The Linkage Between Obesity and Prostate Cancer
David Heber, MD, PhD, FACP, FACN
Professor of Medicine and Director, UCLA Center for Human Nutrition
Reprinted from PCRI Insights May 2004 vol. 7, no. 2
There are a number of plausible biological mechanisms whereby obesity could promote the development and progression of cancer.1 The evidence for a connection between obesity and common forms of cancer is drawn from studies of populations, animal experiments, and limited clinical research on humans. However, this research largely provides biological proof of principle. With the exception of non-melanoma skin cancers, where a low fat diet led to a reduced incidence of tumors and modest weight loss,2 there are no definitive large-scale clinical intervention studies demonstrating that weight loss or dietary changes reduce the incidence of cancer. Nonetheless, there is a broad base of evidence that is sufficient to warrant advising cancer survivors to follow current dietary advice to achieve and maintain a healthy body weight by increasing the amount of fruits, vegetables, and whole grains in the diet while reducing fats. The balance of this article presents an overview of this evidence.
There is a worldwide epidemic of common forms of cancer including prostate cancer in those countries and socioeconomic groups within countries eating a so-called Western Diet. This chaotic “diet” is characterized by a dietary pattern rich in fat, sugar, and red meat, but poor in fiber, fruits and vegetables.3 Since age is the primary risk factor for cancer, all such associations are based on age-adjusted incidences that can be up to five times higher in so-called high risk countries (e.g. U.S.) compared to low risk countries (e.g. Japan). Moreover, individuals migrating from low risk to high-risk countries increase their risk of cancer substantially within a single generation.4
Obesity is also associated with a number of common forms of cancer.5 These data have implicated environmental and lifestyle factors including diet in the etiology of cancer. There is also evidence that obesity is associated with an increased rate of progression of cancer following initial treatment.6 There is an ever-increasing population of cancer survivors and an increasing incidence of obesity. If patients with diagnosed cancer who have survived initial treatment are treated for obesity, it may improve outcomes and increase median survival. Even if these efforts had no effect on any remaining cancer cells, treating cancer survivors for obesity improves their quality of life and reduces the risk of other chronic diseases including heart disease and diabetes.
Common Biological Processes
Obesity, characterized by excess fatty tissue, has been shown to increase the risk for development of several common cancers. There are a number of biological processes common to these two conditions that could lead to a causal interrelationship. Many hormones involved in obesity also play a role in the initiation and promotion of cancer both at a cellular, paracrine, and systemic level.7 In developed countries, the most common forms of cancer (including lung cancer, breast cancer, prostate cancer, pancreatic cancer, ovarian cancer, uterine cancer, kidney cancer and gallbladder cancer) are epithelial cell cancers. And interactions between epithelial and stromal components within the tissue (as well as hormones reaching the organ via the circulation) may play a role in stimulating tumor development and growth.
There are at least four different mechanisms by which increased hormone secretion may promote cancer development. First, obesity leads to increased production of growth-promoting steroid hormones that can bind to nuclear receptors in hormone-dependent tumor cells. For example, estrogens8 are produced in excess amounts through aromatasation of adrenal androgens by adipose stromal tissues in peripheral fat tissues. Second, free hormone levels can be affected by hormone-hormone interactions as in the case where upper body obesity is associated with reduced Sex Hormone Binding Globulin (SHBG) levels leading to increased free levels of circulating estrogens and testosterone.9 Third, steroid hormone action can trigger increased oxidant-stress-promoting cell proliferation and DNA damage.10 Androgens have been demonstrated to increase oxidant stress in prostate cancer cells, and oxidant defense mechanisms have been shown to be impaired early in the cancer process.
Finally, obesity can increase the production of paracrine factors and hormones which stimulate the production of steroid hormones in cancer tissue through interactions between stromal and epithelial compartments in tissues. Many of these paracrine factors are cytokines produced by both fat cells and white blood cells. Obesity is associated with increased circulating levels of cytokines, and these levels are reduced with weight loss.11 The fat cell, which is the source of many of these so-called adipocytokines (see Figure 1), may play a significant role in the ability of fat tissue to preserve immune resistance to infections. It has long been recognized that malnutrition is associated with multiple impairments of immune function including impaired T-helper cell function. Hence, the ability of fat to store calories provides a separate important function to protect immune defenses.12 Today, cancer and heart disease are replacing infectious diseases as the primary cause of death, as obesity becomes more common in developing countries. It is possible that the increased cytokine secretion observed in obesity is simultaneously having a beneficial effect on infectious disease resistance while at the same time increasing the risk of cancer.
Figure 1. Adipocytokines and Other Fat Cell Products
Information Specific to Prostate Cancer
The diagnosis of prostate cancer has improved in recent years due to the development of the PSA test, which detects prostate cancer before it is physically palpable as a mass on rectal examination.13 Approximately 180,000 American men were diagnosed with prostate cancer in 2000.14 Prostate cancer develops as a result of both inherited and environmental factors. It is associated with aging, and it occurs in a latent or clinically inactive form in 30% to 40% of men by age 30 to 50 years and in 75% of men by age 80.15,16 Because latent or clinically inactive cancers were not as effectively diagnosed prior to the development of the PSA test, some uncertainty exists in predicting the behavior of prostate cancer after diagnosis.
The cause of this disease is not fully understood, but a family history, the effects of androgens (like testosterone) and other hormones, and environmental and dietary factors may all be involved. The international variations in the rates of prostate cancer are considerable. (See Figure 2.) The county of Qidong in China has the lowest recorded incidence rate, 0.5 per 100,000 men. By comparison, Sweden has a rate of 55.3 per 100,000 men and the U.S. has a rate of 102.1 per 100,000 men.17 Of course, diagnosing silent cancer by blood PSA increases the statistical incidence of the disease because more clinically silent cancers are diagnosed. Global differences in incidence are probably not due to inheritance. If individuals with the same inherited genes are raised in two different environments, the risk of prostate cancer is associated with the country in which they are raised.18
Figure 2. Prostate cancer incidence around the world.
An American Cancer Society survey of 750,000 individuals demonstrated that being obese increased the risk of prostate cancer.19 Among the various nutritional factors examined, per capita total fat consumption correlates with increased prostate cancer incidence in cross-national studies. In a population-based case-control study of prostate cancer among blacks, whites and Asian-Americans in Los Angeles, San Francisco, Hawaii, Vancouver and Toronto, a positive statistically significant association of prostate cancer risk and total fat intake was found for all ethnic groups combined. This association was attributable to energy intake from saturated fats.20 In Japan, an increase in prostate cancer risk has been noted as the per capita intake of dietary fat has increased.21 In Hawaii, a correlation was found between saturated fat intake and prostate cancer incidence. A representative sample of over 4,000 adults at least 45 years of age from the five main ethnic groups in Hawaii were interviewed regarding their diet, and multiple regression analysis was used to assess the statistical relationship between ethnic-sex-specific dietary intakes and corresponding population-based cancer incidence rates. Significant positive associations were found for prostate cancer with fat intake from saturated and animal sources, and for animal protein intake.22 In the U.S., counties with higher prostate cancer incidence have higher per capita fat intake.5
Using questionnaires that ask how often a particular food is normally eaten, scientists have found clues to the association of dietary fat with cancer. In a retrospective study by West et al23 and a prospective study by Giovannucci et al,24 the more aggressive prostate cancers in patients were significantly correlated with high fat intake. In the Giovannucci study, those individuals eating the highest amount of meat had a risk of developing prostate cancer 2.64 times that of those eating the least. The course of prostate cancer may also be affected by fat intake. Kolonel et al25 found a significant relationship between dietary fat and prostate cancer mortality in Hawaiian men 70 years and older. In addition, several studies have demonstrated a positive association between saturated fat intake from meat and dairy products and prostate cancer.26-31 Other factors in the diet may enhance or diminish the risk for prostate cancer. Several retrospective and prospective studies have found an association between prostate cancer and dietary fat; however, none has shown a negative correlation.
Latent vs. Clinically Active Prostate Cancer
Approximately 60% of all men have latent or clinically silent prostate cancer, and the incidence of this latent form is the same in the United States and Japan.32 These estimates are based on autopsies of men who die for reasons other than prostate cancer. At the same time, clinically significant prostate cancer is much more common in the United States than in Japan. When Japanese men migrate to the United States, their incidence of clinically detected prostate cancer rises within one generation. These facts suggest that nutrition and lifestyle practices in lower-risk countries suppress the growth of prostate cancer so that it remains small and confined and is rarely diagnosed clinically.
The Effects of Aging
Prostate cancer is a disease associated with aging and obesity. It has been said that if you live long enough you will have prostate cancer, and over 90 percent of men over the age of 90 have detectable carcinomas in prostatic tissue. Men who have premature accidental deaths are found to have precancerous lesions such as prostatic intraepithelial neoplasia (PIN) in their prostate glands if they are between 40 and 60 years of age. Above 60 years of age, foci of prostatic cancer are found in addition to PIN lesions. Also commonly associated with increasing age is a shift in the pro-oxidant-anti-oxidant balance of many tissues toward a more oxidative state. Recently, foci of proliferative inflammatory atrophy (PIA) have been found in prostatic cancer biopsy specimens. While the DNA in PIN and cancerous lesions have multiple abnormalities, the DNA in the PIA lesions is normal.
Given the common occurrence of prostatitis, both clinical and sub-clinical, it has been hypothesized that the prostate gland with aging undergoes repeated inflammation leading to DNA damage, mutation, and ultimately the formation of precancerous and cancerous lesions. African-American men have a significantly higher incidence of prostatic cancer compared to Caucasian men and have higher levels of IGF-1 and androgens at puberty. It has been proposed that androgen exposure, which has long been associated with the development of prostate cancer, may be a means by which the pro-oxidant-anti-oxidant balance of prostate cells is altered.
In rats, prostatic cancer can be induced by prolonged administration of testosterone. The ablation of androgens has formed the basis for first-line therapy of metastatic prostate cancer. It has also been proposed that hormones play a role in the progression of prostate cancer from silent to clinically significant forms. Since diet can influence circulating sex steroid hormones, diet and androgens may alter prostate cancer biology via common pathways. Urinary levels of androgens and estrogens were decreased in a group of Caucasian and African American men fed a diet in which fat content was reduced from 40% to 30% of total calories.33 A very low-fat, high-fiber diet has been shown to reduce sex steroid levels in a group of normal men34 Therefore, changes in sex hormones may mediate in part the effects of diet on prostate cancer growth.
As sedentary men age, they often experience an increase in fat mass, a decrease in lean body mass, and a change in hormone levels. These factors have been shown to increase the risk of prostate cancer. In a study of Seventh-Day Adventists, obesity was shown to significantly increase the risk of fatal prostate cancer compared with ideal weight.35 This association was also noted in the American Cancer Society's study of 750,000 individuals.5 With aging, the prevalence of benign prostatic hyperplasia (BPH) increases; this is an androgen-dependent chronic disorder.36
Dihydrotestosterone (DHT) formed from testosterone in the prostate and in the testes appears to promote hyperplasia in humans, dogs and rats. Horton et al37 found increased levels of circulating DHT in elderly men compared with young men (89 ng/dl vs. 49 ng/dl); in this study, nearly all the elderly men had BPH. Since the prostate can convert testosterone to DHT, some have hypothesized that increased metabolic conversion of testosterone to DHT may account for the increased DHT levels in elderly men. Therefore, the effects of a high-fat diet on prostate cancer are partially explained by the changes in hormones resulting from that diet and by a decreasing lean body mass.38
In prostate cancer cell lines exposed to physiological levels of 5-alpha-reductase (5AR) dihydrotestosterone (DHT) and to the synthetic androgen R1881, proliferative responses and changes in oxidative stress were correlated.10 Physiologic levels of androgens are capable of increasing oxidative stress in androgen-responsive LNCaP prostate carcinoma cells. The evidence suggests that this result is due in part to increased mitochondrial activity. Androgens also alter intracellular glutathione levels and the activity of certain detoxification enzymes, such as gamma-glutamyl transpeptidase, that are important for maintenance of the cellular pro-oxidant-anti-oxidant balance.
Although there is no clinical trial data available to define the benefits of weight reduction, there is a clear association of obesity with cancer risk, incidence, or progression for a number of common forms of cancer. Evidence is much stronger for certain forms of cancer than others, but clearly, the endocrine and immune systems may play an important role in mediating the effects of increased adiposity on cancer risk based on the hormones and adipocytokines produced by fat cells. Many of the changes observed in these systems among obese patients are related but secondary phenomena of unknown significance, but others may be important in cancer development, promotion, or progression. Abnormalities in adipocytokine production and action are central to many of the observed metabolic changes in the obese patient, and may play a role in the cause and maintenance of the obese state as well as in associated forms of cancer.
1. Heber D, Blackburn GL, Go VLW (eds). Nutritional Oncology. Academic Press, San Diego CA, 1999.
2. Jaax S, Scott LW, Wolf JE, Thornby JI, and Black HS. General guidelines for a low fat diet effective in the management of nonmelanoma skin cancer. Nutr. Cancer 1997; 27:150-156.
3. Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int. J. Cancer 1975; 15: 617-631.
4. Shimizu H, et al. Cancers of the prostate and breast among Japanese and white immigrants to Los Angeles County. Br. J. Cancer 1991; 63: 963-966.
5. Garfinkel L. Overweight and Cancer. Ann of Int Med. 1985; 103:1034-36.
6. Newman SC, Miller AB, and Howe GR A study of the effect of weight and dietary fat on breast cancer survival time. Am J Epidemiol 1986; 123: 767.
7. Heber D. The role of nutrition in cancer prevention and control. Oncology 1992;6: 9-14.
8. Nimrod A, Ryan KH: Aromatization of androgens by human abdominal and breast fat tissue. J Clin Endo Metab 1975;40:367.
9. Kissebah AH, Evans DJ, Peiris A, et al. Endocrine characteristics in regional obesities: Role of sex steroids. In Vague J, Bjorntorp P, Guy-Grand B et al (eds). : Metabolic Complications of Human Obesities. Amsterdam, Excerpta Medica,1985, p. 115.
10. Ripple MO, Henry WF, Rago RP, Wilding G. Prooxidant-antioxidant shift induced by androgen treatment of human prostate carcinoma cells. J Natl Cancer Inst 1997; 89: 408.
11. Winkler G, Lakatos P, Salamon F, Nagy Z, Speer G, Kovacs M, Harmos G, Dworak O, Cseh K. Elevated serum TNF-alpha level as a link between endothelial dysfunction and insulin resistance in normotensive obese patients. Diabet Med 1999; 16:207-211.
12. Chandra RK. The nutrition-immunity-infection nexis: The enumeration and functional assessment of lymphocyte subsets in nutritional deficiency. Nutr Res 1983; 3:605-615.
13. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA. 1993; 270:948-54.
14. Landis SH, Murray T, Bolden S, Wingo PA. Cancer Statistics, CA Cancer J Clin. 1998; 48:6-29.
15. Tanagho EA, McAninch JW, editors. 1995. Smith’s General Urology. Appleton and Lange, Norwalk, CT.
16. Thompson IM, Coltman CA, Brawley OW, Ryan A. Chemoprevention of
prostate cancer. Semin Urol. 1995; 13:122-29.
17. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, editors. 1997. Cancer Incidence in Five Continents, Volume VII. Scientific Publications #143.
18. Mandel JS, Schuman LM. Epidemiology of cancer of the prostate. Rev Cancer Epidemiol. 1980;1:1-65.
19. Lew EA, Garfinkel L. Variations in mortality by weight among 750,000 men and women. J Chron Dis. 1979; 32:563-76.
20. Whittemore AS, Kolonel LH, Wu AH, John EM, Gallagher RP, Howe GR, Burch JD, Hankin J, Dreon DM, West DW et al. Prostate cancer in relation to diet, physical activity and body size, in blacks, whites and Asians in the United States and Canada. J Nat Cancer Inst. 1995; 87:652-61.
21. Boyle P, Kevi R, Lucchuni F, LaVecchia C. Trends in diet-related cancers in Japan: A conundrum? Lancet. 1993; 349:752.
22. Kolonel LN, Hankin JH, Lee J, Chu SY, Nomura AMY, Hinds MW. Nutrient intakes in relation to cancer incidence in Hawaii. Br J Cancer. 1981;44:332-39.
23. West DW, Slattery ML, Robison LM, French TK, Mahoney AW. Adult dietary intake and prostate cancer risk in Utah: A case-control study with special emphasis on aggressive tumors. Cancer Causes Control. 1991;2:85-94.
24. Giovannucci E, Rimm EB, Colditz GA, Stampfer MJ, Ascherio A et al. A prospective study of dietary fat and risk of prostate cancer. J Nat Cancer Inst 1993; 85:1571-79.
25. Kolonel LN, Yoshizawa CN, Hankin JN. Diet and prostatic cancer: A case-control study in Hawaii. Am J Epidemiol. 1988; 127:999-1012.
26. Mettlin C, Selenskas S, Natarajan N, Huben R. Beta-carotene and animal fats and their relationship to prostate cancer risk. Cancer. 1989; 64:605-12.
27. Snowdon DA, Phillips RL, Choi W. Diet, obesity and risk of fatal prostate cancer. Am J Epidemiol. 1984; 120:244-50.
28. Kaul L, Heshmat MY, Kovi J, Jackson MA, Jackson AG et al. The role of diet in prostate cancer. Nutr Cancer. 1987; 9:123-28.
29. Slattery ML, Schumacher MC, West DW, Robison LM, French TK. Food consumption trends between adolescent and adult years and subsequent risk of prostate cancer. Am J Clin Nutr. 1990; 52:752-57.
30. Ross RK, Shimizu H, Paganini-Hill A, Honda G. Case-control studies of prostate cancer in blacks and whites in Southern California. J Nat Cancer Inst.1987; 78:869-74.
31. Talamini R, LaVecchia C, Decarli A, Negri E, Franceschi S. Nutrition, social factors and prostatic cancer in a Northern Italian population. Br J Cancer. 1986;53:817-21.
32. Yatani R, Shiraishi T, Nakakuki K, Kusano I, Takanari H, Hayashi T. Trends in frequency of latent prostate carcinoma in Japan from 1965-1979 to 1982-1986. J Nat Cancer Inst. 1988; 80:683-87.
33. Hill P, Wynder EL, Garbaczewski L et al. Diet and urinary steroids in black and white North American men and black South African men. Cancer Res. 1987; 47:2982-85.
34. Dorgan JF, Judd JT, Longcope C, Brown C, Scatzkin A et al. Effects of dietary fat and fiber on plasma and urine estrogens in men: A controlled feeding study. Am J Clin Nutr. 1996; 64:850-55.
35. Mills PK, Beeson WL, Phillips RL, Fraser GE. Cohort study of diet, lifestyle and prostate cancer in Adventist men. Cancer. 1989; 64:598-604.
36. Geller J, Albert J. 1982. The effect of aging on the prostate. In Endocrine Aspects of Aging. (Korenman SG, ed.) Elsevier, New York, pp.137-61.
37. Horton R, Hsieh P, Barberia J, Pages L, Cosgrove M. Altered blood androgens in elderly men with prostatic hyperplasia. J Clin Endo Metab. 1975;41:793-96.
38. Snowdon DA, Phillips RL, Choi W. Diet, obesity and risk of fatal prostate cancer. Am J Epidemiol. 1984;120:244-50.