Mikhail G. Kolonin Editor. Adipose Tissue and Cancer
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2 Mikhail G. Kolonin Editor Adipose Tissue and Cancer
3 Adipose Tissue and Cancer
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5 Mikhail G. Kolonin Editor Adipose Tissue and Cancer
6 Editor Mikhail G. Kolonin Institute of Molecular Medicine Center for Stem Cell and Regenerative Medicine University of Texas Health Science Center at Houston Houston, TX, USA ISBN ISBN (ebook) DOI / Springer New York Heidelberg Dordrecht London Library of Congress Control Number: Springer Science+Business Media New York 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (
7 Preface Obesity, the medical condition caused by white adipose (fat) tissue overgrowth, is a clear risk factor for cardiovascular disease and diabetes. Over the past few years, epidemiological studies have revealed the association between obesity and increased risk of certain cancers, as well as poor prognosis of a number of cancers. The pathophysiology underlying the relationship between obesity and cancer is complex and incompletely understood. Until now, it has been unclear if excess fat tissue itself affects cancer progression or if this link is predominantly due to diet and lifestyle of obese individuals. Recent studies show that the state of obesity can accelerate tumor growth irrespective of diet. Based on the apparent link between increased adiposity and several cancers (colorectal, endometrial, breast, and prostate), it has been proposed that adipose tissue has a direct effect on tumors. An emerging body of evidence confirms that this cross talk indeed takes place at several levels. Adipose tissue is composed of adipocytes, as well as vascular and stromal cells, secreting numerous soluble factors collectively termed adipokines. In addition, infiltration of the immune system cells in obesity leads to increased production of a number of inflammatory cytokines by adipose tissue, thus contributing to the establishment of the metabolic syndrome. Endocrine signaling by adipose tissue-derived molecules has been shown to promote cancer in animal models, matching clinical associations. Recent studies have shown that cells from adipose tissue are capable of trafficking to tumors, thus enabling paracrine action of adipokines from within the tumor microenvironment. Investigation of the molecular pathways through which adipose cells traffic to tumors and execute their functions is underway. Extracellular matrix modulation, increased tumor vascularization, immune system suppression, and direct effects on malignant cell survival and proliferation have been investigated as potential activities of systemic and locally produced adipokines within the tumor. The book comes at a very timely moment as it discusses the clinical and experimental data pointing to the role of individual components of obesity in cancer and evaluates individual mechanisms through which adipose tissue excess or restriction could influence cancer progression. An introductory chapter overviews metabolic changes taking place in obesity. Next several chapters discuss the clinical data v
8 vi Preface related to specific cancers promoted by obesity. This is followed by the chapters focusing on molecular players linking obesity and tumor physiology, as well as animal models to study them. Recent discoveries of the roles that host cells from adipose tissue play in tumor microenvironment are covered in the next two chapters. Finally, perspectives for obesity management as an approach to cancer prevention and treatment are discussed. Houston, TX, USA Mikhail G. Kolonin
9 Contents 1 Metabolic Perturbations Associated with Adipose Tissue Dysfunction and the Obesity Cancer Link... 1 Nikki A. Ford, John DiGiovanni, and Stephen D. Hursting 2 Increased Adiposity and Colorectal Cancer Charles Bellows and Herbert Tilg 3 Adiposity and Diabetes in Breast and Prostate Cancer Linda Vona-Davis and David P. Rose 4 Increased Adiposity and Endometrial Cancer Risk Karen H. Lu, Ann H. Klopp, Pamela T. Soliman, and Rosemarie E. Schmandt 5 Adipokines: Soluble Factors from Adipose Tissue Implicated in Cancer Gilberto Paz-Filho, Ameet Kumar Mishra, and Julio Licinio 6 Animal Models to Study the Interplay Between Cancer and Obesity Amitabha Ray and Margot P. Cleary 7 Unraveling the Local Influence of Tumor-Surrounding Adipose Tissue on Tumor Progression: Cellular and Molecular Actors Involved Catherine Muller, Laurence Nieto, and Philippe Valet 8 Trafficking of Cells from Adipose Tissue to Tumor Microenvironment Ines Martin-Padura, Patrizia Mancuso, and Francesco Bertolini vii
10 viii Contents 9 The Impact of Obesity Intervention on Cancer: Clinical Perspectives Ted D. Adams, Jessica L.J. Greenwood, and Steven C. Hunt Index
11 Chapter 1 Metabolic Perturbations Associated with Adipose Tissue Dysfunction and the Obesity Cancer Link Nikki A. Ford, John DiGiovanni, and Stephen D. Hursting Abstract Nearly 35 % of adults and 20 % of children in the USA are obese, defined as a body mass index (BMI) 30 kg/m 2. Obesity, which is accompanied by metabolic dysregulation often manifesting in the metabolic syndrome, is an established risk factor for many cancers. Within the growth-promoting, proinflammatory environment of the obese state, crosstalk between adipocytes, macrophages, and epithelial cells occurs via obesity-associated hormones, cytokines, and other mediators that may enhance cancer risk and/or progression. This chapter synthesizes the evidence on key biological mechanisms underlying the obesity cancer link, with particular emphasis on the relative contributions of increased adiposity per se versus the obesity-associated enhancements in growth factor signaling, inflammation, and vascular integrity processes resulting from adipose tissue dysfunction. These interrelated pathways represent possible mechanistic targets for disrupting the obesity cancer link. N.A. Ford Department of Nutritional Sciences, University of Texas, Austin, TX, USA J. DiGiovanni College of Pharmacy, University of Texas, Austin, TX, USA Department of Nutritional Sciences, University of Texas, Austin, TX, USA S.D. Hursting (*) Department of Nutritional Sciences, University of Texas, Austin, TX, USA Department of Molecular Carcinogenesis, University of Texas-MD Anderson Cancer Center, Smithville, TX, USA shursting@mail.utexas.edu M.G. Kolonin (ed.), Adipose Tissue and Cancer, DOI / _1, Springer Science+Business Media New York
12 2 N.A. Ford et al. 1.1 Introduction The prevalence of obesity, defined as a body mass index (BMI) 30 kg/m 2, has increased dramatically in recent decades in the USA, and nearly 35 % of adults and 20 % of children are now obese [ 1 ]. Worldwide, an estimated 1.1 billion adults are overweight and 500 million adults are ob ese ( ). The obese state is characterized by an excessive expansion of adipose tissue mass, which manifests as adipocyte hypertrophy (increased size), hyperplasia (increased number), and increased intracellular lipids. Excessive adiposity per se can exert untoward structural and biomechanical effects on organs (such as the lungs, liver, and pancreas), blood vessels, musculoskeletal system, and other tissues [ 2 ]. In addition, the resulting adipocyte hyperplasia and hypertrophy are associated with adipocyte dysfunction that can trigger local and systemic changes characteristic of the metabolic syndrome that increase risk and worsen prognosis of several cancers and other chronic diseases [ 3 ] (Fig. 1.1 ). Among obese adults, ~60 % meet the criteria for the metabolic syndrome, a state of metabolic dysregulation characterized by insulin resistance, hyperglycemia, dyslipidemias (particularly hypertriglyceridemia), and hypertension [ 4 ]. In obesity and/ or metabolic syndrome, alterations also occur in circulating levels of insulin, bioavailable insulin-like growth factor (IGF)-1, adipokines (e.g., leptin, adiponectin, and monocyte chemotactic factor), inflammatory factors (e.g., cytokines), and vascular integrity-related factors [e.g., vascular endothelial growth factor (VEGF) and plasminogen activator inhibitor (PAI)-1] [ 5, 6 ]. Through these mediators, obesity and metabolic syndrome are linked to various chronic diseases [ 6, 7 ] including cardiovascular disease, type II diabetes, and the focus of this chapter, cancer. Importantly, not all obese individuals develop the metabolic dysregulation usually associated with obesity and metabolic syndrome, and these metabolically healthy obese individuals do not have elevated cancer risk. An estimated 30 % of obese Fig. 1.1 Obesity, adipocyte dysfunction, and cancer: overview of mechanisms. An arrow preceding text denotes a directional effect (e.g., activity or concentration). IGF-1 insulin-like growth factor-1, VEGF vascular endothelial growth factor, PAI-1 plasminogen activator inhibitor-1, PI3K phosphoinositide 3-kinase, mtor mammalian target of rapamycin, NF-kB nuclear factor kb, COX-2 cyclooxygenase-2
13 1 Metabolic Perturbations Associated with Adipose Tissue Dysfunction 3 individuals in the USA are metabolically healthy [ 8 ]. Conversely, some nonobese individuals can develop the metabolic perturbations usually associated with obesity, and these individuals appear to be more prone to chronic diseases including cancer [ 9 ]. Thus, an emerging hypothesis is that the obesity-related metabolic perturbations, and not specific dietary components or increased adiposity, are at the crux of the obesity cancer connection. A central goal of this chapter is to identify the primary targets for breaking the obesity cancer link and to weigh the evidence regarding the importance of obesity-associated adiposity versus the metabolic changes that typically accompany the obese state. Evidence-based guidelines for cancer prevention urge maintenance of a lean phenotype [ 10 ]. Overall, an estimated % of all cancer deaths in the USA are attributable to overweight and obese body types [ 11 ]. Obesity is associated with increased mortality from cancer of the prostate and stomach in men; breast (postmenopausal), endometrium, cervix, uterus, and ovaries in women; and kidney (renal cell), colon, esophagus (adenocarcinoma), pancreas, gallbladder, and liver in both genders [ 11 ]. While the relationships between metabolic syndrome and specific cancers are less well established, first reports from the Metabolic Syndrome and Cancer Project, a European cohort study of ~580,000 adults, confirm associations between obesity (or BMI) in metabolic syndrome and risks of colorectal, thyroid, and cervical cancer [ 12 ]. With the increasing prevalence of obesity and metabolic syndrome, strategies to break the links between these conditions and cancer are urgently needed [ 6 ]. Herein, we discuss possible mechanisms underlying the links between obesity, metabolic syndrome, and cancer, with emphasis on obesity-associated enhancements in adipocyte dysfunction, inflammation, growth factor signaling, and vascular integrity. Emphasis will be placed on the crosstalk between adipocytes, macrophages, endothelial cells, and epithelial cells in many cancers. Specifically, we describe the dysregulation of growth signals (including insulin, IGF-1, downstream signaling pathways, and adipokines), cytokines, and cellular crosstalk, and vascular integrity factors in the obese state that may contribute to multifactorial enhancement of cancer processes. Components of these interrelated pathways offer possible mechanism-based targets for the prevention and control of cancers related to, or caused by, excess body weight and the metabolic syndrome. 1.2 Obesity and Adipose Tissue Dysfunction and Remodeling Adipose Tissue Function Adipose tissue is loosely characterized as fat depots with widely varying structure, size, and function but in general serves to store neutralized triacylglycerides, which can then be released into the blood stream by lipolysis during fasting or times of heightened energy requirements [ 13 ]. Typically, in response to low energy states, cytosolic lipolysis within adipocytes releases free fatty acids into the blood stream,
14 4 N.A. Ford et al. which can be used for beta-oxidation by peripheral tissues. In a diseased state (type 2 diabetes, metabolic syndrome, and fatty liver disease), adipose tissue fails to appropriately respond to changes in nutritional requirements resulting in altered metabolic signaling characterized by elevated adipokine and cytokine release into the plasma. During obesity, adipose tissue responds to the excess energy by increasing adipocyte size (hypertrophy) and enhancing adipocyte proliferation (hyperplasia) [ 14 ]. Adipocyte size strongly correlates with insulin resistance and secretion of proinflammatory cytokines [ 3 ]. Moreover, location of the adipose tissue also determines risk for metabolic diseases. In particular, increased visceral adipose (adipocytes located around internal organs) mass, is positively associated with insulin resistance likely because it is more metabolically active characterized by lipolytic release of more free fatty acids into the blood stream than other adipose depots (i.e., subcutaneous) [ 13 ] Hypoxia and Inflammation Healthy adipose tissue must be able to rapidly respond to excess energy intake by inducing adipocyte hypertrophy and hyperplasia, remodeling of the extracellular matrix, and enhanced neovascularization to nourish the adipose tissue. In pathological states such as insulin resistance associated with obesity, rapid adipocyte hypertrophy occurs with restricted angiogenesis resulting in cellular hypoxia, and thereby resulting in local inflammation [ 15 ]. Macrophages surrounding necrotic adipocytes phagocytize fatty acids, which are released from the adipocyte. This produces bloated, lipid overburdened macrophages, which is characteristic of chronic inflammation and often observed in obese individuals [ 14 ]. Furthermore, macrophages are predominantly differentiated to an M1 proinflammatory phenotype, which has been positively associated with systemic insulin resistance [ 14 ]. Hypoxia modulates the production of several inflammation-related cytokines and adipokines, including increased IL-6, leptin, and macrophage migratory inhibition factor production together with reduced adiponectin synthesis [ 15 ]. Increased glucose transport into adipocytes is also observed with hypoxia, largely as a result of the upregulation of GLUT-1 expression, consistent with changes in cellular glucose metabolism [ 15 ]. Crosstalk between infiltrating macrophages and adipocytes creates a positive feedback loop for further production of inflammatory cytokines within adipose tissue. Taken together, hypoxia appears to be a critical factor in the underlying cause of adipose tissue dysfunction resulting in many of the metabolic and inflammatory perturbations associated with obesity Ectopic Fat and Adipose Tissue Dysfunction When lipid storage capacity in adipose tissue is exceeded, surplus lipids often accumulate within muscle, liver, and pancreatic tissue [ 16 ]. As a consequence, hepatic
15 1 Metabolic Perturbations Associated with Adipose Tissue Dysfunction 5 and pancreatic steatosis can develop; both have been positively associated with insulin resistance and ultimately lead to impairment of lipid processing and clearance within these tissues [ 16 ]. As a result of lipotoxic and inflammation-mediated adipocyte dysfunction, the liver and pancreas are unable to cope with the overflow of lipids and lipotoxic effects of free fatty acids [ 17 ]. Consequently, lipid intermediates impair function of cellular organelles and cause release of cytokines, which foster insulin resistance by activating phosphokinases, thus impairing insulin receptor signaling. Evidence is accumulating that pancreatic adipocyte infiltration and fat accumulation may be one of the earliest steps in obesity-associated pancreatic endocrine dysfunction, and this can trigger pancreatic steatosis (PS), nonalcoholic fatty pancreatic disease (NAFPD), and pancreatitis [ 5, 7 ]. Moreover, fatty pancreas has been positively associated with visceral adipose tissue mass and systemic insulin resistance [ 18 ]. Together pancreatic steatosis and fatty pancreas contribute to the broader metabolic and inflammatory perturbations associated with obesity and metabolic syndrome. The term nonalcoholic fatty liver disease (NAFLD) refers to a disease spectrum that includes variable degrees of simple steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis [ 19, 20 ]. Simple steatosis is benign, whereas NASH is defined by the presence of hepatocyte injury, inflammation, and/or fibrosis, which can lead to cirrhosis, liver failure, and hepatocellular carcinoma. NAFLD is diagnosed when liver fat content is >5 10 % by weight in the absence of excess alcohol consumption or other liver disease [ 21 ]. NASH occurs in 20 % of cases of NAFLD and ~5 20 % of NASH cases progress to cirrhosis; 80 % of cryptogenic cirrhosis cases present with NASH [ 22 ]. Of this group, ~0.5 % will eventually progress to hepatocellular carcinoma, although in the presence of hepatitis C the risk increases [ 22 ]. NAFLD is one of the most common chronic diseases and in the USA and Europe [ 23, 24 ] the incidence in adults and children is rising rapidly [ 25, 26 ]. Pediatric NASH is also a global problem and the prevalence of fatty liver disease has increased concomitantly with the increase in pediatric obesity during the past 30 years. At least part of the increase may be attributed to increased recognition of this condition and NAFLD can be considered the hepatic manifestation of metabolic syndrome [ 27 ]. In Western populations, overnutrition/obesity is the most common cause of NAFLD, with an estimated incidence of %, and an increasing number of patients presenting risk factors for its development [ ]. Overnutrition- and obesity-related NAFLD is a multifactorial disorder and is linked to hypertriglyceridemia, obesity, and insulin resistance, as observed in patients with metabolic syndrome [ 32 ]. There is no single causal explanation for the development of primary hepatic steatosis and for how intrahepatic lipid accumulation leads to the development of inflammation. Initially, Day and James [ 33 ] proposed a two-hit model claiming that the reversible intracellular deposition of triacylglycerols ( first hit ) leads to metabolic and molecular alterations that sensitize the liver to the second hit, i.e., oxidative stress and subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis [ 33 ]. Hepatic steatosis ultimately leads to impairment of lipid processing and clearance in the liver. Lipotoxic and inflammation- mediated mechanisms have been suggested to be responsible for adipocyte dysfunction and
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