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3 Diet arid the Mechanisms of Carcinogenesis Much of what we know about the causes of the most common cancers in humans has been provided by empirical studies of the epidemiology of cancer, rather than by laboratory studies of mechanisms. For example, the carcinogenicity of cigarette smoke was established for humans even though the laboratory investigator had not found a susceptible labora- tory animal. But our understanding of the mechanisms of carcinogenesis has come mostly from observations of experimental animal models. The study of experimentally induced cancers in animals, especially the production of skin cancer in mice and rabbits, has shown that car- cinogenesis can be divided into early stages ~ initiation') and later stages ('promotion ). With rare exception, agents that are powerful initiators have proved to be powerful mutagens (or to be capable of being metabolized into mutagens). In contrast, the most powerful promoters have proved to be agents that alter various cell properties, especially the structure of the cell surface and the pattern of gene expression. Despite these studies, the molecular biology of carcino- genesis remains obscure; it is not known whether~nutagens act as ini- tiators because they produce mutations or for some other reason, and the processes underlying promotion remain equally obscure. There is no unanimity in the scientific community on this point; however, numerous investigators believe that many, if not most, cancers in humans will eventually be shown to be the result of our exposure to the mutagenic initiators and the promoters in our environment. It is not at all clear that the sequence of steps leading to the 'spontaneous cancers in animals can always be separated into these two stages. For example, the stages in the production of feline leukemia and bovine e sophageal cancer certainly do not f it comfortably into that dichotomy. Similarly, the main risk factor for liver cancer in humans is chronic infection with hepatitis B virus, even though this virus does not appear to be a mutagen and there is no evidence that it would score as positive in any test for ability to promote the later steps of carcinogene si s. Therefore, as we try to disentangle the effects of diet on cancer incidence by hunting through the foods we eat for mutagenic initiators and for agents that promote the later steps of carcinogenesis, we should keep in mind that the important dietary determinants of cancer rates in humans may not fall readily into one of these two classes. For example, it has not been easy to decide what mechanic so is most likely to be responsible for the observed effect of a high fat diet on the incidence of cancer. The following suggestions have been made: 9

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10 DIET, NUTRITION, AND CANCER: DIRECTIONS FOR RESEARCH o Fat could enhance carcinogenesis by contributing to the forma- tion of peroxides and other reactive forms of oxygen, which could then damage DNA. A high fat diet may increase excretion of sterol metabolites in the gut, which in turn may promote tumorigenesis in the colonic epithe- l ion . Certain fatty acids in the diet could be incorporated into cell membranes, possibly producing changes in cell behavior that are asso- ciated with promotion. 0 Certain essential fatty acids participate in the synthesis of prostaglandins, and these may influence twmorigenesis. A high fat diet could lead to a change in the level of certain hormones that in turn might affect the incidence of breast cancer and some other cancers. Lastly, fat may increase cancer rates for reasons that we cannot at present guess, simply because we do not yet know enough about the pathways that lead to cancer. We do not know the extent to which the 'initiator-promoter model is applicable, but the answer to this question may not be critical to the design of laboratory experiments or epidemiological studies in the near future. From the evidence accumulated thus far, however, it seems clear that carcinogenesis is usually a multistep process. Furthermore, it has been observed in both epidemiological and laboratory studies that the effects of diet seem to operate more often upon the later steps than upon the earlier ones. Up to this point, we have discussed only those agents that stimulate the production of cancer. Recent evidence has indicated that there are other agents that inhibit carcinogenesis. Therefore, as a start to the further study of the effects of diet, we would like to find out whether the critical variable is the degree of exposure to agents that stimu- late the production of cancers (which otherwise would not occur) or to agents that inhibit the production of cancers (which otherwise would arise spontaneously). Even though our primary interest is in studying those agents in our environment that stimulate or inhibit the occurrence of cancer, we should remember that the action of such agents may often be modified by familial, possibly genetic, factors. For example, al- though the incidence of breast cancer is apparently related to fat intake and age at first pregnancy, it is well known to be strongly ink fluenced by familial factors, which may have an environmental as well as a genetic component. Certain technical advances are now offering us a new source of information about the mechanisms by which cancers are produced in

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Diet and the Mechanisms of Carcinogenesis 11 humans. Until recently, the process of looking for signs of DNA damage or changes in gene composition and expression was like looking for a needle in a haystack. But new methods may enable us to identify the fundamental abnormalities that determine the properties of cancer cells, i.e., which genes are changed, which show altered expression, and which cellular products are present in an abnormal form or quan- tity. Thus, we can see that the time may soon come when the molecular biologist will be able to give the epidemiologist some clues about factors that are likely to be critical in the production of certain cancers. It seems generally true that the benefits derived from fundamental discoveries about mechanisms tend to arise in completely unexpected ways. For example, one of the advances that has made the study of cancer genes possible was the discovery of the restriction enzymes of bacteria--a result of studies that had no obvious connection with carcinogenesis. (Because of our knowledge of these enzymes, which are absolutely specific to certain base sequences and can be used to break up DNA molecules into short stretches, it has been possible to work out the exact sequence of whole groups of genes and to determine exactly the way in which certain cancer cells differ in sequence from their nonnal counterparts.) Thus, although the following chapters contain numerous recommendations for specific research areas to be pursued in the study of diet, nutrition, and cancer, the committee recognizes that important insights into the mechanisms and dietary causes of cancer may also come from research in areas that are not discussed in this report. RESEARCH RECOMMENDATIONS This chapter contains no recommendations, because the general mecha- nisms of carcinogenesis are not within the purview of this report. Suggestions for research on the mechanists) of action of individual dietary components are included in the chapters that follow.