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Food and Cancer: Cause and Effect?
Nutrition and Cancer I
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Food and Cancer: Cause and Effect?
G. M. Williams, M.D.,* and]. H. Weisburger, Ph.D.t
The clinician well knows from the various approaches required in the treatment of cancer in different organs that cancer represents many distinct diseases. This is also true from the perspective 6f etiology. Thus, a detailed analysis of the complex factors inherent in the occurrence of each specific type of cancer is essential to delineate the elements causing, enhancing, or reducing the risk of that particular disease. It is now evident that most of the main human cancers in the world do not stem from intentional or even inadvertent chemical contaminants in the environment. Rather, lifestyle elements have been established to be involved in the multifactorial causality of most neoplastic diseases. In this article, the data relating to the main risk factors responsible for cancer in the upper alimentary tract, stomach, large bowel, pancreas, breast, and prostate will be reviewed. The application of this knowledge to the primary prevention of these cancers and control of their recurrences will be considered.
MECHANISMS OF CANCER INDUCTION The induction of neoplasms is a multi-event process that may be divided into two distinct sequences on the basis of the underlying mechanisms: (1) the conversion, "initiation," of a normal cell to a neoplastic cell and (2) the development, "promotion," and progres" sion of the neoplastic cell to form a clinically apparent, invasive cancer. 58 Chemicals and components of foods are involved in the *Chief, Division of Pathology and Toxicology, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York tDirector, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York
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processes in both sequences in a variety of ways, including both enhancing and inhibiting effects. The basic mechanisms and the application to the field of nutrition and cancer have been reviewed elsewhere. 55, 57
Genotoxic Effects Carcinogens that initiate the process of neoplastic conversion are usually reactive chemical species, either in their parent form or following activation by host enzyme systems. The biotransformation of carcinogens is predominantly to detoxified products, but a quantitatively minor reaction, bioactivation, yields reactive species, either electrophilic reactants or free radicals, that combine with cellular macromolecules to form covalent adducts. A key target macromolecule is DNA. Chemical damage to DNA can be repaired. Nevertheless, if the cell divides while the damage is still present, a permanent change in the newly replicated base sequence, that is, a mutation, can result. The critical genes affected by such changes may be cellular oncogenes. Carcinogens with the ability to damage DNA through formation of covalent adducts are referred to as DNA-reactive or genotoxic carcinogens. These agents initiate carcinogenesis by producing genetic alterations leading to neoplastic conversion in exposed cells. A few chemicals that do not themselves react with DNA can, nevertheless, give rise to DNA-damaging moieties, such as reactive oxygen species, generated intracellularly. When the alterations in the genome by a carcinogen are sufficient, full neoplastic conversion may ensue. However, in many experimental systems, as well as in human disease conditions, altered populations of cells, considered to be "preneoplastic," precede the appearance of neoplasms. Such populations may represent stages in the transition of normal to neoplastic cells. Agents referred to as co-carcinogens enhance the effects of DNA-reactive carcinogens, usually by increasing the ratio of metabolic bioactivation or by stimulating cell proliferation, which sensitizes tissues to the effects of DNA damage.
Epigenetic Effects The neoplastic cell develops into a tumor, usually monoclonal in its early stages, through sustained proliferation. Preneoplastic and even neoplastic cells are restrained from proliferation by tissue homeostatic factors. Such factors may be transmitted to cells in a variety of ways, including through plasma membrane organelles. Agents referred to as promoters facilitate the proliferation of latent neoplastic cells such that they form tumors. The expression time
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from carcinogen exposure to tumor appearance is thereby shortened. Promoters enhance proliferation by several mechanisms, which do not involve genetic effects and, hence, are designated as epigenetic. One of these, inhibition of intercellular communication, would serve to block the transmission of the regulatory signals that may restrain neoplastic cells. Once neoplastic cells have proliferated to a cell number sufficient to insulate themselves from controlling influences, their further growth is no longer dependent on promoters. Chemicals that facilitate the progression of transformed or neoplastic cells to tumor formation will function operationally as carcinogens in situations in which pre-existing abnormal cells are present. Apparently, a background of neoplastic cells is quite common in experimental animals inasmuch as most strains have significant incidences of certain cryptogenic neoplasms. Cancer-causing agents that are not DNA reactive, but for which mechanistic studies have revealed a nongenotoxic effect that could be the basis of cancer induction, have been categorized as epigenetic carcinogens. During the progressive growth of neoplasms, the cells may acquire new, permanently abnormal characteristics, resulting in further deviation from the normal, a process referred to as progression.
DEFINITION OF RISK FACTORS Comparative studies in human populations and laboratory investigations have been instrumental in providing sound information on specific risk factors for cancers. The key elements are: 1. Incidence and mortality data from different geographic areas throughout the world identify populations as having high or low risk for specific cancers. Worthwhile information also stems from studies of select populations within geographic areas but with lifestyles different from other inhabitants, reflecting, for example, religious beliefs, cultural differences, or ethnic traditions. 2. Changes in disease incidence in migrants between regions of different risk provide insight into contributions of environmental factors. 3. Long-term observations of incidence or mortality as recorded by established, reliable cancer registries in different parts of the world provide a picture of trends with which changing lifestyle patterns can be compared. 4. Laboratory studies for each type of cancer in human subjects through the techniques of biochemical epidemiology or in animal models through other appropriate techniques help define the effect
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of suspected risk factors and generate information on the underlying mechanisms of action of each agent or groups of agents, particularly with respect to the genotoxic or epigenetic effects, discussed previously.
Upper Alimentary Tract Cancer Risk Factors. In North America and other Western countries, smoking and alcohol consumption are associated with cancers of the mouth and esophagus. In a high-risk population in Uruguay, an association with consumption of a hot herbal drink was established. 48 Genotoxic Carcinogens. Certain nitrosamines, such as nitrosonornicotine (NNN), found at appreciable levels in tobacco, and polycyclic aromatic hydrocarbons from incomplete combustion processes, are part of the genotoxic carcinogens in tobacco smoke. NNN and related compounds occur in tobacco chews. 3 Such specific genotoxic carcinogens may be involved in cancers of the oral cavity and esophagus. This is supported by observations in animals that certain nitrosamines are selective esophageal carcinogens. 58 In eastern Iran, the southern Soviet Union, and central China, cancer of the esophagus occurs in people who do not smoke and drink heavily. The key risk factors remain to be discovered. The chewing of opium tars has been suggested. The nutritional intake of green or yellow vegetables, fruits, and other foods containing vitamins C and A is low, which may facilitate the endogenous formation of carcinogenic nitrosamines. Recent data from China,32 the easternmost extension of the belt of high incidence of esophageal cancer, suggest that nitrosamines are present in the diet, especially in pickled, salted foods. Obviously, cancer in the oral cavity and esophagus may have multiple, diverse etiologic factors, but specific nitrosamines are one type of plausible candidate. Epigenetic Agents. Enhancing factors for upper alimentary tract cancer have not been identified. However, the role of alcohol in increasing risk in smokers needs to be elucidated. The higher risk of populations that consume herbal teas 48 also deserves investigation for promoting elements. Prolonged deficiencies of specific micronutrients such as vitamins A and C, riboflavin, and nicotinic acid as well as trace elements zinc, molybdenum, magnesium, and iron have been suggested as etiologic factors. Preventive Approaches. In the United States, where tobacco and alcohol use are the main risk factors, control through education, especially of the young, and through economic and political measures, would be the definitive solution. In oral cancer patients, a nutritionally optimal diet, particularly as regards micronutrients,
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may be of value. The survival of esophageal cancer patients is so poor that specific diets have little to offer.
Stomach Cancer Risk Factors. Pathologically, two types of gastric cancer can be distinguished: diffuse and glandular-intestinal. Not much is known about the etiology of diffuse cancer. Glandular cancer predominates in high-risk countries such as Japan, Iceland, mountainous interior regions of central and western Latin America, and some Eastern European countries. In contrast, Western Europe, many AngloSaxon countries (except Wales in the United Kingdom), and the United States now have a low incidence. Over the last 50 years, the rate of glandular gastric cancer in the United States has steadily declined and is beginning to diminish in some high-risk areas. Dietary factors associated with risk of glandular gastric cancer are a high consumption of dried, salted fish, pickled vegetables, and smoked fish, with a low vegetable and fruit intake, particularly on a seasonal basis. 7 , 17 Elevated levels of nitrate in food and drinking water may also be involved, but this correlation holds only in the seasonal absence of fresh vegetables as sources of vitamin C, an antagonist of nitrite in the formation of nitrosamines or aryl-diazo compounds. When nitrate-rich vegetables and fruits are consumed regularly, measurement of urine nitrate alone fails to correlate with risk. An important source of nitrate, crude salt or saltpeter, is used in the preservation or pickling of foods. A higher intake of fresh vegetables such as celery, lettuce, tomatoes, and fruit juices by Japanese migrants to Hawaii correlated with a lower risk of gastric cancer as compared with indigenous Japanese. Genotoxic Carcinogens. Alkylnitrosoureido compounds such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) given intragastrically reliably induce glandular stomach cancer in rodents. Such carcinogens are formed through the reaction of nitrite and suitable secondary amides. Ascorbic acid inhibits these nitrosation reactions. 36,38 Direct-acting mutagenic products were obtained by reaction of nitrite with foods typically eaten in regions at high risk for gastric cancer, including soy sauce, fava beans, and certain kinds of fish. 39, 55, 64 A mutagenic extract from the reaction of nitrite and Sanma, a type of fish consumed in Japan, induced adenocarcinomas of the stomach in rats. 55 The structure of the carcinogen is not yet known, but some evidence points to a reactive diazo compound of the type also found in the commercially cultivated mushroom Agaricus bisporus, which has induced glandular stomach cancer in mice. 47 This evidence leads to the conclusion that consumption of salted,
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pickled, and smoked foods may result in gastric cancer through the action of a genotoxic agent (or agents) formed from nitrite and specific substrates. The fact that the formation of such carcinogens may be blocked by vitamin C or by vitamin E is most important. 38 Reduced use of pickled foods and better nutrition may underlie the sharp decline in the incidence of gastric cancer in the United States. Epigenetic Agents. Studies in animal models have shown that salt can act as a co-carcinogen, enhancing the effect of stomach carcinogens. A study of disease incidence in Japan, however, did not reveal an association between salt use and gastric cancer. 26 The lower risk associated with high consumption of yellow and green vegetables and fruits as noted in migrant studies, or the observation of reduced gastric cancer in areas of Japan, suggests that the vitamin A or beta carotene content of foods may be protective. Vitamin A plays a role in differentiation and other mechanisms decreasing the development of neoplasia. 44 Preventive Approaches. Decreasing the use of salted, pickled, or smoked foods should reduce the risk for gastric cancer and also hypertension and stroke. For patients with high-risk conditions such as chronic, atrophic gastritis or partial gastrectomy, this would be particularly valuable. Increased intake of vegetables and fresh fruit may also be of value. It should be noted that taking vitamin supplements will not counteract the formation of carcinogens in the stomach unless ingestion occurs with meals.
Large Bowel Cancer Risk Factors. Large bowel cancer includes at least three kinds of diseases with different incidence and mortality parameters in diverse regions of the world and with distinct male to female incidence ratios and different parameters for average time to occurrence. 53 In areas of the world in which large bowel cancer is relatively uncommon, the disease usually occurs in the ascending right-sided or in the transverse colon. Not much is known about risk factors for right-sided colon cancer. In high incidence regions, cancer is often found in the descending left-sided segment, from the splenic flexure to the rectosigmoid junction. Rectal cancer appears to have different risk factors from either of the previous two. In Anglo-Saxon countries, which have a high incidence of distal colon cancer, populations consume 40 to 45 per cent of their daily caloric intake as total fat, saturated plus unsaturated, or about 130 to 150 g of fat per day. In contrast, the traditional dietary intake of fat in Japan, with a formerly low incidence of distal colon cancer, accounted for 10 to 15 per cent of calories, and more of the fat was unsaturated, derived from fish oils. 24
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An important exception among Western countries was the low incidence of colon cancer in Finland, especially in rural areas. This situation prevailed in spite of the fact that the total fat intake, particularly, saturated fat from heavy use of dairy products, was similar to that found in high-risk Anglo-Saxon countries. The high intake of saturated fat, in part, accounted for a high incidence of coronary heart disease. Data from studies of biochemical epidemiology indicated that individuals in rural Finland had a high intake of cereal fiber, yielding, in turn, a sizable stool bulk and, in part, increased stool frequency. In addition, Domellof and colleagues ll have described populations in northern Sweden, as has Graham 14 in the United States, that, despite a high fat intake, had a lower risk of colon cancer, intermediate between that of people in New York and those in Japan or Finland. The lower-risk population in northern Sweden consumed more cereal fiber, and the U.S. population consumed more yellow and green vegetables, especially cabbage. Mormons in Utah, who have a low risk for colon cancer, have a basically American dietary pattern, but it includes cereal products and grains with a higher fiber content than that consumed by the general American population. Jansson 23 noted an inverse association between the occurrence of colon cancer and soil selenium content. Genotoxic Carcinogens. The specific carcinogens causing large bowel cancer are not known, but several leads have emerged. The stools of some individuals in populations at high risk for large bowel cancer (United States and Canada) contained greater mutagenic activity compared with the stools of individuals in vegetarian populations in the United States or Africa, which contained no mutagenic activity; fewer positive samples were found in a rural population in Kuopio, Finland. 41 The chemical structure of a fecal mutagen produced by colonic bacteria has been identified as a highly unsaturated, reactive chemical, classed as a fecapentaene, unstable in oxygen. 16, 19 Its carcinogenic activity is currently under investigation, with emphasis on its possible effect on the large bowel. A diet containing more cereal fiber or increased amounts of vitamin C or E lowered fecal mutagenicity. 16 An entirely different lead stemmed from the discovery45 that the surface of charcoal-broiled fish or meat contained agents with powerful mutagenic activity. These mutagens also form during frying and broiling. Cooking in water or in a microwave oven yields no mutagenic activity. Several genotoxic chemicals have been isolated from fried meat or fried fish that belong to a new clas~ of heterocyclic amines, which includes agents such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Several of these heterocyclic amines can rapidly induce neoplasms in the mammary gland, intestine, pancreas, bladder, and liver in rodents. 45 , 46 A structurally related compound,
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3,2' -dimethyl-4-aminobiphenyl, is a known carcinogen for the colon, mammary gland, and prostate of rats. Thus, the new class of potent carcinogens produced during cooking affects organs typically related to nutritional carcinogenesis. Epigenetic Agents. In confirmation of epidemiologic studies linking fat consumption with colon cancer rates,24 dietary fat strongly modulated the response of rodents to colon carcinogenesis. 4O Irrespective of the type of colon carcinogen used or its own particular mode of action, rats placed on a diet containing 20 per cent total fat (saturated and unsaturated) by weight (40 per cent of calories), mimicking the caloric fat intake of Western high-risk populations, uniformly had a higher incidence of colon cancer than those on a diet with a fat content of 10 per cent of calories, mimicking a lowrisk situation similar to the traditional Japanese diet. Olive oil and fish oils, however, seemed to be protective. Experiments with cereal fiber gave results that are not as clearcut but usually showed that cereal fiber such as wheat bran inhibited colon carcinogenesis. 50 Studi~s in which a protective effect could not be demonstrated or in a few cases in which an increased incidence was found can be explained. One kind of failure can be traced to use of a large amount of colon carcinogen, since the inhibition by cereal fiber is subtle. In other instances, large amounts (20 per cent of cereal bran) were used that have an irritating effect on the colon mucosa, yielding increased shedding of cell surface layers, in turn leading to a higher level of DNA synthesis in stem cells and in migration rates in the crypt. These conditions favor carcinogenesis. 29 Other fibers such as pectin, with quite different chemical properties, undergo partial hydrolysis and absorption in the large bowel with distinct biochemical consequences. 50 Pectin inhibited the effect of carcinogens such as azoxymethane that require biochemical activation in the liver and in the colon but not that of other carcinogens such as N -nitrosomethylurea. 50 Additional research is necessary to describe the specific properties of each kind of fiber in relation to its mechanisms of action. Still, appropriate amounts of bran cereal fibers that increase stool bulk have a definite inhibiting effect in animal models and in humans. Certain vegetables, such as Brussels sprouts and cauliflower, containing indole derivatives that can act as enzyme inducers, under certain conditions seem to inhibit the carcinogenic process. 51 Synthetic antioxidants such as butylated hydroxyanisole (BRA) also inhibited colon carcinogenesis. 42 These effects appear to relate to a reduced ratio of bioactivation. The relevance to human cancer is not evident, in view of the dose required to obtain inhibition. Dietary intake of calcium salts decisively lowers the toxicity of bile acids and slows rates of intestinal cell duplication. 27. 49 The exact
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mechanism may be complex, ranging from a simple elimination of bile acids as water-insoluble calcium salts to a more subtle molecular inhibition of promotion by calcium salts at the cellular membrane level. The effect of colon carcinogens in rats can also be inhibited by selenium compounds. Recently, it has been shown that feeding of the Bowman-Birk protease inhibitor derived from soybeans protected against colon cancer in mice. 52 This observation appears to support the report that E-amino caproic acid sUp'presses colon carcinogenesis in mice. 6 Because soy products in the human diet are cooked, protease inhibitors would be destroyed. Therefore, some sort of dietary additive would be required, but in light of observations of enhanced pancreatic carcinogenesis by raw soy diets (see subsequent discussion), further study is required. Populations that ingest high levels of dietary fat excreted increased amounts of cholesterol and cholesterol metabolites, including bile acids, than did populations traditionally using a lower-fat diet. Neutral sterols such as cholesterol, coprostanone, coprostanol, and cholesterol epoxide had no effect in increasing or decreasing the effect of a carcinogen for the colon of rats. 41 On the other hand, bile acids had an appreciable promoting effect, less for primary bile acids such as cholic acid than for the secondary bile acids such as deoxycholic or lithocholic acid. 40 Humans and animals on diets in which fat is 40 per cent of caloric intake uniformly excrete more bile acids, on the order of 12 mg per g of stool, compared with populations or animals on a lowfat (10 per cent of fat calories) diet in which the bile acid concentration is about 4 mg per g. The population in Kuopio, Finland, also exhibited a concentration of bile acids of about 4 mg per g, because of the larger stool bulk compared with that of the corresponding New York or Copenhagen populations. 41 This finding is important, as current views on the properties of promoters note that their effect is highly dependent on dose and on chronicity of exposure. In familial diseases with a predisposition to colon cancer (familial polyposis coli and hereditary colon cancer), the fecal excretion of undegraded cholesterol was high, with little of the microbial metabolites coprostanol and coprostanone, compared with the control population. 28 A likely explanation is that the cholesterol stems from desquamated cells. The higher cholesterol level would signify a higher cell turnover and shedding rate in such patients. 8 These findings suggest that the chemical analysis of stools might be useful in screening the members of these families. Preventive Approaches. On the basis of current concepts, a 50 per cent reduction of customary Western intake of total fat, to about 20 per cent of calories, and an increase in cereal bran fiber to
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produce a daily stool of about 200 to 250 g would be effective in decreasing risk of colon cancer not only in the general population, but also especially in individuals at higher risk of recurrence, such as those with adenomatous polyps or Dukes A carcinoma, who received endoscopic or surgical intervention. Furthermore, a daily intake of 2 to 3 glasses of skim milk as a source of calcium may be beneficial, not only in respect to colon cancer, but perhaps also for a lower risk of hypertension and osteoporosis.
Pancreatic Cancer Risk Factors. Cancer of the exocrine pancreas occurs in high incidence in northern Europe, North America; Australia, and New Zealand. In the United States, mortality rates have increased approximately threefold from 1930 to 1980. Smoking and tobacco use, generally, is one etiologic factor incriminated, through as yet unclear mechanisms. 34 Various assessments of dietary factors have been made. Alcohol as a risk factor is controversial, but if there is a risk at all, it is not high. 33, 34, 60 The suggestion of an association with coffee drinking35 has not been corroborated. 13, 33, 34, 62 Significantly decreased risks were associated with consumption of raw fruits and vegetables and diet soda, and significantly increased risks appeared with consumption of white bread. 13 Intake of dietary fat has also been correlated with pancreatic cancer. 30 Genotoxic Carcinogens. No definite evidence is available as to the possible genotoxic carcinogens for cancer of the pancreas. However, neoplasms of the pancreas were noted in tests of the heterocyclic amine IQ, found in fried foods. 45 , 46 Also, carcinogens from tobacco may be contributory. Epigenetic Agents. Feeding animals diets high in unsaturated fat after exposure to a carcinogen produced an increase of pancreatic carcinomas in hamsters2 and in rats. 31 This enhancement is also influenced by the level of essential fatty acids. 43 Another dietary factor shown to influence the development of pancreatic acinar cell carcinomas in animal models is raw soya-bean flour,21,59 an effect perhaps due to inhibition of trypsin and a consequent increased release of the hormone cholecystokinin, which has a trophic effect on the exocrine pancreas. The relevance of this observation to the human situation is not clear, as soy products are usually heated or cooked, which destroys protease inhibitors. Also, people traditionally eating cooked soy products have a low rate of pancreatic cancer. Moreover, feeding of the soy-derived Bowman-Birk protease inhibitor to mice had no effect on the pancreas, 52 which may indicate species differences in protease inhibition, cholecystokinin release, or pancreatic response.
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Preventive Approaches. Since tobacco use and a Western diet are risk factors, it is clear that cessation of smoking and a lower intake of fat would contribute to prevention, especially if carried out early in adulthood.
Breast Cancer Risk Factors. Breast cancer rates are significantly different among countries, paralleling, in general, colon cancer rates. The key difference in environmental factors between low-risk countries such as Japan and high-risk Western countries such as the United States is dietary, with the main variable being the quantity and type of fat.4,37 In contrast to the increase in risk of colon cancer occurring in first-generation migrants from a low-risk region (Japan) to a highincidence area (United States), it is not until the second generation that the incidence rises to that seen in the high incidence region. 37 Thus, for breast cancer, residence in a high-risk area at the time of puberty and breast development may be critical. Relevant are observations that female Sprague-Dawley rats are more sensitive to mammary carcinogens at or around puberty, at which time the rate of cell division is high. An intriguing observation is that former college athletes have a lower prevalence of breast cancer and cancers of the reproductive system than nonathletes. 12 Whether this is related to dietary practices or body habitus is not certain, but it is consistent with the concept that lifestyle during developmental stages is of importance. Genotoxic Carcinogens. The DNA-reactive carcinogen or carcinogens that cause human breast cancer have not been identified but may stem from cooking of meat, which yields potent carcinogens, one 'of which has induced mammary cancer in rats. 46 Epigenetic Agents. When breast cancer was induced in rats by chemicals, such as 7,12-dimethylbenz(a)anthracene (DMBA) and Nnitrosomethylurea (NMU), diets with 20 per cent fat or 40 per cent of calories significantly increased the frequency of mammary gland cancer, as compared with diets containing 0.5 to 5 per cent fat. 5 The effect was exerted primarily on the promotional phase of neoplasm development, and polyunsaturated fats seemed more effective promoters than were saturated fats. The promotional effect of a high-fat diet on mammary tumorigenesis was reversed by subsequently lowering the level of dietary fat.25 A 20 per cent, but not a 5 per cent, fat intake increased carcinogenesis in ovariectomized rats, a model for human postmenopausal breast cancer, suggesting a lower fat intake would assist its control. Caloric restriction can inhibit the effect of a high-fat diet.
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Menhaden oil (from fish oils) inhibited tumorigenesis, and olive oil at 40 per cent of calories had a minimal enhancing effect. 4 The amount of essential fatty acids in fats seems to playa role in tumor development,4. 22 possibly mediated by altered levels of biologically active prostaglandins. Postulated mechanisms by which the amount and type of dietary fat may influence breast cancer are those involving direct effects on host metabolism and those involving secondary effects of obesity. There is no question but that hormones are involved in growth control of the mammary epithelium. Dietary fat may elicit its tumorenhancing effects by altering host endocrine metabolism, in particular, that component of the endocrine system that regulates prolactin secretion and hormonal balances generally. 5 Preventive Approaches. Reduction of the level of dietary fat from 40 per cent to 20 to 25 per cent of calories, especially if accompanied by a reduced overall caloric intake, might help to prevent the development and recurrence of breast cancer. This is the basis for planned clinical intervention trials to lower the recurrence rate in cancer patients by adjuvant therapy with a low-fat diet. 61 Because in Japan the current dietary fat level is 20 per cent, it may be significant that breast cancer recurs less in Japanese women than in American women. 61 Also, greater use of olive oil and fish oils (through a higher intake of fish with such oils) may be beneficial.
Prostate Cancer Risk Factors. Epidemiology has provided data on the incidence of prostate cancer as a function of several factors such as race, age, area of residence, endocrine levels, and diet. 15, 20, 63 Caucasians in the Western world have a higher incidence than do the Japanese. As for breast cancer, first-generation Japanese migrants to the United States retain their low risk, but later generations have a higher risk. Native Japanese, however, have in situ lesions,1 as do other low-risk populations. 9 It has been suggested that the population differences in occurrence of latent versus clinical prostatic carcinoma are due to operation of epigenetic environmental factors in the sequence of neoplasm development. In general, populations that have a high risk of breast, colon, and endometrial cancer also have a high risk of prostate cancer. 18 An association with diet has been documented for breast and colon cancer, as described previously, and therefore, dietary fat may also play a role in the etiology of prostate cancer. Until recently, a reliable and realistic animal model involving specific chemical carcinogens for prostate cancer has not been
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Table 1. Nutritional Factors Involved in Major Human Cancers in North America
TYPE OF CANCER
Esophagus, oral cavity
POSTULATED SOURCE AND GENOTOXIC CARCINOGENS
EPIGENETIC (PROMOTING OR CO-CARCINOGENIC) FACTORS
PROTECTIVE OR INHIBITING ELEMENTS
Tobacco (nitrosamines, polycyclic aromatic hydrocarbons) Salting and pickling processes (nitrosamines)
Alcohol Low intake of micronutrients, zinc deficiency
Dried, salted fish; pickled vegetables; smoked fish; fava beans (nitrite + promutagen) High nitrate level in food and water
Salt (sodium chloride) Low intake of fresh fruits and vegetables Low intake of vitamin C
Increased intake of fresh vegetables and fruit Vitamins A, C, and E
Carcinogens formed in fried or broiled meat and fish (heterocyclic amines)
High level of dietary fat Bile acids
Cereal bran fiber, certain vegetables (cabbage, Brussels sprouts, cauliflower), selenium, calcium Olive oil? Fish oils?
Rectum
??
Alcohol?
Fiber?
Pancreas
Tobacco?
Alcohol? Coffee?
Fresh fruits and vegetables
Fried meats/fish?
High dietary intake of fat Raw soya flour
Breast
Fried meats/fish?
High dietary intake of fat Endocrine imbalance
Low-fat diet Olive oil? Fish oils?
Prostate
??
High dietary intake of fat
Low-fat diet, adequate zinc and selenium
Stomach
Colon
Green or yellow vegetables, fruits high in vitamins A, C, and E
Vitamin C and E
available. Several new approaches are currently under investigation, based on mechanistic considerations that a tissue stimulated to proliferate during carcinogen administration is more susceptible to carcinogenesis. These models, if validated, should permit exploration of the conditions required for tumor production and the effect of dietary modulators such as the level of fat or micronutrients. Preventive Approaches. As is indicated for other nutritionally linked cancers, a 50 per cent reduction of total fat intake may serve to lower the risk for this important cancer. Other areas of nutrition
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involving micronutrients, such as the adequacy of zinc or selenium supplies, require more research.
CONCLUSIONS Evidence from many types of studies leads to the conclusion that diet is a major factor in the causation of some of the most important and prevalent human cancers (Table 1). A number of investigators lO , 54, 56 have calculated that nutrition or similar "lifestyle" factors may have a direct impact on the occurrence of as much as 30 to 40 per cent of cancers in men and 50 to 60 per cent of cancers in women in the United States and other Western countries. The etiologies of most cancers are complex and clearly multifactorial. For some, such as stomach cancer, the main determining factor appears to be one or more genotoxic carcinogens, whereas for others, including colon, breast, and perhaps pancreas and prostate cancers, epigenetic-enhancing elements seem to be decisive. With respect to both the genotoxic and epigenetic agents, relatively minor alterations in dietary habits, involving reduced salt (pickled foods) and fat intake and a higher consumption of fresh vegetables and fruits, bran-type fibers, and calcium-rich foods such as skim (not whole) milk or lowfat yogurt, offer clear promise for meaningful reduction of risk. Ideally, sound dietary practices should begin in childhood. This may be particularly important in the control of breast and prostate cancer. Nevertheless, since epigenetic factors are involved in the "late stage" of tumor development, reduction of exposure of adults to such factors as contributed by high-fat diets may translate into a relatively rapid reduction of disease risk. In addition to modification of specific elements, avoidance of obesity by matching caloric intake to energy needs and increased physical exercise is of obvious Significance in moderating chronic disease risks. Important corollary benefits in other major diseases would ensue, as adjustment of nutritional traditions would also yield a lower risk of hypertension, stroke, arteriosclerosis, and coronary heart disease. These approaches should be useful for the general population in the United States, but they are clearly highly indicated for individuals at greater risk, such as those who have presented with intestinal polyps or cystic breast disease. Moreover, dietary modification offers promise as an adjuvant in the treatment of patients with certain cancers to prevent recurrences or second cancers. In both these situations, the surgeon has a crucial role to play. Indeed, in subpopulations at elevated risk, such as those with premalignant conditions, amelioration of cancer risk may be achieved relatively
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rapidly. Of additional public health benefit, such observations by the physician would contribute to a better foundation on which to base large-scale intervention.
REFERENCES 1. Akazaki, K., and Stemmerman, G. N.: Comparative study of latent carcinoma of the prostate among Japanese in Japan and Hawaii. J. Natl. Cancer Inst., 50:1137-1144, 1973. 2. Birt, D. F., Salmasi, S., and Pour, P. M.: Enhancement of experimental pancreatic cancer in Syrian golden hamsters by dietary fat. J. Natl. Cancer Inst., 67:1327-1332, 1981. 3. Brunnemann, K. D., Genoble, L., and Hoffmann, D.: N-nitrosamines in chewing tobacco: An international comparison. J. Agric. Food Chem., 33:1178-1181, 1985. 4. Carroll, K. K., and Braden, L. M.: Dietary fat and mammary carcinogenesis. Nutr. Cancer, 6:154-159, 1985. 5. Cohen, L. A.: Dietary fat and mammary cancer. In Reddy, B. S., and Cohen, L. A. (eds.): Diet, Nutrition, and Cancer: A Critical Evaluation. Volume I. Macronutrients and Cancer. Boca Raton, Florida, CRC Press, 1986, pp. 77-100. 6. Corasanti, J. G., Habika, G. H., and Markus, G.: Interference with dimethylhydrazine induction of colon tumors in mice by E-aminocaproic acid. Science, 216:1020-1021, 1982. 7. Correa, P., Cuello, C., Fajardo, L. F., et al.: Diet and gastric cancer: Nutrition survey in a high-risk area. J. N atl. Cancer lnst., 70:673-678, 1983. 8. Deschner, E. E.: The influence of dietary cholic acid and beta-sitosterol on MNU-induced colon carcinogenesis. In Sherlock, P., Morson, B. C., Barbara, L., et al. (eds.): Precancerous Lesions of the Gastrointestinal Tract. New York, Raven Press, 1983, pp. 219-222. 9. Dhom, G.: Epidemiologic aspects of latent and clinically manifest carcinoma of the prostate. J. Cancer Res. Clin. Oncol., 106:210-218, 1983. 10. Doll, R., and Peto, R.: The causes of cancer: Qualitative estimate of avoidable risks of cancer in the United States today. J. Natl. Cancer lnst., 66:1191-1308, 1981. 11. Domellof, L., Darby, L., Hanson, D., et al.: Fecal sterols and bacteriall3-glucuronidase activity: A preliminary metabolic epidemiology study of healthy volunteers from Umea, Sweden, and metropolitan New York. Nutr. Cancer, 4:120-127, 1982. 12. Frisch, R. E., Wyshak, G., Albright, N. L., et al.: Lower prevalence of breast cancer and cancers of the reproductive system among former college athletes compared to non-athletes. Br. J. Cancer, 52:885-891, 1985. 13. Gold, E. B.. Gordis, L., and Diener, M. D., et al.: Diet and other risk factors for cancer of the pancreas. Cancer, 55:460-467, 1985. 14. Graham, S.: Results of case-control studies of diet and cancer in Buffalo, New York. Cancer Res., 43:2409s-2413s, 1983 . 15. GUileyardo, J. M., Johnson, W. D., and Welsh, R. A., et al.: Prevalence oflatent prostate carcinoma in two U.S. populations. J. Natl. Cancer lnst., 65:311-316, 1980. 16. Gupta, I., Baptista, J., Bruce, W. R., et al.: Structures of fecapentaenes, the mutagens of bacterial origin isolated from human feces. Biochemistry, 22:24 1-245, 1983. 17. Hill, M. J.: Environmental and genetic factors in gastrointestinal cancer. In Sherlock, P., Morson, B. C., Barbara, L., et al. (eds.): Precancerous Lesions of the Gastrointestinal Tract. New York, Raven Press, 1983, pp. 1. 18. Hill, P., Wynder, E. L., Garnes, H., et al.: Environmental factors, hormone status, and prostatic cancer. Prevo Med., 9:657-662, 1980. 19. Hirai, N., Kingston, D. G. I., Van Tassell, R. L., et al.: Structure elucidation of a potent mutagen from human feces. J. Am. Chem. Soc., 104:6149-6150, 1982. 20. Hirayama, T.: Epidemiology of prostate cancer with special reference to the role of diet. Natl. Cancer lnst. Monogr., 53:149-156, 1979.
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21. Howatson, A. G., and Carter, D. C.: Pancreatic carcinogenesis--enhancement by cholecystokinin in the hamster-nitrosamine mode!. Br. J. Cancer, 51:107-114, 1985. 22. lp, C., Carter, C. A., and lp, M. M.: Requirement of essential fatty acid for mammary tumorigenesis in the rat. Cancer Res., 45:1997-2001, 1985. 23. Jansson, B.: Geographic mappings of colorectal cancer rlites: A retrospect of studies, 1974-1984. Cancer Detect. Prevent., 8:341-348, 1985. 24. Jensen, O. M.: Colon cancer epidemiology. In Autrup, H., and Williams, G. M. (eds.): Experimental Colon Carcinogenesis. Boca Raton, Florida, CRC Press, 1983, pp. 3-26. 25. Kalamegham, R., and Carroll, K. K.: Reversal of the promotional effect of high-fat diet on mammary tumorigenesis by subsequent lowering of dietary fat. Nutr. Cancer, 6:22-31, 1984. 26. Kono, S., Ideda, M., and Ogata, M.: Salt and geographical mortality of gastric cancer and stroke in Japan. J. Epidemio!. Commun. Health, 37:43-46, 1983. 27. Lipkin, M., and Newmark, H.: Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. N. Eng!. J. Med., 313:1381-1384, 1985. 28. Lipkin, M., Reddy, B. S., Weisburger, J. H., et al.: Nondegradation offecal cholesterol in subjects at high risk for cancer of the large intestine. J. Clin. Invest., 67:304-307, 1981. 29. Lipkin, M., Winawer, S. J., and Sherlock, P.: Early identification of individuals at high risk for colorectal cancer. In Glass, G. B. J., and Sherlock, P. (eds.): Progress in Gastroenterology. Volume IV. New York, Grune & Stratton, 1983, pp. 373-392. 30. Longnecker, D. S., and Morgan, R. G. H.: piet and cancer of the pancreas. EpidemiOlogical and experimental evidence. In Reddy, B. S., and Cohen, L. A. (eds.): Diet, Nutrition and Cancer: A Critical Evaluation. Volume 1. Macronutrients and Cancer. Boca Raton, Florida, CRC Press, 1986, pp. 11-26. 31. Longnecker, D. S., Roebuck, B. D., and Kuhlmann, E. T.: Enhancement of pancreatic carcinogenesis by a dietary unsaturated fat in rats treated with saline or N -nitroso(2hydroxypropl)(2-oxopropyl)amine. J. Nat!. Cancer Inst., 74:219-222, 1985. 32. Lu, S. H., Camus, A.-M., Wang, Y. L., et a!.: Mutagenicity in Salmonella typhimurium of N -3-methylbutyl-N -l-methylacetonylnitrosamine and N -methyl-N-benzylnitrosamine, N-nitrosation products isolated from corn-bread contaminated with commonly occurring lT)oulds in Linshien county, a high incidence area for oesophageal cancer in Northern China. Carcinogenesis, 1:867-870, 1980. 33. Mack, R. M.: Pancreas. In Schottenfeld, D., and Fraumeni, J. F., Jr. (eds.): Cancer Epidemiology and Prevention. Philadelphia, W. B. Saunders, 1982, pp. 638-667. 34. Mack, R. M., Yu, M. C., Hanisch, R., et al.: Pancreas cancer and smoking, beverage consumption, and past medical history. J. Nat!. Cancer lnst., 76:49-60, 1986. 35. MacMahon, B., Yen, S., Trichopoulos, D., et al.: Coffee and cancer of the pancreas. N. Eng!. J. Med., 304:630-633, 1981. 36. Magee, P. N. (ed): Nitrosamines and Human Cancer. Banbury Rept. 12: Cold Spring Harbor, New York, Cold Spring Harbor Laboratories, 1982. 37. Miller, A. B.: Nutrition and the epidemiology of breast cancer. In Reddy, B. S., and Cohen, L. A. (eds.): Diet, Nutrition, and Cancer: A Critical Evaluation. Volume I. Macronutrients and Cancer. Boca Raton, Florida, CRC Press, 1986, pp. 67-76. 38. Mirvish, S. S.: The etiology of gastric cancer. J. Nat!. Cancer Inst., 71:631-647, 1983. 39. Ochiai, M., Wakabayashi, K., Nagao, M., et a!.: Tyramine is a major mutagen precursor in soy sauce, being convertible to a mutagen by nitrite. Gann (Tokyo), 75:1-3, 1984. 40. Reddy, B. S.: Diet [lnd colon cancer: Evidence from human and animal model studies. In Reddy, B. S., and Cohen, L. A. (eds.): Diet, Nutrition and Cancer: A Critical Evaluation. Volume 1. Boca Raton, Florida, CRC Press, 1986. 41. Reddy, B. S., Cohen, L. A., McCoy, G. D., et al.: Nutrition and its relationship to cancer. Adv. Cancer Res., 32:237-245, 1980. 42. Reddy, B. S., Maeura, Y., and Weisburger, J. H.: Effect of various levels of dietary butylated hydroxyanisole on methylazoxymethanol acetate-induced colon carcinogenesis in CF1 mice. J. Nat!. Cancer lnst., 71:1299-1305, 1984. 43. Roebuck, B. D., Longnecker, D. S., Baumgartner, K. J., et al.: Carcinogen-induced lesions in the rat pancreas: Effects of varying levels of essential fatty acid. Cancer Res., 45:5252-5256, 1985.
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44. Sporn, M. B., and Roberts, A. B.: Role of retinoids in differentiation and carcinogenesis. Cancer Res., 43:3034-3040, 1983. 45. Sugimura, T.: Carcinogenicity of mutagenic heterocyclic amines formed during the cooking process. Mutat. Res., 150:33-41, 1985. 46. Tanaka, T., Barnes, W. S., Weisburger, J. H., et al.: Multipotential carcinogenicity of the fried food mutagen 2-amino-3-methylimidazol[4,5-flquinoline (IQ) in rats. Gann (Tokyo), 76:570-576, 1985. 47. Toth, B., Nagel, D., and Ross, A.: Gastric tumorigenesis by a single dose of 4(hydroxymethyl)benzenediazonium ion of Agaricus bisporus. Br. J. Cancer, 46:417-422, 1982. 48. Vassallo, A., Correa, P., DeStefani, E., et al.: Esophageal cancer in Uruguay: A casecontrol study. J. Natl. Cancer lnst., 75:1005-1009, 1985. 49. Wargovich, M. J., Eng, V. W. S., Newmark, H. 1., et al.: Calcium ameliorates the toxic effect of deoxycholic acid on colonic epithelium. Carcinogenesis, 4:1205-1207, 1983. 50. Watanabe, K., Reddy, B. S., Weisburger, J. H., et al.: Effect of alfalfa, pectin and wheat bran on azoxymethane or methylnitrosourea-induced colon carcinogenesis in F344 rats. J. Natl. Cancer lnst., 63:141-145, 1979. 51. Wattenberg, 1. V.: Anticarcinogenic effects of several minor dietary components. In Wynder, E. L., Leveille, G. A., Weisburger, J. H., et al. (eds.): Environmental Aspects of Cancer: The Role of Macro and Micro Components of Foods. Westport, Connecticut, Food and Nutrition Press, 1983, pp. 157-166. 52. Weed, H. G., McGandy, R. B., ~nd Kennedy, A. R.: Protection against dimethylhydrazine-induced adenomatous tumors of the mouse colon by the dietary addition of an extract of soybeans containing the Bowman-Birk protease inhibition. Carcinogenesis, 6:1239-1241, 1985. 53. Weisburger, J. H.: Nutrition and colon cancer. Clin. Nutrit., 4:131-137, 1985. 54. Weisburger, J. H., and Williams, G. M.: Chemical carcinogenesis. In Holland, J. H., and Frei, E. (eds.): Cancer Medicine. Edition 2. Philadelphia, Lea & Febiger, 1982, pp. 42-95. 55. Weisburger, J. H., and Wynder, E. 1.: The role of genotoxic carcinogens and of promoters in carcinogenesis and in human cancer causation. Acta Pharmacol. Toxicol., 55 (Suppl II):53-68, 1984. 56. Willett, W. C., and MacMahon, B.: Diet and cancer-an overview. Part 1. N. Engl. J. Med., 310:633-638, 1984. 57. Williams, G. M.: Food and cancer. Nutr. Int., 1:49-59, 1985. 58. Williams, G. M., and Weisburger, J. H.: Chemical carcinogens. In Doull, J., Klaassen, C. D., and Amdur, M. d (eds.): Casarett and Doull's Toxicology. The Basic Science of Poisons. Edition 3. New York, Macmillan, 1986. 59. Wormsley, K. G.: Carcinoma of the pancreas. Proc. Nutrit. Soc., 44:113-114, 1985. 60. Wynder, E. L.: An epidemiological evaluation of the causes of cancer of the pancreas. Cancer Res., 35:2228-2233, 1975. 61. Wynder, E. L., and Cohen, 1. A.: A rationale for dietary intervention in the treatment of postmenopausal breast cancer patients. Nutr. Cancer, 3:195-199, 1982. 62. Wynder, E. L., Hall, N. E. L., and Polansky, M.: Epidemiology of coffee and pancreatic cancer. Cancer Res., 43:3900-3906, 1983. 63. Wynder, E. 1., Laakso, K., Sotarauta, M., et al.: Metabolic epidemiology of prostatic cancer. Prostate, 5:47-53, 1984. 64. Yang, D., Tannenbaum, S. R., Biichi, G., et al.: 4-Chloro-6-methoxyindole is the precursor of a potent mutagen (4-chloro-6-methoxy-2-hydroxy-1-nitroso-indolin-3-one oxime) that forms during nitrosation of the fava bean (Vicia Jaba). Carcinogenesis, 5:1219-1224, 1984. Naylor Dana Institute for Disease Prevention American Health Foundation Valhalla, New York 10595
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G. M. Williams, M.D.,* and]. H. Weisburger, Ph.D.t
The clinician well knows from the various approaches required in the treatment of cancer in different organs that cancer represents many distinct diseases. This is also true from the perspective 6f etiology. Thus, a detailed analysis of the complex factors inherent in the occurrence of each specific type of cancer is essential to delineate the elements causing, enhancing, or reducing the risk of that particular disease. It is now evident that most of the main human cancers in the world do not stem from intentional or even inadvertent chemical contaminants in the environment. Rather, lifestyle elements have been established to be involved in the multifactorial causality of most neoplastic diseases. In this article, the data relating to the main risk factors responsible for cancer in the upper alimentary tract, stomach, large bowel, pancreas, breast, and prostate will be reviewed. The application of this knowledge to the primary prevention of these cancers and control of their recurrences will be considered.
MECHANISMS OF CANCER INDUCTION The induction of neoplasms is a multi-event process that may be divided into two distinct sequences on the basis of the underlying mechanisms: (1) the conversion, "initiation," of a normal cell to a neoplastic cell and (2) the development, "promotion," and progres" sion of the neoplastic cell to form a clinically apparent, invasive cancer. 58 Chemicals and components of foods are involved in the *Chief, Division of Pathology and Toxicology, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York tDirector, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York
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processes in both sequences in a variety of ways, including both enhancing and inhibiting effects. The basic mechanisms and the application to the field of nutrition and cancer have been reviewed elsewhere. 55, 57
Genotoxic Effects Carcinogens that initiate the process of neoplastic conversion are usually reactive chemical species, either in their parent form or following activation by host enzyme systems. The biotransformation of carcinogens is predominantly to detoxified products, but a quantitatively minor reaction, bioactivation, yields reactive species, either electrophilic reactants or free radicals, that combine with cellular macromolecules to form covalent adducts. A key target macromolecule is DNA. Chemical damage to DNA can be repaired. Nevertheless, if the cell divides while the damage is still present, a permanent change in the newly replicated base sequence, that is, a mutation, can result. The critical genes affected by such changes may be cellular oncogenes. Carcinogens with the ability to damage DNA through formation of covalent adducts are referred to as DNA-reactive or genotoxic carcinogens. These agents initiate carcinogenesis by producing genetic alterations leading to neoplastic conversion in exposed cells. A few chemicals that do not themselves react with DNA can, nevertheless, give rise to DNA-damaging moieties, such as reactive oxygen species, generated intracellularly. When the alterations in the genome by a carcinogen are sufficient, full neoplastic conversion may ensue. However, in many experimental systems, as well as in human disease conditions, altered populations of cells, considered to be "preneoplastic," precede the appearance of neoplasms. Such populations may represent stages in the transition of normal to neoplastic cells. Agents referred to as co-carcinogens enhance the effects of DNA-reactive carcinogens, usually by increasing the ratio of metabolic bioactivation or by stimulating cell proliferation, which sensitizes tissues to the effects of DNA damage.
Epigenetic Effects The neoplastic cell develops into a tumor, usually monoclonal in its early stages, through sustained proliferation. Preneoplastic and even neoplastic cells are restrained from proliferation by tissue homeostatic factors. Such factors may be transmitted to cells in a variety of ways, including through plasma membrane organelles. Agents referred to as promoters facilitate the proliferation of latent neoplastic cells such that they form tumors. The expression time
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from carcinogen exposure to tumor appearance is thereby shortened. Promoters enhance proliferation by several mechanisms, which do not involve genetic effects and, hence, are designated as epigenetic. One of these, inhibition of intercellular communication, would serve to block the transmission of the regulatory signals that may restrain neoplastic cells. Once neoplastic cells have proliferated to a cell number sufficient to insulate themselves from controlling influences, their further growth is no longer dependent on promoters. Chemicals that facilitate the progression of transformed or neoplastic cells to tumor formation will function operationally as carcinogens in situations in which pre-existing abnormal cells are present. Apparently, a background of neoplastic cells is quite common in experimental animals inasmuch as most strains have significant incidences of certain cryptogenic neoplasms. Cancer-causing agents that are not DNA reactive, but for which mechanistic studies have revealed a nongenotoxic effect that could be the basis of cancer induction, have been categorized as epigenetic carcinogens. During the progressive growth of neoplasms, the cells may acquire new, permanently abnormal characteristics, resulting in further deviation from the normal, a process referred to as progression.
DEFINITION OF RISK FACTORS Comparative studies in human populations and laboratory investigations have been instrumental in providing sound information on specific risk factors for cancers. The key elements are: 1. Incidence and mortality data from different geographic areas throughout the world identify populations as having high or low risk for specific cancers. Worthwhile information also stems from studies of select populations within geographic areas but with lifestyles different from other inhabitants, reflecting, for example, religious beliefs, cultural differences, or ethnic traditions. 2. Changes in disease incidence in migrants between regions of different risk provide insight into contributions of environmental factors. 3. Long-term observations of incidence or mortality as recorded by established, reliable cancer registries in different parts of the world provide a picture of trends with which changing lifestyle patterns can be compared. 4. Laboratory studies for each type of cancer in human subjects through the techniques of biochemical epidemiology or in animal models through other appropriate techniques help define the effect
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of suspected risk factors and generate information on the underlying mechanisms of action of each agent or groups of agents, particularly with respect to the genotoxic or epigenetic effects, discussed previously.
Upper Alimentary Tract Cancer Risk Factors. In North America and other Western countries, smoking and alcohol consumption are associated with cancers of the mouth and esophagus. In a high-risk population in Uruguay, an association with consumption of a hot herbal drink was established. 48 Genotoxic Carcinogens. Certain nitrosamines, such as nitrosonornicotine (NNN), found at appreciable levels in tobacco, and polycyclic aromatic hydrocarbons from incomplete combustion processes, are part of the genotoxic carcinogens in tobacco smoke. NNN and related compounds occur in tobacco chews. 3 Such specific genotoxic carcinogens may be involved in cancers of the oral cavity and esophagus. This is supported by observations in animals that certain nitrosamines are selective esophageal carcinogens. 58 In eastern Iran, the southern Soviet Union, and central China, cancer of the esophagus occurs in people who do not smoke and drink heavily. The key risk factors remain to be discovered. The chewing of opium tars has been suggested. The nutritional intake of green or yellow vegetables, fruits, and other foods containing vitamins C and A is low, which may facilitate the endogenous formation of carcinogenic nitrosamines. Recent data from China,32 the easternmost extension of the belt of high incidence of esophageal cancer, suggest that nitrosamines are present in the diet, especially in pickled, salted foods. Obviously, cancer in the oral cavity and esophagus may have multiple, diverse etiologic factors, but specific nitrosamines are one type of plausible candidate. Epigenetic Agents. Enhancing factors for upper alimentary tract cancer have not been identified. However, the role of alcohol in increasing risk in smokers needs to be elucidated. The higher risk of populations that consume herbal teas 48 also deserves investigation for promoting elements. Prolonged deficiencies of specific micronutrients such as vitamins A and C, riboflavin, and nicotinic acid as well as trace elements zinc, molybdenum, magnesium, and iron have been suggested as etiologic factors. Preventive Approaches. In the United States, where tobacco and alcohol use are the main risk factors, control through education, especially of the young, and through economic and political measures, would be the definitive solution. In oral cancer patients, a nutritionally optimal diet, particularly as regards micronutrients,
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may be of value. The survival of esophageal cancer patients is so poor that specific diets have little to offer.
Stomach Cancer Risk Factors. Pathologically, two types of gastric cancer can be distinguished: diffuse and glandular-intestinal. Not much is known about the etiology of diffuse cancer. Glandular cancer predominates in high-risk countries such as Japan, Iceland, mountainous interior regions of central and western Latin America, and some Eastern European countries. In contrast, Western Europe, many AngloSaxon countries (except Wales in the United Kingdom), and the United States now have a low incidence. Over the last 50 years, the rate of glandular gastric cancer in the United States has steadily declined and is beginning to diminish in some high-risk areas. Dietary factors associated with risk of glandular gastric cancer are a high consumption of dried, salted fish, pickled vegetables, and smoked fish, with a low vegetable and fruit intake, particularly on a seasonal basis. 7 , 17 Elevated levels of nitrate in food and drinking water may also be involved, but this correlation holds only in the seasonal absence of fresh vegetables as sources of vitamin C, an antagonist of nitrite in the formation of nitrosamines or aryl-diazo compounds. When nitrate-rich vegetables and fruits are consumed regularly, measurement of urine nitrate alone fails to correlate with risk. An important source of nitrate, crude salt or saltpeter, is used in the preservation or pickling of foods. A higher intake of fresh vegetables such as celery, lettuce, tomatoes, and fruit juices by Japanese migrants to Hawaii correlated with a lower risk of gastric cancer as compared with indigenous Japanese. Genotoxic Carcinogens. Alkylnitrosoureido compounds such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) given intragastrically reliably induce glandular stomach cancer in rodents. Such carcinogens are formed through the reaction of nitrite and suitable secondary amides. Ascorbic acid inhibits these nitrosation reactions. 36,38 Direct-acting mutagenic products were obtained by reaction of nitrite with foods typically eaten in regions at high risk for gastric cancer, including soy sauce, fava beans, and certain kinds of fish. 39, 55, 64 A mutagenic extract from the reaction of nitrite and Sanma, a type of fish consumed in Japan, induced adenocarcinomas of the stomach in rats. 55 The structure of the carcinogen is not yet known, but some evidence points to a reactive diazo compound of the type also found in the commercially cultivated mushroom Agaricus bisporus, which has induced glandular stomach cancer in mice. 47 This evidence leads to the conclusion that consumption of salted,
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pickled, and smoked foods may result in gastric cancer through the action of a genotoxic agent (or agents) formed from nitrite and specific substrates. The fact that the formation of such carcinogens may be blocked by vitamin C or by vitamin E is most important. 38 Reduced use of pickled foods and better nutrition may underlie the sharp decline in the incidence of gastric cancer in the United States. Epigenetic Agents. Studies in animal models have shown that salt can act as a co-carcinogen, enhancing the effect of stomach carcinogens. A study of disease incidence in Japan, however, did not reveal an association between salt use and gastric cancer. 26 The lower risk associated with high consumption of yellow and green vegetables and fruits as noted in migrant studies, or the observation of reduced gastric cancer in areas of Japan, suggests that the vitamin A or beta carotene content of foods may be protective. Vitamin A plays a role in differentiation and other mechanisms decreasing the development of neoplasia. 44 Preventive Approaches. Decreasing the use of salted, pickled, or smoked foods should reduce the risk for gastric cancer and also hypertension and stroke. For patients with high-risk conditions such as chronic, atrophic gastritis or partial gastrectomy, this would be particularly valuable. Increased intake of vegetables and fresh fruit may also be of value. It should be noted that taking vitamin supplements will not counteract the formation of carcinogens in the stomach unless ingestion occurs with meals.
Large Bowel Cancer Risk Factors. Large bowel cancer includes at least three kinds of diseases with different incidence and mortality parameters in diverse regions of the world and with distinct male to female incidence ratios and different parameters for average time to occurrence. 53 In areas of the world in which large bowel cancer is relatively uncommon, the disease usually occurs in the ascending right-sided or in the transverse colon. Not much is known about risk factors for right-sided colon cancer. In high incidence regions, cancer is often found in the descending left-sided segment, from the splenic flexure to the rectosigmoid junction. Rectal cancer appears to have different risk factors from either of the previous two. In Anglo-Saxon countries, which have a high incidence of distal colon cancer, populations consume 40 to 45 per cent of their daily caloric intake as total fat, saturated plus unsaturated, or about 130 to 150 g of fat per day. In contrast, the traditional dietary intake of fat in Japan, with a formerly low incidence of distal colon cancer, accounted for 10 to 15 per cent of calories, and more of the fat was unsaturated, derived from fish oils. 24
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An important exception among Western countries was the low incidence of colon cancer in Finland, especially in rural areas. This situation prevailed in spite of the fact that the total fat intake, particularly, saturated fat from heavy use of dairy products, was similar to that found in high-risk Anglo-Saxon countries. The high intake of saturated fat, in part, accounted for a high incidence of coronary heart disease. Data from studies of biochemical epidemiology indicated that individuals in rural Finland had a high intake of cereal fiber, yielding, in turn, a sizable stool bulk and, in part, increased stool frequency. In addition, Domellof and colleagues ll have described populations in northern Sweden, as has Graham 14 in the United States, that, despite a high fat intake, had a lower risk of colon cancer, intermediate between that of people in New York and those in Japan or Finland. The lower-risk population in northern Sweden consumed more cereal fiber, and the U.S. population consumed more yellow and green vegetables, especially cabbage. Mormons in Utah, who have a low risk for colon cancer, have a basically American dietary pattern, but it includes cereal products and grains with a higher fiber content than that consumed by the general American population. Jansson 23 noted an inverse association between the occurrence of colon cancer and soil selenium content. Genotoxic Carcinogens. The specific carcinogens causing large bowel cancer are not known, but several leads have emerged. The stools of some individuals in populations at high risk for large bowel cancer (United States and Canada) contained greater mutagenic activity compared with the stools of individuals in vegetarian populations in the United States or Africa, which contained no mutagenic activity; fewer positive samples were found in a rural population in Kuopio, Finland. 41 The chemical structure of a fecal mutagen produced by colonic bacteria has been identified as a highly unsaturated, reactive chemical, classed as a fecapentaene, unstable in oxygen. 16, 19 Its carcinogenic activity is currently under investigation, with emphasis on its possible effect on the large bowel. A diet containing more cereal fiber or increased amounts of vitamin C or E lowered fecal mutagenicity. 16 An entirely different lead stemmed from the discovery45 that the surface of charcoal-broiled fish or meat contained agents with powerful mutagenic activity. These mutagens also form during frying and broiling. Cooking in water or in a microwave oven yields no mutagenic activity. Several genotoxic chemicals have been isolated from fried meat or fried fish that belong to a new clas~ of heterocyclic amines, which includes agents such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Several of these heterocyclic amines can rapidly induce neoplasms in the mammary gland, intestine, pancreas, bladder, and liver in rodents. 45 , 46 A structurally related compound,
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3,2' -dimethyl-4-aminobiphenyl, is a known carcinogen for the colon, mammary gland, and prostate of rats. Thus, the new class of potent carcinogens produced during cooking affects organs typically related to nutritional carcinogenesis. Epigenetic Agents. In confirmation of epidemiologic studies linking fat consumption with colon cancer rates,24 dietary fat strongly modulated the response of rodents to colon carcinogenesis. 4O Irrespective of the type of colon carcinogen used or its own particular mode of action, rats placed on a diet containing 20 per cent total fat (saturated and unsaturated) by weight (40 per cent of calories), mimicking the caloric fat intake of Western high-risk populations, uniformly had a higher incidence of colon cancer than those on a diet with a fat content of 10 per cent of calories, mimicking a lowrisk situation similar to the traditional Japanese diet. Olive oil and fish oils, however, seemed to be protective. Experiments with cereal fiber gave results that are not as clearcut but usually showed that cereal fiber such as wheat bran inhibited colon carcinogenesis. 50 Studi~s in which a protective effect could not be demonstrated or in a few cases in which an increased incidence was found can be explained. One kind of failure can be traced to use of a large amount of colon carcinogen, since the inhibition by cereal fiber is subtle. In other instances, large amounts (20 per cent of cereal bran) were used that have an irritating effect on the colon mucosa, yielding increased shedding of cell surface layers, in turn leading to a higher level of DNA synthesis in stem cells and in migration rates in the crypt. These conditions favor carcinogenesis. 29 Other fibers such as pectin, with quite different chemical properties, undergo partial hydrolysis and absorption in the large bowel with distinct biochemical consequences. 50 Pectin inhibited the effect of carcinogens such as azoxymethane that require biochemical activation in the liver and in the colon but not that of other carcinogens such as N -nitrosomethylurea. 50 Additional research is necessary to describe the specific properties of each kind of fiber in relation to its mechanisms of action. Still, appropriate amounts of bran cereal fibers that increase stool bulk have a definite inhibiting effect in animal models and in humans. Certain vegetables, such as Brussels sprouts and cauliflower, containing indole derivatives that can act as enzyme inducers, under certain conditions seem to inhibit the carcinogenic process. 51 Synthetic antioxidants such as butylated hydroxyanisole (BRA) also inhibited colon carcinogenesis. 42 These effects appear to relate to a reduced ratio of bioactivation. The relevance to human cancer is not evident, in view of the dose required to obtain inhibition. Dietary intake of calcium salts decisively lowers the toxicity of bile acids and slows rates of intestinal cell duplication. 27. 49 The exact
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mechanism may be complex, ranging from a simple elimination of bile acids as water-insoluble calcium salts to a more subtle molecular inhibition of promotion by calcium salts at the cellular membrane level. The effect of colon carcinogens in rats can also be inhibited by selenium compounds. Recently, it has been shown that feeding of the Bowman-Birk protease inhibitor derived from soybeans protected against colon cancer in mice. 52 This observation appears to support the report that E-amino caproic acid sUp'presses colon carcinogenesis in mice. 6 Because soy products in the human diet are cooked, protease inhibitors would be destroyed. Therefore, some sort of dietary additive would be required, but in light of observations of enhanced pancreatic carcinogenesis by raw soy diets (see subsequent discussion), further study is required. Populations that ingest high levels of dietary fat excreted increased amounts of cholesterol and cholesterol metabolites, including bile acids, than did populations traditionally using a lower-fat diet. Neutral sterols such as cholesterol, coprostanone, coprostanol, and cholesterol epoxide had no effect in increasing or decreasing the effect of a carcinogen for the colon of rats. 41 On the other hand, bile acids had an appreciable promoting effect, less for primary bile acids such as cholic acid than for the secondary bile acids such as deoxycholic or lithocholic acid. 40 Humans and animals on diets in which fat is 40 per cent of caloric intake uniformly excrete more bile acids, on the order of 12 mg per g of stool, compared with populations or animals on a lowfat (10 per cent of fat calories) diet in which the bile acid concentration is about 4 mg per g. The population in Kuopio, Finland, also exhibited a concentration of bile acids of about 4 mg per g, because of the larger stool bulk compared with that of the corresponding New York or Copenhagen populations. 41 This finding is important, as current views on the properties of promoters note that their effect is highly dependent on dose and on chronicity of exposure. In familial diseases with a predisposition to colon cancer (familial polyposis coli and hereditary colon cancer), the fecal excretion of undegraded cholesterol was high, with little of the microbial metabolites coprostanol and coprostanone, compared with the control population. 28 A likely explanation is that the cholesterol stems from desquamated cells. The higher cholesterol level would signify a higher cell turnover and shedding rate in such patients. 8 These findings suggest that the chemical analysis of stools might be useful in screening the members of these families. Preventive Approaches. On the basis of current concepts, a 50 per cent reduction of customary Western intake of total fat, to about 20 per cent of calories, and an increase in cereal bran fiber to
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produce a daily stool of about 200 to 250 g would be effective in decreasing risk of colon cancer not only in the general population, but also especially in individuals at higher risk of recurrence, such as those with adenomatous polyps or Dukes A carcinoma, who received endoscopic or surgical intervention. Furthermore, a daily intake of 2 to 3 glasses of skim milk as a source of calcium may be beneficial, not only in respect to colon cancer, but perhaps also for a lower risk of hypertension and osteoporosis.
Pancreatic Cancer Risk Factors. Cancer of the exocrine pancreas occurs in high incidence in northern Europe, North America; Australia, and New Zealand. In the United States, mortality rates have increased approximately threefold from 1930 to 1980. Smoking and tobacco use, generally, is one etiologic factor incriminated, through as yet unclear mechanisms. 34 Various assessments of dietary factors have been made. Alcohol as a risk factor is controversial, but if there is a risk at all, it is not high. 33, 34, 60 The suggestion of an association with coffee drinking35 has not been corroborated. 13, 33, 34, 62 Significantly decreased risks were associated with consumption of raw fruits and vegetables and diet soda, and significantly increased risks appeared with consumption of white bread. 13 Intake of dietary fat has also been correlated with pancreatic cancer. 30 Genotoxic Carcinogens. No definite evidence is available as to the possible genotoxic carcinogens for cancer of the pancreas. However, neoplasms of the pancreas were noted in tests of the heterocyclic amine IQ, found in fried foods. 45 , 46 Also, carcinogens from tobacco may be contributory. Epigenetic Agents. Feeding animals diets high in unsaturated fat after exposure to a carcinogen produced an increase of pancreatic carcinomas in hamsters2 and in rats. 31 This enhancement is also influenced by the level of essential fatty acids. 43 Another dietary factor shown to influence the development of pancreatic acinar cell carcinomas in animal models is raw soya-bean flour,21,59 an effect perhaps due to inhibition of trypsin and a consequent increased release of the hormone cholecystokinin, which has a trophic effect on the exocrine pancreas. The relevance of this observation to the human situation is not clear, as soy products are usually heated or cooked, which destroys protease inhibitors. Also, people traditionally eating cooked soy products have a low rate of pancreatic cancer. Moreover, feeding of the soy-derived Bowman-Birk protease inhibitor to mice had no effect on the pancreas, 52 which may indicate species differences in protease inhibition, cholecystokinin release, or pancreatic response.
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Preventive Approaches. Since tobacco use and a Western diet are risk factors, it is clear that cessation of smoking and a lower intake of fat would contribute to prevention, especially if carried out early in adulthood.
Breast Cancer Risk Factors. Breast cancer rates are significantly different among countries, paralleling, in general, colon cancer rates. The key difference in environmental factors between low-risk countries such as Japan and high-risk Western countries such as the United States is dietary, with the main variable being the quantity and type of fat.4,37 In contrast to the increase in risk of colon cancer occurring in first-generation migrants from a low-risk region (Japan) to a highincidence area (United States), it is not until the second generation that the incidence rises to that seen in the high incidence region. 37 Thus, for breast cancer, residence in a high-risk area at the time of puberty and breast development may be critical. Relevant are observations that female Sprague-Dawley rats are more sensitive to mammary carcinogens at or around puberty, at which time the rate of cell division is high. An intriguing observation is that former college athletes have a lower prevalence of breast cancer and cancers of the reproductive system than nonathletes. 12 Whether this is related to dietary practices or body habitus is not certain, but it is consistent with the concept that lifestyle during developmental stages is of importance. Genotoxic Carcinogens. The DNA-reactive carcinogen or carcinogens that cause human breast cancer have not been identified but may stem from cooking of meat, which yields potent carcinogens, one 'of which has induced mammary cancer in rats. 46 Epigenetic Agents. When breast cancer was induced in rats by chemicals, such as 7,12-dimethylbenz(a)anthracene (DMBA) and Nnitrosomethylurea (NMU), diets with 20 per cent fat or 40 per cent of calories significantly increased the frequency of mammary gland cancer, as compared with diets containing 0.5 to 5 per cent fat. 5 The effect was exerted primarily on the promotional phase of neoplasm development, and polyunsaturated fats seemed more effective promoters than were saturated fats. The promotional effect of a high-fat diet on mammary tumorigenesis was reversed by subsequently lowering the level of dietary fat.25 A 20 per cent, but not a 5 per cent, fat intake increased carcinogenesis in ovariectomized rats, a model for human postmenopausal breast cancer, suggesting a lower fat intake would assist its control. Caloric restriction can inhibit the effect of a high-fat diet.
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Menhaden oil (from fish oils) inhibited tumorigenesis, and olive oil at 40 per cent of calories had a minimal enhancing effect. 4 The amount of essential fatty acids in fats seems to playa role in tumor development,4. 22 possibly mediated by altered levels of biologically active prostaglandins. Postulated mechanisms by which the amount and type of dietary fat may influence breast cancer are those involving direct effects on host metabolism and those involving secondary effects of obesity. There is no question but that hormones are involved in growth control of the mammary epithelium. Dietary fat may elicit its tumorenhancing effects by altering host endocrine metabolism, in particular, that component of the endocrine system that regulates prolactin secretion and hormonal balances generally. 5 Preventive Approaches. Reduction of the level of dietary fat from 40 per cent to 20 to 25 per cent of calories, especially if accompanied by a reduced overall caloric intake, might help to prevent the development and recurrence of breast cancer. This is the basis for planned clinical intervention trials to lower the recurrence rate in cancer patients by adjuvant therapy with a low-fat diet. 61 Because in Japan the current dietary fat level is 20 per cent, it may be significant that breast cancer recurs less in Japanese women than in American women. 61 Also, greater use of olive oil and fish oils (through a higher intake of fish with such oils) may be beneficial.
Prostate Cancer Risk Factors. Epidemiology has provided data on the incidence of prostate cancer as a function of several factors such as race, age, area of residence, endocrine levels, and diet. 15, 20, 63 Caucasians in the Western world have a higher incidence than do the Japanese. As for breast cancer, first-generation Japanese migrants to the United States retain their low risk, but later generations have a higher risk. Native Japanese, however, have in situ lesions,1 as do other low-risk populations. 9 It has been suggested that the population differences in occurrence of latent versus clinical prostatic carcinoma are due to operation of epigenetic environmental factors in the sequence of neoplasm development. In general, populations that have a high risk of breast, colon, and endometrial cancer also have a high risk of prostate cancer. 18 An association with diet has been documented for breast and colon cancer, as described previously, and therefore, dietary fat may also play a role in the etiology of prostate cancer. Until recently, a reliable and realistic animal model involving specific chemical carcinogens for prostate cancer has not been
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Table 1. Nutritional Factors Involved in Major Human Cancers in North America
TYPE OF CANCER
Esophagus, oral cavity
POSTULATED SOURCE AND GENOTOXIC CARCINOGENS
EPIGENETIC (PROMOTING OR CO-CARCINOGENIC) FACTORS
PROTECTIVE OR INHIBITING ELEMENTS
Tobacco (nitrosamines, polycyclic aromatic hydrocarbons) Salting and pickling processes (nitrosamines)
Alcohol Low intake of micronutrients, zinc deficiency
Dried, salted fish; pickled vegetables; smoked fish; fava beans (nitrite + promutagen) High nitrate level in food and water
Salt (sodium chloride) Low intake of fresh fruits and vegetables Low intake of vitamin C
Increased intake of fresh vegetables and fruit Vitamins A, C, and E
Carcinogens formed in fried or broiled meat and fish (heterocyclic amines)
High level of dietary fat Bile acids
Cereal bran fiber, certain vegetables (cabbage, Brussels sprouts, cauliflower), selenium, calcium Olive oil? Fish oils?
Rectum
??
Alcohol?
Fiber?
Pancreas
Tobacco?
Alcohol? Coffee?
Fresh fruits and vegetables
Fried meats/fish?
High dietary intake of fat Raw soya flour
Breast
Fried meats/fish?
High dietary intake of fat Endocrine imbalance
Low-fat diet Olive oil? Fish oils?
Prostate
??
High dietary intake of fat
Low-fat diet, adequate zinc and selenium
Stomach
Colon
Green or yellow vegetables, fruits high in vitamins A, C, and E
Vitamin C and E
available. Several new approaches are currently under investigation, based on mechanistic considerations that a tissue stimulated to proliferate during carcinogen administration is more susceptible to carcinogenesis. These models, if validated, should permit exploration of the conditions required for tumor production and the effect of dietary modulators such as the level of fat or micronutrients. Preventive Approaches. As is indicated for other nutritionally linked cancers, a 50 per cent reduction of total fat intake may serve to lower the risk for this important cancer. Other areas of nutrition
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involving micronutrients, such as the adequacy of zinc or selenium supplies, require more research.
CONCLUSIONS Evidence from many types of studies leads to the conclusion that diet is a major factor in the causation of some of the most important and prevalent human cancers (Table 1). A number of investigators lO , 54, 56 have calculated that nutrition or similar "lifestyle" factors may have a direct impact on the occurrence of as much as 30 to 40 per cent of cancers in men and 50 to 60 per cent of cancers in women in the United States and other Western countries. The etiologies of most cancers are complex and clearly multifactorial. For some, such as stomach cancer, the main determining factor appears to be one or more genotoxic carcinogens, whereas for others, including colon, breast, and perhaps pancreas and prostate cancers, epigenetic-enhancing elements seem to be decisive. With respect to both the genotoxic and epigenetic agents, relatively minor alterations in dietary habits, involving reduced salt (pickled foods) and fat intake and a higher consumption of fresh vegetables and fruits, bran-type fibers, and calcium-rich foods such as skim (not whole) milk or lowfat yogurt, offer clear promise for meaningful reduction of risk. Ideally, sound dietary practices should begin in childhood. This may be particularly important in the control of breast and prostate cancer. Nevertheless, since epigenetic factors are involved in the "late stage" of tumor development, reduction of exposure of adults to such factors as contributed by high-fat diets may translate into a relatively rapid reduction of disease risk. In addition to modification of specific elements, avoidance of obesity by matching caloric intake to energy needs and increased physical exercise is of obvious Significance in moderating chronic disease risks. Important corollary benefits in other major diseases would ensue, as adjustment of nutritional traditions would also yield a lower risk of hypertension, stroke, arteriosclerosis, and coronary heart disease. These approaches should be useful for the general population in the United States, but they are clearly highly indicated for individuals at greater risk, such as those who have presented with intestinal polyps or cystic breast disease. Moreover, dietary modification offers promise as an adjuvant in the treatment of patients with certain cancers to prevent recurrences or second cancers. In both these situations, the surgeon has a crucial role to play. Indeed, in subpopulations at elevated risk, such as those with premalignant conditions, amelioration of cancer risk may be achieved relatively
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rapidly. Of additional public health benefit, such observations by the physician would contribute to a better foundation on which to base large-scale intervention.
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44. Sporn, M. B., and Roberts, A. B.: Role of retinoids in differentiation and carcinogenesis. Cancer Res., 43:3034-3040, 1983. 45. Sugimura, T.: Carcinogenicity of mutagenic heterocyclic amines formed during the cooking process. Mutat. Res., 150:33-41, 1985. 46. Tanaka, T., Barnes, W. S., Weisburger, J. H., et al.: Multipotential carcinogenicity of the fried food mutagen 2-amino-3-methylimidazol[4,5-flquinoline (IQ) in rats. Gann (Tokyo), 76:570-576, 1985. 47. Toth, B., Nagel, D., and Ross, A.: Gastric tumorigenesis by a single dose of 4(hydroxymethyl)benzenediazonium ion of Agaricus bisporus. Br. J. Cancer, 46:417-422, 1982. 48. Vassallo, A., Correa, P., DeStefani, E., et al.: Esophageal cancer in Uruguay: A casecontrol study. J. Natl. Cancer lnst., 75:1005-1009, 1985. 49. Wargovich, M. J., Eng, V. W. S., Newmark, H. 1., et al.: Calcium ameliorates the toxic effect of deoxycholic acid on colonic epithelium. Carcinogenesis, 4:1205-1207, 1983. 50. Watanabe, K., Reddy, B. S., Weisburger, J. H., et al.: Effect of alfalfa, pectin and wheat bran on azoxymethane or methylnitrosourea-induced colon carcinogenesis in F344 rats. J. Natl. Cancer lnst., 63:141-145, 1979. 51. Wattenberg, 1. V.: Anticarcinogenic effects of several minor dietary components. In Wynder, E. L., Leveille, G. A., Weisburger, J. H., et al. (eds.): Environmental Aspects of Cancer: The Role of Macro and Micro Components of Foods. Westport, Connecticut, Food and Nutrition Press, 1983, pp. 157-166. 52. Weed, H. G., McGandy, R. B., ~nd Kennedy, A. R.: Protection against dimethylhydrazine-induced adenomatous tumors of the mouse colon by the dietary addition of an extract of soybeans containing the Bowman-Birk protease inhibition. Carcinogenesis, 6:1239-1241, 1985. 53. Weisburger, J. H.: Nutrition and colon cancer. Clin. Nutrit., 4:131-137, 1985. 54. Weisburger, J. H., and Williams, G. M.: Chemical carcinogenesis. In Holland, J. H., and Frei, E. (eds.): Cancer Medicine. Edition 2. Philadelphia, Lea & Febiger, 1982, pp. 42-95. 55. Weisburger, J. H., and Wynder, E. 1.: The role of genotoxic carcinogens and of promoters in carcinogenesis and in human cancer causation. Acta Pharmacol. Toxicol., 55 (Suppl II):53-68, 1984. 56. Willett, W. C., and MacMahon, B.: Diet and cancer-an overview. Part 1. N. Engl. J. Med., 310:633-638, 1984. 57. Williams, G. M.: Food and cancer. Nutr. Int., 1:49-59, 1985. 58. Williams, G. M., and Weisburger, J. H.: Chemical carcinogens. In Doull, J., Klaassen, C. D., and Amdur, M. d (eds.): Casarett and Doull's Toxicology. The Basic Science of Poisons. Edition 3. New York, Macmillan, 1986. 59. Wormsley, K. G.: Carcinoma of the pancreas. Proc. Nutrit. Soc., 44:113-114, 1985. 60. Wynder, E. L.: An epidemiological evaluation of the causes of cancer of the pancreas. Cancer Res., 35:2228-2233, 1975. 61. Wynder, E. L., and Cohen, 1. A.: A rationale for dietary intervention in the treatment of postmenopausal breast cancer patients. Nutr. Cancer, 3:195-199, 1982. 62. Wynder, E. L., Hall, N. E. L., and Polansky, M.: Epidemiology of coffee and pancreatic cancer. Cancer Res., 43:3900-3906, 1983. 63. Wynder, E. 1., Laakso, K., Sotarauta, M., et al.: Metabolic epidemiology of prostatic cancer. Prostate, 5:47-53, 1984. 64. Yang, D., Tannenbaum, S. R., Biichi, G., et al.: 4-Chloro-6-methoxyindole is the precursor of a potent mutagen (4-chloro-6-methoxy-2-hydroxy-1-nitroso-indolin-3-one oxime) that forms during nitrosation of the fava bean (Vicia Jaba). Carcinogenesis, 5:1219-1224, 1984. Naylor Dana Institute for Disease Prevention American Health Foundation Valhalla, New York 10595