Obesity and Cancer

According to the National Institute of Health, nearly two-thirds of adults in the United States are overweight or obese (2007). Research suggests that obesity may be the most preventable risk factor of cancer for non-smokers, and many studies are testing for the effects that obesity has in all cancers and at specific cancer sites. It is known that obesity plays a significant role in cancer; however, the knowledge of the relationship to all cancers and the overall health effect of excess weight in terms of total mortality from cancer is limited (Calle, Redriguez, Walker-Thurmond, & Thun, 2003). In this paper I will examine the research available on obesity and its relationship to breast cancer (in post-menopausal women), endometrial, colon, esophagus, kidney, and pancreatic cancers, and briefly mention a few other cancers currently being studied for a possible link to obesity. The rise of obesity in the last 25 years has been most prominent in the United States. It is not, however, limited to the United States; for instance, similar trends are being seen in other developing countries. As it becomes easier to access tasty but unhealthy food options and as physical activity declines, caloric intake is now exceeding caloric expenditure. Genetic factors have been shown to predispose an individual to become obese, but environmental factors are the ultimate cause for the rise of obesity within populations. It is the metabolic consequences of obesity that are having an effect on cancer cell growth. The effects of circulating peptide and steroid hormones along with their binding factors are culprits linking obesity to cancer (Calle & Thun, 2000). Obesity creates an environment conducive for cancer cell proliferation. In this paper, I examine the effects of an altered stromal environment, insulin, insulin-like growth factors (IGFs), blood glucose levels, leptin, growth hormone (GH), sex hormone-binding globulin (SHBG), androgens, and estrogens and how their interactions promote cancer cell proliferation.
Breast Cancer
Early studies of Calle and Thun (2004) found the connection between body size and risk of breast cancer to be linked to menopausal status; the heavier the post-menopausal women were, proportionally increased their risk of breast cancer. Obesity has been shown in post-menopausal women, especially with central adiposity, to increase rates of breast cancer by 30-50% (Calle & Thun, 2004). A. Lee and D. Lee (1999) published that breast cancer death rates of very obese women are three times higher than those of lean women. This statistic reflects the biological effect of adiposity on breast cancer’s ability to proliferate in obese individuals. The association between obesity and post-menopausal breast cancer is also stronger in women who have not used hormone replacement therapy. In women who do not use hormone replacement therapy the hypothesis is that the larger the BMI the more endogenous estrogen the body will make, and two-thirds of all breast tumors have been shown to have estrogen receptors and require estrogen for growth (A. Lee & D. Lee, 1999). Estrogen receptor (ER)-positive tumors are thus receiving continuous stimulation in obese women, with more endogenous estrogen than compared with the lean women. Estrogen is a sex-steroid hormone that stimulates the proliferation of mammary epithelial cells in development and oncogenesis. Fat tissue, associated with obese and overweight individuals, is the major site of uptake, storage, action, and metabolism of sex-steroids. Ovarian production of estrogen falls to very low levels after menopause and aromatization of androgens to estrogens in adipose tissue becomes one of the most important sources of estrogen in the circulation and for peripheral tissues (Calle & Thun, 2004). Barnard, Gonzalez, Liva, & Ngo, (2006) added that obesity contributes to hyperinsulinaemia, which causes a reduction in the hepatic synthesis of and circulating levels of sex-hormone binding globulin (SHBG). SHBGs bind endogenous estrogen. The New England Journal of Medicine published a study on the mechanisms of disease regarding estrogen carcinogenesis in breast cancer, showing that carcinogenesis in the breast is caused by the metabolism of estrogens into estrone (E1) and estradial (E2) and when combined with the effects of reduced levels of SHBG leads to an increase of free circulating estrogens in the body that diffuse into and act on target cells in breast tissue stimulating tumor growth (Yager & Davidson, 2006). The evidence in Yager and Davidson’s (2006) study suggests the free circulating estrogens promote cellular proliferation by affecting growth factor pathways. The mechanisms in which free estrogens, E1 and E2, contribute to each phase of the carcinogenic process are complex; two known ways estrogens affect growth pathways are by the following: inhibiting apoptosis by regulating bcl-2, which is a key protein involved in apoptosis, and increasing the production of proteases that can enhance the invasiveness of tumor cells (Yager & Davidson, 2006).
Another factor in the development and proliferation of breast cancer involves insulin, insulin-like growth factors (IGFs), and growth hormone (GH). IGFs are polypeptides with a high sequence similarity to insulin; they are part of the cell’s communication system and are required for achieving normal growth (A. Lee & D. Lee, 1999). IGF-1 is a potent mitogen for normal and transformed breast epithelial cells and is associated with mammary gland hyperplasia and mammary cancer in animals (A. Lee & D. Lee, 1999). Variation in the levels of insulin, GH, and IGFs are affected by the following: genetics, time of day, age, sex, exercise status, stress, nutrition level, estrogen levels, and BMI (A. Lee & D. Lee, 1999). Excess adipose tissue results in high concentrations of GH, another steroid hormone, and high concentrations of GH indirectly stimulate high concentrations of IGFs (A. Lee & D. Lee, 1999). Excess adiposity leads to insulin resistance, therefore increasing the levels of insulin in the blood and tissues. Increased insulin affects the liver by reducing the amount of insulin-like growth factor binding proteins (IGFBP) it synthesizes (A. Lee & D. Lee, 1999). IGF-1 is also secreted in the liver, but as a result of stimulation by growth hormone (GH), which in obese individuals is present in high concentrations (A. Lee & D. Lee, 1999). The low levels of IGFBPs increase the levels of circulating, unbound, IGFs. IGF-1 receptors have been found in normal human breast tissue and in human breast tumors. Le, et al. (2007) evaluated the impact of obesity on mammary glands and the surrounding tumor stroma using non-linear imaging to understand the influence of the microenvironment on mammary tumorigenesis. They used out-bred Sprague-Dawley rats at 21 days old and divided them up into four groups comprised of 10 lean rat chow and 8 obese Western rats with no tumors and 9 lean rat chow tumor and 9 obese Western tumor rats (Le et al., 2007). This study was done to demonstrate that cancer cells are motivated by intrinsic cellular factors as well as extrinsic factors such as the microenvironment. The microenvironment which affects the mammary stroma is comprised of adipocytes, collagen fibrils, blood vessels, and others. The surrounding stromal environment was found to have an integral role in mammary tumorigenesis (Le et al., 2007). Analysis showed that proteins secreted by adipocytes induced epithelial cells to proliferate, invade, and survive (Le et al., 2007). Also type-1 collagen was revealed to, in addition to playing a role in the structural support of the extra-cellular matrix (ECM), be an important binding site for a large number of mitogenic growth factors (Le et al., 2007). Remodeling of this collagen, due to the adipocytes, is associated with tumor invasiveness (Le et al., 2007). Le et al. (2007) reported direct correlations between obesity and the size of adipocytes in mammary tissue and between obesity and the ECM collagen content in the mammary stroma. A high concentration of leptin (a protein hormone) was found in the obese rats. Leptin, which controls energy balance and food intake, can also act on several peripheral organs and tissues (Calle & Thun, 2004). Leptin, found in high levels in these obese rats, stimulated the expression of collagen type-I fibrils which bind mitogenic growth factors such as unbound, circulating, IGFs that promote cellular proliferation and inhibit apoptosis (Le et al., 2007). This study further enhanced other studies on the link between obesity and breast cancer by suggesting that obesity, in addition to promoting breast cancer, also promotes a stromal environment favorable for proliferation and invasion of the mammary tumors.
Endometrial Cancer Similar to breast cancer, the proposed mechanism for the increased risk of endometrial cancer is the high levels of circulating estrogens in obese post-menopausal women (Calle & Thun, 2004). The key pathway seems to be that the increased estrogens are not balanced by progesterone. In obese pre-menopausal women anovulatory cycles may contribute to a deficiency of progesterone, which normally opposes the mitogenic effect of estrogen on the endometrial mucosa (Rapp et al., 2005). Petridou, et al. (2002) studied the relationship of leptin and BMI to endometrial cancer and found that leptin is positively coupled with this type of cancer. Leptin, a protein hormone encoded by the ob gene, is synthesized and secreted by adipose tissue. According to Petridou et al. (2002) leptin is able to induce the growth and transformation of cancer, but not normal cells, stimulating cell invasion and tumor metastasis. The expression of leptin in the adipose tissue is enhanced by insulin, glucocorticoids, and estrogens. Leptin is inhibited by the presence of progesterone in the human endometrium (Petridou et al., 2002). As with breast cancer, obese individuals have an increased conversion of androgens in the body into estrogens—estrone (E1) and estradial (E2). The increased risk of obese women’s developing endometrial cancer is accredited to the alterations in sex-hormonal patterns, where progesterone does not balance the free estrogens, eventually influencing the endometrial epithelium to develop cancer.
Colon Cancer
Obesity has been shown to correlate with high risks of colon cancer in men and in women. The International Agency for Research on Cancer states that colon cancer is the second most common cause of cancer-related deaths in the western world (2007). Central adiposity is a stronger predictor of colon cancer risk than peripheral adiposity or general excess weight (Calle & Thun, 2004). The mechanism by which central adiposity increases colon cancer is through its effect on insulin production. Obese individuals develop insulin resistance and thus have increased levels of insulin in the blood and tissues. Insulin and IGFs have been shown to promote the growth of colonic mucosal cells, and the growth of colonic carcinoma cells in vitro studies (John, Irukulla, Abulafi, Kumar, & Mendalls, 2006). IGFs also inhibit apoptosis (John et al., 2006). Both normal colon epithelia and cancer cells express IGF-1 receptors. In colon cancer cells, high concentrations of IGF-1 induce the production of angiogenic factors that promote tumor growth (John et al., 2006). Case-control studies have found an increased risk of colon cancer and large adenomas with increasing levels of IGF-1, which are indirectly linked to high levels of insulin that act on the liver to reduce the production of IGFBPs (A. Lee & D. Lee, 1999).
Obesity may also contribute to the development of colon cancer through its influence on bowel inflammation. Obesity induces pro-inflammatory pathways which stimulate genes to promote cell survival. Biologically active proteins are secreted by adipose tissue; these are adipokines (A. Lee & D. Lee, 1999). Over 50 adipokines have been identified thus far and they regulate processes of lipid homeostasis, immune function, insulin sensitivity, blood pressure, and other pathways (John et al., 2006). As adipocytes hypertrophy they secrete increasing amounts of these adipokines, which one function is to stimulate the pro-inflammatory pathway. Long-term activation of this pathway promotes tumorigenesis (John et al., 2006). Lack of exercise, smoking, and reduced fiber intake are also associated with increased levels of bowel inflammation (John et al., 2006).
Anti-inflammatory drugs already have a role in preventing colon cancer reoccurrence. In addition to anti-inflammatory drugs, physical exercise suppresses colon cancer adenoma by promoting regular bowel movements, thus reducing the length of time the colon epithelia is exposed to carcinogens (American Cancer Society, 2006).
Esophageal Cancer Esophageal cancer has increased in North America and Europe over the last three decades. The reasons for the increase are mostly unknown, but a likely connection between the rise in obesity and the rise of esophageal cancer may be the answer. A high BMI can increase the amount of gastroesophageal reflux, which has been shown to be a predecessor to esophageal cancer (Veugelers, Porter, Guernsey, & Casson, 2006). Veugelers et al. (2006) revealed that when compared to persons of normal weight, obese individuals had a five-fold increased risk for esophageal cancer. Those who were obese at age 20 were particularly at a high risk for development of the cancer. The underlying mechanisms between BMI and gastroesophageal reflux progressing into esophageal carcinoma have not yet been clearly defined but may be due to obese individuals’ having increased intra-abdominal pressure (Calle & Thun, 2004).
Similar to the other cancers mentioned, the metabolic consequences of obesity most likely play a role in esophageal cancer as well, through the pathways involving leptin, insulin and insulin-like growth factors (IGFs) which either directly or indirectly stimulate cell proliferation and inhibit apoptosis of epithelial cancer cells (Calle & Thun, 2004).
Kidney Cancer
Renal cell cancer, the predominant form of kidney cancer, has been increasing in the U.S. and in most western countries. Today, renal cell cancer accounts for about two percent of all the cancer cases in the United States (Bergstrom et al., 2001). The highest rates are found in North America and Europe, and the lowest rates are found in Asia (Chow, Gridley, Fraumeni, & Jarvolm, 2000). Rising rates of renal cell cancer and rising rates of obesity lead to speculation on whether or not obesity is a factor in renal cell cancer. Renal cell cancer is equivalent between the sexes: one group is not at a higher risk than the other. Increasing BMI is accompanied by elevated levels of fasting glucose and thus, through the pathways we have seen in the previously discussed cancers, results in elevated levels of IGFs in both men and women. Insulin and IGF-I could contribute to the growth and proliferation of renal cancer cells as well. Epidemiological studies indicate that patients with diabetes have an increased risk of renal cell cancer (Chow et al., 2000). Obesity could also have other effects on the kidneys. Obese individuals have been reported to have higher glomerular filtration rates and renal plasma flow, which may increase the risk of kidney damage (Chow et al., 2000). Damaged kidneys are more susceptible to carcinogens. The New England Journal of Medicine’s report on obesity, hypertension, and the risk of kidney cancer stated that even small excesses in BMI and blood pressure are significant regarding the development of renal cell cancer risk factors that can be easily controlled (Chow et al., 2000).
Pancreatic Cancer Obese individuals, especially those with central adiposity are at risk for development of pancreatic cancer. Evidence from in vitro animal and human studies indicates that insulin, insulin resistance, and abnormal glucose metabolism may take part in the development of pancreatic cancer (Larsson, Hakansson, Naslund, Bergkvist & Wolk, 2005). The chronic hyperinsulinemia and glucose intolerance associated with diabetes is seen as positively correlated with pancreatic cancer (Larsson et al., 2005). Diabetes and obesity are also correlated, indicating that obesity does actually play an indirect part in pancreatic cancer through diabetes. Those with a history of diabetes are at a two-fold elevated risk of pancreatic cancer (Larsson et al., 2005). Like the other cancers in this discussion, high insulin concentrations contribute to cancer cell proliferation. The exocrine cells of the pancreas are exposed to high levels of insulin from the insulin-producing pancreatic islets (Larsson et al., 2005). High insulin concentrations activate the IGF pathways which have growth-promoting effects on cells.
Other Cancers
Other studies are looking at cancers of the gall bladder, which are thought to be linked to obesity indirectly by the increased risk of gallstones, which damage the gall bladder and leave it susceptible to cancer. Even more studies have been done on obesity and its link to cancers of the liver, stomach, uterine cervix, and hematopoietic system, but data on these are limited, inconsistent, and inconclusive.
The American Cancer Society’s study on prospective mortality illustrated that an increased BMI is associated with increased death rates from all cancers combined and for cancers at multiple specific sites (Calle & Thun, 2004). Estimated 90,000-plus deaths from cancer per year are attributable to obese and overweight individuals (Calle & Thun, 2004).
The metabolic consequences of obesity have been shown to have deleterious effects on individuals who have cancer by stimulating tumor growth and/or the proliferation of cancerous tumors. Cell proliferation is promoted by excess insulin and IGFs the secretion of which are indirectly increased by the presence of adipocytes. Excess androgens in women are produced by fat tissue. Sex-hormone binding globulin (SHBG) is able to bind these steroids, but high levels of insulin decrease the synthesis of these proteins, and other binding proteins in the liver. When overwhelmed by an increase in production of the steroids, due to an increase in fatty tissue, the estrogens and the IGFs are left circulating where they can cause damage by stimulating cell growth of harmful cancerous cells. Leptin is present in increased levels in obese individuals due to the greater amount of fatty tissue. These mechanisms can be modified and/or controlled by limiting the amount of excess weight on the body. Adopting a lifestyle which includes physical activity and a healthy, low-fat diet is the best way to promote long-term weight loss, good health, and a cancer free body.

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