Polyps (PreSAP) Trial, reported by Arber et al., randomized high-risk patients to celecoxib at a dose of 400 mg daily versus placebo. Colorectal adenoma recurrence was determined by colonoscopy during 3 years of on-treatment surveillance [8]. These researchers found a 51% reduction in advanced adenomas for celecoxib users. This regimen was not associated with increased cardiovascular toxicity, as the relative risk of events defined in a manner similar to that used in the APC Trial was 1.3 (95% confidence interval 0.65–2.62). A third study, the Adenomatous Polyp Prevention with Rofecoxib (APPROVe) Trial, tested 25 mg daily of another selective COX-2 inhibitor, rofecoxib, in a high-risk adenoma cohort. This study showed a 30% reduction in advanced adenomas and also found increased cardiovascular toxicity among rofecoxib users, with a threefold increased risk of serious cardiovascular complications in the treatment arm [133, 134].

11

Efficacy Against Established Colon Cancers

In addition to efficacy against premalignant neoplasia, a large number of preclinical studies support a role for NSAIDs in disrupting the growth of invasive or metastatic cancers. Virtually all of the preclinical experiments described in earlier sections of this chapter were conducted using established cancer cell lines or tumor xenografts. Clinical correlation for these results is provided by observational studies showing that regular use of aspirin after the diagnosis of CRC improves overall survival, with this effect most prominent in patients whose tumors expressed high levels of COX-2

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[135]. A secondary endpoint analysis from a prospective trial of adjuvant therapy for stage III colon cancer also showed that aspirin users experienced significantly reduced risk of posttreatment disease recurrence, but that this effect was present only for those whose primary tumors overexpressed COX-2 [136]. There are also substantial data from both preclinical and clinical studies demonstrating that NSAIDs increase response to standard chemotherapeutic agents or to radiation therapy [137–139]. Tumor COX-2 expression was associated with reduced chemotherapy response in a variety of tumors, including those of cervix [140], lung [141], and ovary [142]. For example, in patients with stage IV CRC, intratumoral COX-2 gene expression measured by RT-PCR was associated with reduced overall survival following fluoropyrimidine-based chemotherapy [143]. In a three-arm randomized phase II trial involving 134 patients with advanced non-small cell lung cancer (NSCLC), either celecoxib, zileuton (a 5-lipoxygenase inhibitor), or both were added to standard chemotherapy [144]. There were no survival differences between the arms; however, pretreatment tumor COX-2 expression was a negative prognostic factor for overall survival (hazard ratio 2.51). The mechanisms by which COX-2 and PGE2 mediate chemotherapy resistance are unknown. In human breast cancer cell lines, COX-2 expression correlates with the presence of MDR-1 P-glycoprotein 170 (MDR-1/Pgp170), a molecule responsible for chemoresistance [145]. Clinical studies of NSCLC show that preoperative treatment with taxanes results in residual disease at surgery that demonstrates increased intra-tumor expression of COX-2 and PGE2 [146]. This may result from a direct of effect by taxanes upon COX-2 expression, as in vitro studies of NSCLC cells found taxane-induced upregulation of AP-1-mediated COX-2 gene transcription [141, 147]. It is, therefore, possible that chemotherapy itself induces COX-2 activity, perhaps due to generation of an inflammatory response to dying tumor cells. In support of this, concomitant treatment of lung tumors with taxanes and a selective COX-2 inhibitor abrogated chemotherapy-associated increases in intratumor PGE2 levels [141].

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Clinical Trials in Cancer Treatment

The first indication that anti-inflammatory agents might alter the behavior of established tumors came from a study of NSAIDs administered with palliative intent. In a study of 135 patients with advanced solid tumors and malignancy-associated malnutrition, indomethacin reduced pain as well as consumption of other analgesics [148]. In addition, median survival doubled from 250 to 510 days (p < 0.05) in patients treated with indomethacin. Although it is well known that patients with advanced cancer who achieve adequate pain control live longer, this dramatic difference led to early speculation that NSAIDs had a direct antitumor effect. The efficacy of both first- and second-line chemotherapy in combination with selective COX-2 inhibitors has been examined for the treatment of NSCLC [149], breast cancer [150, 151], pancreatic cancer [152], esophageal cancer [153], metastatic

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differentiated thyroid cancer [154], multiple myeloma [155], and glioblastoma [156]. Results were promising but not dramatic in each instance. Based upon the hypothesis that COX-2 induction contributed to taxane resistance, patients with NSCLC were treated with celecoxib and docetaxol in a phase II design [157]. Objective responses were achieved in 2 of 13 cases. A second phase II study treated 29 patients with NSCLC with celecoxib, paclitaxel, and carboplatin prior to tumor resection. The objective response rate was 65% [149]. A few trials determined the effect of celecoxib in advanced CRC. A phase I study of stage IV CRC involved the addition of both celecoxib and glutamine to irinotecan, 5-fluorouracil, and leucovorin (IFL) [158]. The goal of the study was to reduce IFL-related gastrointestinal toxicity. Although the phase I design did not permit definitive analysis, the addition of celecoxib and glutamine did not appear to alter the efficacy or toxicity of IFL in these patients. In addition, antitumor response did not correlate with tumor COX-2 protein expression. In a phase II study, 48 patients with stage IV CRC who progressed following treatment with oxaliplatin-based first-line chemotherapy were treated with continuous infusion 5-fluorouracil, irinotecan, and rofecoxib [159]. Partial responses were observed in 48%, with 30% achieving stable disease. The toxicity profile of this combination was similar to that seen with 5-fluorouracil and irinotecan without rofecoxib. The first definitive results concerning the efficacy of chemotherapy in combination with a selective COX-2 inhibitor are expected from a clinical trial from the US Cancer Cooperative Groups. In an ongoing study for patients with stage III colon cancer (CALGB Protocol 80702), patients who have undergone resection of a stage III colon cancer are being randomized to adjuvant therapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) with or without 400 mg celecoxib daily. The primary outcome of the study is overall survival. Secondary analyses will examine tumor COX-2 expression, as well as serum and tissue markers of inflammation such as serum C-reactive protein, interleukin-6, and soluble TNFa-receptor 2 levels. Another currently active CALGB study randomizes patients with stage IV NSCLC whose tumors overexpress COX-2 to receive standard chemotherapy with or without celecoxib (CALGB Protocol 30801). As an indicator of anti-prostaglandin activity, this study will also determine urinary levels of the PGE2 metabolite, PGEM, and correlate this variable with COX-2 expression, celecoxib treatment, and treatment outcome.

13

Summary and Future Directions

Inflammation is a powerful promoter of epithelial tumorigenesis. This condition, which involves a complex network of tissue-specific interactions, is driven by upregulation of cyclooxygenase enzymes, particularly COX-2, and its primary effector in the colorectal epithelium is PGE2. Inflammation in general and wound healing in particular share many characteristics of tumorigenesis, including epithelial stem cell proliferation, angiogenesis, increased epithelial cell migration, and

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decreased apoptosis. Human randomized clinical trials and long-term cohort studies show that inhibition of these effects by NSAIDs achieves effective, although not complete, prevention of colorectal neoplasia. In addition, it appears likely that NSAIDs will also have an adjuvant role in treating established cancers. A number of exciting new avenues of research are focused upon improving the antitumor effects of COX-2 suppression. One focus is upon therapies directed against cells that lack functional APC protein, and therefore exhibit activation of b-catenin– Tcf4 nuclear transcription [160]. Specific elimination of these tumor progenitor cells would prevent disease progression, although these therapies also carry a risk of gastrointestinal toxicity by inhibiting otherwise healthy intestinal stem cells. Another goal is to prevent the undesirable side effects of NSAIDs. Nonselective NSAIDs can cause renal damage, gastrointestinal ulceration, and bleeding, yet these drugs are highly effective in preventing CRC incidence and mortality and also have an important roll in managing chronic arthritis and pain. As a result, clinical trials to enhance their long-term tolerability, such as by coadministration of proton pump inhibitors, are warranted. New research must also provide a better understanding of the risks of all NSAIDs, both selective and nonselective, in terms of cardiovascular toxicity. An additional area of promising research is the development of COX-2-directed imaging agents. It is clear that elevated COX-2 expression is an early indicator of neoplasia, particularly in epithelial tissues such as the breast, and the gastrointestinal, respiratory, and urinary tracts. The ability to accurately detect persistent elevations of COX-2 would make it possible to identify individuals at high risk for tumor formation who should benefit from NSAID chemoprevention. The same imaging could then be used to monitor response to therapy and to determine when it is possible to discontinue chemoprevention, thereby avoiding adverse side effects. A number of selective COX-2 inhibitors and other NSAIDs have been modified to produce probes for PET and SPECT imaging [161–164]. Finally, an improved understanding of the nature of tumorigenesis and its relationship to chronic inflammation provides a wealth of new targets for cancer detection, prevention, and treatment. An emphasis upon development of pathway targeted drugs for oncology use yields a wide range of opportunities for combination therapy of neoplasia at all stages. One approach to cancer prevention is to use lowNSAID doses in combination with other chemopreventive agents, such as difluoromethylornithine, hedgehog pathway inhibitors, EP receptor antagonists, or PPARg ligands. Given the tissue-specific nature of tumorigenesis, understanding the effectiveness of combination treatments will require a major clinical trials investment, spanning many different tumor types.

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Index

A Adenomatous polyposis coli (APC), 24, 25, 27, 28, 31, 49, 52, 53, 55, 58, 59, 66, 67, 142, 164, 166, 167, 171, 174 AOM. See Azoxymethane (AOM) APC. See Adenomatous polyposis coli (APC) ApcD716 mice, 57, 161, 162, 164 ApcMin/+ mice, 49, 65–73, 164, 165, 167, 168 Arachidonic acid, 158, 159, 166 Azoxymethane (AOM), 48, 72, 119, 164

B BRAF mutations, 133–137

C Calcium, 48–56, 143 Colorectal cancer (CRC), 3, 23, 59, 66, 115, 132, 141–151, 158 COX-2. See Cyclooxygenase-2 (COX-2) CRC. See Colorectal cancer (CRC) Cyclooxygenase-2 (COX-2), 71, 87, 157–174

D Diabetes, 2, 35, 94–96, 100, 112, 116, 122, 123, 151 Diet, 48–50, 52–58, 60, 70–73, 82, 88, 96, 97, 101, 102, 114, 116, 121, 142, 143, 148–150, 163

E ECA. See Esophageal adenocarcinoma (ECA) Esophageal adenocarcinoma (ECA), 4, 6, 7, 9, 12, 16, 17, 77, 80, 81 Exercise, 65–73, 146, 148

F Familial adenomatous polyposis (FAP), 24–26, 31, 48, 52, 58, 66, 67, 158, 170

G Gastric cardia adenocarcinoma, 13 Gastro-esophageal reflux disease (GERD), 12, 13, 17, 77–80, 82–89 Genome wide association studies (GWAS), 31–34, 94, 103 GERD. See Gastro-esophageal reflux disease (GERD) Glycolysis, 55, 131–137 Gut microbiota, 121–122 GWAS. See Genome wide association studies (GWAS)

H Hereditary non polyposis colorectal cancer (HNPCC), 25–27, 29, 58, 59, 142

S.D. Markowitz and N.A. Berger (eds.), Energy Balance and Gastrointestinal Cancer, Energy Balance and Cancer 4, DOI 10.1007/978-1-4614-2367-6, © Springer Science+Business Media, LLC 2012

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184 I IBD. See Inflammatory bowel disease (IBD) Inflammation, 47–60, 71, 78, 89, 99, 101–103, 112, 113, 119, 122, 150, 157–174 Inflammatory bowel disease (IBD), 48, 56, 160 Insulin resistance, 2, 6, 11, 17, 35, 88, 99–103, 111–123 Intestinal metaplasia, 78, 80, 83, 87 J Juvenile polyposis, 29–31, 33 L Liver cancer, 3–5, 9, 14, 16, 17 M Metabolic syndrome (MetSyn), 2, 6–7, 17, 18, 35, 36, 88, 116, 117, 122, 163 MUTYH-associated polyposis, 28, 29 N Non steroidal anti-inflammatory drugs (NSAIDs), 48, 85, 157, 158, 166–169, 172, 174 O Obesity, 1–18, 35, 65, 77–89, 93–104, 111–123, 141, 143–146, 150, 163 P Pancreatic cancer, 4–6, 10, 14–17, 93–104, 172 Physical activity, 5, 65, 66, 69, 88, 89, 96, 97, 114, 142–144, 146–148, 150

Index Physical inactivity, 114, 116, 143, 150 Prognosis, 27, 66, 94, 103, 136, 141–151, 161 Prostaglandins, 69, 73, 87, 157, 159, 163

R Ras/Raf signaling, 132–137 Recurrence, 51, 66, 94, 142, 144–146, 148, 150, 171, 172

S State 3-IKO mice, 49 Survival, 5, 6, 15, 16, 18, 30, 66, 68, 73, 94, 98–99, 101–103, 132, 134, 135, 137, 142, 144–149, 158, 165, 168, 169, 171–173

T TGF-b. See Transforming growth factor-b (TGF-b) TNF. See Tumor necrosis factor (TNF) Toll like receptors (TLR), 56 Transforming growth factor-b (TGF-b), 31, 33, 35, 36, 59, 102, 118, 165 Tumor necrosis factor (TNF), 49, 167

V Vitamin D, 48–56, 58, 59, 143, 150

W Western diet, 71, 116, 143