Reflectionson Diet, Nutrition,And Cancer1

[CANCER RESEARCH 43. 3024-3027. June 1983] 0008-5472/83/0043-0000$02.00 Letter to the Editor Reflectionson Diet, Nutrition,and Cancer1

Ernst Wynder

American Health Foundation, Valhalla, New York 10595-1599

The recent report by the National Research Council-National studies attempting to assess the effect of certain dietary com Academy of Sciences Committee on Diet, Nutrition, and Cancer ponents, such as fat, fiber, and. J-carotene, in appropriate animal covered a broad range of nutritional factors that appear to relate models; and (d) certain mechanistic considerations derived from to human carcinogenesis (30). The Committee carefully evalu such studies in man and in animals in the light of contemporary ated the various parameters whereby diet does or could influence concepts of the mechanisms of carcinogenesis and cancer caus cancer development, made recommendations to the scientific ation. In turn, there are problems with: (a) nutrition methodology community and the public based upon its findings, and concluded to delineate typical dietary patterns in populations; (b) classifi that, of all the nutrients that affect the development of cancer in cation of the mode of action of key dietary components involved humans, only for dietary fat was there sufficiently convincing in nutritional carcinogenesis; (c) the biological plausibility of the evidence to term its effect on breast and colon cancer develop relationship between nutritional elements and certain cancers; ment as "causative." The report reflects the majority opinion of and (d) societal implications. These elements will be discussed. experts in nutritional, experimental, and human carcinogenesis. It is a significant document and a valuable resource to everyone concerned with nutrition and cancer. As such, the Committee's METHODOLOGICAL CONSIDERATIONS recommendations are likely to serve as a catalyst for future Nutritional intake within a given population is difficult to study progress in an important area of environmental carcinogenesis because of inherent difficulties with nutritional surveys and inter and thus in cancer causation and prevention. view techniques (13, 15). The problem is magnified by the fact The report has caused many to reflect on the broad scientific that the intake of various dietary components is interrelated. and public health opportunities that have emerged from the study Thus, population groups who get a preponderance of calories of nutrition and cancer. It is not that the concept of nutrition from fat are likely to have a low intake of starches and wee affecting human cancer is new; in fact, as early as 1937, Fred versa. Conclusions generally have to be reached indirectly by erick Hoffman (19), an actuarial statistician and lawyer, wrote a provocative 750-page book on cancer and diet. In the middle comparing nutritional intakes in different geographical population 1940's, Tannenbaum (40) conducted a series of elegant studies groups, such as Japanese versus Western customary diets, or in migrant populations, or in special groups within a population, demonstrating the effects of diet in terms of total calories and fat on breast tumor growth in animals. In the 1950's and 1960's, such as Mormons, Seventh-Day Adventists, or members of religious orders (6,17,18, 38). increasing epidemiological evidence came forth, linking, first, specific life-style habits such as alcohol consumption to human A further problem is that nutrition exerts its major impact on carcinogenesis at important target organs in humans, such as cancer and, subsequently, a broad range of dietary intakes, including both micro- and macronutrients. the colon, breast, endometrium, or prostate, as a modifier rather than an initiator of tumorigenesis (7, 8, 27, 28). The question of Particularly within the last decade, epidemiological evidence the significance of the dietary and fecal mutagens in the context supported by extensive experimental studies has steadily ad of these types of cancer awaits clarification and documentation vanced the concept that nutrition does, in fact, affect human (30, 31, 46). It is true that generally we are trained to think in carcinogenesis at specific target organs by various mechanisms, terms of carcinogens, whether chemical, viral, or physical, as a some of which are as yet unclear (1, 31, 50). key to carcinogenesis (17, 46). Thus, it is more difficult to However, in contrast to such fields as genetics, immunology, formulate concepts related to agents that act as enhancers of and virology, the number of investigators who have been en growth and development of initiated cells. Even those scientists gaged in the study of nutritional carcinogenesis has been rela who deal with the mechanistic aspects of tumor promotion are tively small. Unfortunately, there has been a tendency to regard concerned largely with such potent but unphysiological factors nutrition as being out of the mainstream of academic science in as croton oil (phorbol esters) rather than with physiologically cancer studies even when its biological effects have been relevant agents that may be involved in the promotion process soundly documented through: (a) observations in humans in such as alcohol, bile acids, or hormones and their effect on studies of epidemiology and geographic pathology in populations endocrine balances (14, 35, 36). with varied specific dietary customs; (b) deliberately planned Yet, as concluded by the Committee, nutrition and diet play human studies of metabolic epidemiology; (c) carefully designed major roles in human carcinogenesis. While an understanding of the exact mechanism by which nutrition and diet can affect 1The concepts presented herein are based on research performed at the human carcinogenesis may not be essential to establishing caus American Health Foundation facilities at the Naylor Dana Institute for Disease ation, it would be of great value in the attempt to define a cause- Prevention, Valhalla, N.Y., and the Mahoney Institute for Health Maintenance, 320 and-effect relationship and is of obvious importance in designing E. 43rd St., New York, N.Y. 10017. Received August 16. 1982; accepted March 2, 1983. lasting preventive strategies.

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MECHANISTIC CONSIDERATIONS the biosynthesis of estrogens from extraovarian sources via the aromatization of androgens (48). The above illustrate some of Each kind of cancer has specific causes and modifying factors. The deliberate study of the causes for each type of cancer, such the mechanisms whereby total fat levels, both saturated and unsaturated fats, can influence tumor growth and where the as cancer of the stomach, colon, or pancreas, has delineated action of total fat in carcinogenesis differs from the role of fat in specific risk factors or modifying components. The exacting atherosclerosis in which only the saturated fatty acid component analysis of the mode of action and the role played by each such factor has provided the current knowledge relative to organo- appears to have the most deleterious effect. tropic carcinogenesis. Except for the cases of esophageal and stomach cancer (10, The diet can include genotoxic carcinogens such as, for in 21, 24, 37), the main effect of nutrition is seen largely as depending on developmental, enhancing phenomena of an epi- stance, aflatoxin or polycyclic aromatic hydrocarbons or may provide precursors for the formation of nitrosamines or nitros- genetic nature rather than genotoxic processes (46). We may conclude that experiments with nutritional factors have to involve amides (10, 21, 28, 37, 46). It is likely, however, for most of the larger concentrations and the agents need to be present over a kinds of cancer seen in man that the most important effects of longer period of time, in contrast to tests dealing with genotoxic nutrition are associated with nutritional deficiencies, and even agents (4, 11, 47). Extrapolation of such experiments to the more so with excesses as seen in the association of a Western human setting suggests that lower concentrations of modifying, diet with cancers of the breast, endometrium, colon, and pros epigenetic agents at the target organ would meaningfully reduce tate. As an example of deficiencies, the high incidence of esopha- disease risk, especially since their action is reversible up to a certain point (48). Since most currently known nutritional and geal cancer in certain parts of Iran and China has been suggested dietary factors such as the levels of fat or fiber, for example, act to be related to dietary deficiencies, specifically diets low in fresh at the promotional phase of carcinogenesis, manipulation of fruits and vegetables, and hence with low estimated intakes of promotion with dietary means would seem to be a sound, vitamin A, vitamin C, and riboflavin (9, 23). It has also been feasible, and effective method of preventing fatalities due to suggested that dietary nutritional deficiencies such as zinc, mag certain cancers. nesium, nicotinic acid, and riboflavin in populations at high risk for esophageal cancer may also occur in alcohol abusers and might increase the susceptibility of the esophageal epithelium to BIOLOGICAL PLAUSIBILITY neoplastic transformation (43). Vitamin A and its analogues and As stated in the Surgeon General's first report on Smoking derivatives may preserve the integrity of epithelial cells by main and Health (42) published in 1964, "the causal significance of an taining them in a differentiated state, thereby protecting them to association is a matter of judgment which goes beyond any some extent (33,39). Vitamin C and vitamin E block the formation statement of statistical probability." The criteria upon which such of nitrosamines and nitrosamides, an action that may be impor a judgment is based include the consistency, strength, specific tant in the etiology of gastric cancer where a seasonal low ity, and coherence of the association, as well as the empirical consumption of vitamin C appears to be a factor (21,29,32,37, relationship of the events involved. Using these criteria, it seems 46). Dietary deficiencies of certain compounds found in vegeta eminently plausible that dietary deficiencies or excesses could bles, for example, having the capacity to inhibit neoplastic effects play an important role in carcinogenesis by leading to the for of chemical carcinogens may also play a role (22, 44). mation of tumor promoters or by affecting metabolic parameters In the instance of dietary excesses, the role of fat has been which, in turn, can affect activation or deactivation of carcino reviewed recently (12,30). The stage of carcinogenesis at which gens. The epidemiolÃ³gica! evidence is particularly plausible be dietary fat operates appears to be primarily the promotion phase cause of extensive support from animal experiments. Thus, the (7, 8). There are numerous mechanisms whereby the level of relative lack of attention given to the field of nutritional carcino dietary fat intake can and does control tumor growth. With regard genesis by oncologists is especially perplexing given the fact to colon cancer, dietary fat increases bile acid secretion and that the relationship has had considerable biological plausibility, hence the amount of colonie bile acid metabolites that are rationale, and internal consistency from the very beginning. possible tumor-promoting agents. Dietary cereal bran and related fibers reduce the concentration of bile acids and also other as SOCIETAL IMPLICATIONS yet unknown compounds associated with neoplasia in the large bowel and thus appear to lower colon cancer risk in humans and The Committee of the National Academy of Sciences recom in animal models (5, 35). Dietary fat also influences the synthesis mended a dietary pattern quite similar to that of the previously and release of prolactin (and also other hormones), a potential published national dietary guidelines of the United States De mammary gland tumor promoter, in both rats and humans (35, partment of Agriculture (41) as well as those suggested by the 36). Furthermore, dietary fat may affect the hormonal milieu American Health Foundation (3, 26, 49). Whereas these earlier within the breast with respect to steroid hormone levels and recommendations were directed towards reducing the risk for balances and can bear on the composition and physical charac cardiovascular disease, the present suggestions are directed teristics of membranes, thus influencing the interactions between towards the prevention of certain types of cancers, providing an peptide hormones and their membrane-bound receptors (25,34, even more powerful incentive for the public to heed the recom 48). The production of growth-regulating substances such as mendations since benefits would accrue in terms of lower risk prostaglandins, which are derivatives of dietary essential fatty both for important types of cancer and for coronary heart dis acids, may also be influenced by fat intake (20). There is also ease. evidence that dietary fat affects breast cancer survival rates, The responsible segments of the American agricultural and particularly in postmenopausal women, perhaps by regulating food industries can make it easier for the public to adhere to the

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guidelines by providing leaner meats; lower fat-containing dairy Spring Harbor, N. Y.: Cold Spring Harbor Laboratories, 1980. 7. Carroll. K. K. Influenceof diet on mammary cancer. Nutr. Cancer. 2:232-236, products and baked goods; by producing an attractive variety of 1981. fresh and frozen vegetable products, fruits, and juices; by low 8. Carroll, K. K. Neutral fats and cancer. Cancer Res., 41:3695-3699,1981. ering the salt content of products; and by providing whole-grain 9. Cook-Mozaffari, P. J., Azordegan, F., Day, W. E., Ressicaud, A., Sabai, C., and Aramesh, B. Oesophageal cancer studies in the Caspian littoral of Iran: breads, cereals, and other food products enriched with fibers results of a case control study. Br. J. Cancer, 39: 293-309, 1979. that increase stool bulk (26). Moreover, through their managerial 10. Correa. P. Precursors of gastric and esophageal cancer. Cancer (Phila.),50: 2554-2564,1982. and promotional skill, industry can help to motivate the accept 11. Diamond, L., O'Brien, T. G., and Baird, W. M. Tumor promoters and the ance of those more healthful foods for our largely sedentary mechanismsof tumor promotion. Adv. Cancer Res., 32:1-75,1980. 12. Fink, D. J., and Kritchevsky, D. (eds.). Workshop on fat and cancer. Cancer public. Res.. 41 (Part 2V 3681-3826,1981. Since dietary habits are established early in life and since 13. Graham,S. Epidemiologietests of hypothesis relatingdiet and cancer. Banbury biological parameters may also be set relatively early in our Rep., 7:395-408,1981. 14. GroupÃ©,V.,and Salmoiraghi, G. C. (eds.). Alcohol and cancer workshop. development, it is of particular importance that we apply the Cancer Res.. 39: 2853-2908. 1979. dietary guidelines to children, preferably starting with infants 15. Harper,A. E., and Simopoulos, A. P. (eds.).Conferenceon the assessment of right after breast feeding or at the beginning of bottle feeding. nutritional status. Am. J. Clin. Nutr., 35S: 1089-1325, 1982. 16. 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Ernst Wynder

Cancer Res 1983;43:3024-3027.

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