Obesity and Cancer
THE TERM cancer refers to all malignant neoplasms or new cell growth. he molecular basis of cancer begins with nonlethal genetic damage to an individual cell. he processes through which a normal cell undergoes neoplastic transformation, deviates from its normal growth pattern, and progresses to a malignant phenotype have been separated into four phases. hey are: (1) change in the deoxyribonucleic acid (DNA) pattern or its expression in the target cell; (2) growth of the transformed cell; (3) invasion into adjacent structures; and (4) metastases and relocation to distant tissues. Cell division in the normal cell is remarkably accurate, and have multiple redundant systems that monitor cell integrity and detect DNA damage. Tumor suppressor gene products can arrest cell division until damage is repaired. Carcinogens exert damage by binding directly to the DNA or by modifying host detoxiication enzyme systems that convert procarcinogens to more polar metabolites. Sometimes a metabolite becomes an “ultimate carcinogen” capable of damaging DNA. Several cancers develop because the host has inherited mutations (germ-line mutations) that increase DNA susceptibility to damage. If acquired or inherited, mutations limit the ability of the cell to detect and correct DNA damage, or if proliferative signals from mediators and mutant oncogenes stimulate cell growth in spite of growth controls, the damaged cell will divide and produce daughter cells that contain “heritable” defecta that can be transmitted to all cell progeny. Further proliferative signals to cells with heritable DNA defects have potential to generate further mutations in the growing clone. Fortunately, genes that code for proteins make up only a small portion of the total genome. he eiciency of DNA repair, combined with the small number of scattered targets throughout the genome explain how organisms can survive “in a sea of carcinogens” without developing the disease. Heritable damage at a functional DNA locus is termed initiation. his damage modiies the behavior of the cell in one of two ways. It enhances the ability of the cell to (1) reproduce without consideration of normal cell restraints and (2) invade other tissues and travel to distant sites reserved for other cell types. Promoters are agents that, while not carcinogenic themselves, facilitate the growth of initiated cells by globally stimulating proliferation in the tissue or organ. In normal cells, the efects of growth promoters, hormones and other promoters are reversible. he life cycle of a cell proceeds through an orderly progression from birth to death, leaving no progeny. If the promoting inluence is removed from normal tissue, proliferation stops, cells progress through their life cycle and die, thus hyperplasia can regress. In contrast, the progeny of transformed (initiated) cells stimulated to undergo unrestrained proliferation do not die but accumulate until clinically detected as a tumor. As the transformed cell proliferates in deiance of DNA repair and normal cell cycle controls, it accumulates additional DNA damage that further augments its aggressive behavior. A transformed clone overgrows its neighbors, takes up essential nutrients, and prospers at the expense of the organism. Several physiological changes are characteristic of the mutant clone: (1) self-suiciency in growth signals, (2) insensitivity to growth inhibitory signals, (3) evasion of apoptosis, (4) defects in DNA repair, (5) limitless replicative potential, (6) sustained ability to stimulate ingrowth of new blood vessels (angiogenesis), and (7) ability to evade immune defenses and rejection. As the mutant clone expands, it acquires subpopulations with additional phenotypic attributes including altered hormonal responsiveness and reduced susceptibility to antineoplastic drugs (termed progression). hus, despite its origin as a single initiated cell, considerable genetic and phenotypic heterogeneity is observed in a tumor while it is still small and clinically undetectable. Ominously, some transformed cells acquire the ability to invade and metastasize at an early, undetectable stage.
RISK DUE TO CARCINOGENS, PROMOTERS, AND ANTICARCINOGENS IN FOOD
Environmental carcinogens, including chemicals, radiation and viruses, have potential to damage DNA and transform cells leading to cancer in animals. While some of the most potent carcinogens are produced in the extraction and incomplete combustion of fossil fuels, or are synthetic products created by industry, an enormous number of potentially carcinogenic chemicals are produced naturally by plants as defense against predators, as by-products of food processing, and by microorganism consumed in food. Because obesity results from storage of food ingested in excess of requirements, the obese subject may be at greater risk for cancer secondary to ingestion of a greater quantity of carcinogens in the food supply. At the same time, social, psychological, and biological factors that inluence food intake can result in consumption of foods that contain high levels of carcinogens. Some of the more common carcinogens in food include nitrostable amines and nitrates used to preserve food. Sodium nitrite is used to preserve bacon and processed meats such as ham and salami and is converted by gut bacteria to N-nitroso-compounds, carcinogenic in all species studied. Alatoxin produced by the fungus Aspergillus flavus grows on improperly stored grains, nuts, and legumes and has been implicated as a hepatocarcinogen. Additionally, food preparation methods that expose food to high heat for a long time is known to alter protein structure and create carcinogenic heterocyclic amines, lipid peroxides and other mutagens. Meat also contains heme iron and other components implicated in production of endogenous N-nitroso compounds and in increased risk for several cancers including prostate, colon, and rectum. Dietary fat is also implicated in cancer risk. In 1982, the National Academy of Sciences reviewed studies relating tumor growth to diet in experimental animals and large population studies demonstrating increased rates of breast, colon, prostate, and endometrial cancers correlated with per capita animal fat consumption. Based on this evidence, guidelines recommending reduction of fat intake to 30 percent of daily calorie intake were developed. Since then, a large body of experimental evidence has revealed that the relationship of dietary fat to cancer is more complex than originally thought. he inluences of total fat intake and total energy intake have not been irmly distinguished in animal models or in human studies, nor have the carcinogenic efects of red meat been separated from the effects of meat fat. Additionally, individual dietary fatty acids, even within a fatty acid type, may have diferent efects on carcinogenesis, tumor growth, and metastasis. Dietary fatty acids modulate cancer risk and metastasis through their role as substrate for local synthesis of eicosanoid metabolites such as prostaglandins and leukotrienes. hese hormones modulate processes such as tumor-endothelial cell adhesion, proteolytic enzyme activity, and other biological cascades that facilitate tumor growth and spread. While the mechanisms through which a speciic dietary fatty acid type modulates risk have not been fully elucidated, the eiciency of membrane fatty acid conversion to eicosanoids may be involved. Fatty acids of the omega-6 type, derived from grains, produce eicosanoids implicated in cancer risk. In contrast, fatty acids of the omega-3 type, derived from green plants and cold-water ish, replace omega-6 fatty acids in the cell membrane. Eicosanoids produced from diferent fatty acids have diferent structure and may account for the observed diference in cancer risk. Other dietary components also inluence risk. Over 250 epidemiologic studies conducted in numerous countries with diverse diets support the association between fruit and vegetable consumption and reduced risk. In addition to fruits and vegetables, other whole foods including whole grains, legumes, tea, cofee, and chocolate contain a myriad of components including carotenoids, vitamins C, E, and K, dietary iber, lavanoids, indoles, procyanidins, isoprenoids, and other bioactive components. Phytochemicals as well as substances in animal products are under intensive investigation for their ability to reduce DNA damage, modulate cell cycle activity, modify detoxifying enzymes that convert procarcinogens to ultimate carcinogens, mimic estrogens and other hormones by binding their receptors, and other activities that inhibit the initiation, promotion, and progression of cancer.
RISK FROM CHRONIC POSITIVE ENERGY BALANCE
he possibility that chronic caloric overload increased risk for cancer has been investigated for over 50 years. Experiments with overfed animal models demonstrated increased numbers of cancers, while chronically restricted animals lived longer and were cancer free. Epidemiological studies that measured body size and height subsequently revealed that growth exerts a modest inluence on risk for all cancers, especially for hormone-dependent breast, uterine, and prostate cancer. Possible mechanisms for this increased risk include growth promoters and stimulatory hormones such as sex hormones, glucocorticoids, and insulin, as well as inlammatory mediators associated with obesity. Obesity has been generally associated with insulin resistance and elevated plasma insulin levels. Experimental and epidemiologic studies support the hypothesis that the growth promoting efects of insulin increase risk for colon carcinogenesis. Insulin may directly activate its own receptor, or the receptors for insulin-like growth factor (IGF) expressed on normal colorectal cells and on cancer cells. Since insulin is only weakly mitogenic, its action is likely to be indirect, mediated through the growth-promoting efect of nonesteriied fatty acids released from adipose tissue, which potentiate insulin resistance. Alternatively, elevated insulin levels may lead to increased concentrations of IGF and its binding proteins. hese peptides are involved in regulation of cell growth and proliferation as well as cell transformation and death. hus, the interactions of insulin, IGF, and IGF-binding proteins provide a mechanism linking excess energy intake with processes underlying the development and spread of cancer. Obesity and chronic hyperinsulinemia are also associated with changes in total and bioavailable plasma sex steroid levels in both pre- and postmenopausal women. Increased bioavailability of sex steroids, especially estrogens, may result from several interactions with insulin and IGF. Increase in insulin and bioactive IGF concentrations in the obese organism inhibit the hepatic synthesis of sex-hormone–binding globulin (SHBG). Insulin and IGF can also enhance the synthesis of androgens by the gonads and adrenal glands. Finally, androgens undergo increased conversion to estrogen metabolites by aromatization in adipose tissue. hus, in postmenopausal women, the body mass index (BMI) is positively related to plasma levels of estrogen metabolites as well as to levels of bioavailable estrone not bound to SHBG. he “unopposed estrogen” hypothesis proposes that mitogenic efects of estrogens, when insuiciently counterbalanced by progesterone can result in growth promotion in hormone dependent tissues. Recent investigations have revealed that estrogen can also act as a “complete” carcinogen, capable of inlicting DNA damage by oxidative mechanisms. Finally, adipose tissue accumulation is associated with the production of several proinlammatory factors including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein 1, inducible nitric oxide synthase, and transforming growth factor ß1. Macrophages enter adipose tissue where they scavenge large dying adipocytes and release reactive oxidative products and other mediators. While the link between chronic exposure to inlammatory mediators and cancer has not been clearly developed, inlammatory peptides induce rapid cell proliferation and produce DNA-damaging free radicals. Rapid cell division increases the likelihood of replication errors and inefective DNA repair at critical regulatory sites. In an inlammatory environment, key enzyme cascades are upregulated, resulting in synthesis of inlammatory eicosanoids and other mediators known to facilitate tumor growth, invasion, and metastases. One molecular basis for this relationship is through the nuclear factor kappa beta(NFKβ) pathway that regulates apoptosis, cell proliferation, and cell growth arrest and enhances growth of new blood vessels by inducing vascular endothelial growth factor expression. Clinical evidence for the link between chronic inlammation and cancer is seen in the development of hepatic cancer in chronic hepatitis and colon cancer in chronic colitis, and in the inverse association between long-term use of nonsteroidal antiinlammatory drugs (NSAID) and reduced risk of several cancers. In the endometrium, unopposed estrogens, as well as other established risk factors, induce an inlammatory efect. Insulin and estrogen exposure, in conjunction with inlammatory mediators, have been implicated in the development of endometrial cancer. A proinlammatory milieu can initiate and promote neoplastic transformation directly. It can also increase estrogen production, which may facilitate carcinogenesis by disrupting the estrogen-progestogen balance. In summary, increased body size (BMI) and obesity is associated with moderately increased risk for cancers of all types. he data are confounded by diiculties in measurement and the multifactorial nature of the risk factors. he food supply contains both carcinogens and anticarcinogens, thus the choices made by the obese subject may play a major role in actual risk. Accumulation of metabolically active adipocytes and associated macrophages have a signiicant impact on whole body homeostasis. Further, there is evidence that dietary and lifestyle patterns modify the inluence of adipose tissue on metabolic parameters. Mechanistic and clinical investigations are needed to guide recommendations.
