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The Wistar Institute, Philadelphia, PA 19104
3 To whom correspondence should be addressed. E-mail: kritchevsky{at}mail.wistar.upenn.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • energy (caloric) restriction • nutritional epidemiology
The American Institute for Cancer Research (AICR) was founded in 1982. In the ensuing 20 years it has become prominent in the field of nutrition and cancer research. The educational programs initiated by AICR have had a positive impact on our dietary habits. The research sponsored by AICR has always been at the cutting edge of the field. Annual conferences have been sponsored by AICR since 1990 and the published proceedings have represented important additions to the cancer literature. The AICR conference proceedings have often anticipated trends in nutrition and cancer. The earliest meeting contained findings on effects of vitamins, antioxidants, carotenoids, and minerals such as selenium and sulfur. Effects of exercise and calories were subjects of presentation at an AICR conference well before they became topics for general discussion. The list of subjects is long (immune response, gene expression, phytochemicals, insulin, tea, energy restriction) and is remarkable to see how early in time these topics, which are now standards, were introduced.
It is not the purpose of this exposition to describe the data discussed at AICR-sponsored conferences. The value of these contributions is well established. However, although important advances have been made in the research area and in suggestions of modifying dietary behavior, successful dietary interventions relating to cancer have not followed. We have expanded the tools of the trade—such as DNA chip technology, proteomics, and knowledge of nutrient-gene interaction. However, application of this knowledge to the laboratory and clinic has been slow, laborious, and often contrary to expectations. Although we have made significant advances in understanding the dietary, environmental, and genetic factors affecting the process of carcinogenesis, we have still not been able to use this knowledge to conduct successful intervention trials. A major problem is focusing on one particular aspect of a total diet. Information on nutrient-nutrient interaction lags behind the field.
Armstrong and Doll (1) conducted an epidemiologic study involving 23 countries to relate dietary factors to incidence and mortality of cancer at various sites. In general, fat was the dietary component most highly correlated with risk of cancers of the colon, rectum, breast, ovary, and prostate. They cautioned that correlations between specific foods and cancer "should be taken only as suggestions for further research and not as evidence of causations or as bases for preventative action". However, few of us have been able to resist the temptation of indicting a specific dietary component as the prime suspect. Six years later, Doll and Peto (2) discussed at length the avoidable risks of cancer in the United States. In a table that has achieved iconic proportions they listed a dozen possible factors. Diet was estimated to have caused the most cancer deaths. The best estimate was that dietary factors contributed 35% of cancer deaths but the confidence limits were 10–70%. In the text they explain, "We have attributed the largest risk to dietary factors for reasons that are discussed in detail in section 5.3. It must be emphasized that the figure (35% of cancer related to diet) chosen is highly speculative and chiefly refers to dietary factors which are not yet reliably identified."
We have, since then, identified a variety of factors that affect the course of carcinogenesis. Most of our training leads to reductionist thinking, resulting in attempts to identify a single factor, but diets containing a variety of items and the interactions among them remain to be elucidated. The greatest epidemiologic effort has been devoted to diet and colon and breast cancers. In assessing the influence of dietary fiber on colon cancer, there is no unanimity. Most of the findings report a protective effect but many find no effect. It might be informative to critically compare positive and negative findings and attempt to reconcile the differences. A very recent epidemiologic study examined the association between dietary fiber intake and incidence of colon cancer in 591,978 European subjects and concluded that increasing the fiber intake of subjects presently consuming a low fiber diet could result in a 40% reduction in their risk of colorectal cancer (3).
Cancer progresses through several stages and it is reasonable to assume that the same dietary components do not exert the same effect throughout carcinogenic development. Boutron et al. (4,5) studied the effects on risk of various factors in the stages of adenoma-carcinoma sequence (Table 1). Thus tobacco enhances adenoma formation but not adenoma growth or colon carcinoma. Alcohol, on the other hand, has slight effect on adenoma formation but enhances adenoma growth. Smoking effects are seen principally in the proximal colon whereas the greatest alcohol effect is seen at the rectal site (Table 2) (6,7). These different effects at different sites make the problem of treatment more complex but at the same time may point the way for research on specific aspects of colorectal cancer and diet. Giovannucci et al. (8) found that dietary fiber significantly reduced the risk of colorectal adenomas in men but later they reported that dietary fiber had no significant effect on risk of colorectal cancer (9). It could be argued that the metabolic and physical properties of dietary fiber inhibited formation of adenomas but once the adenomas were established other nutritional priorities set in and fiber did not affect any of them.
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-tocopherol, carotene and vitamin A effects on lung cancer (12,13) have failed to achieve their goals. Were the interventions carried out too late in the cycle? Factors that influence various stages of carcinogenesis have been identified. Perhaps dietary interventions should be instituted at the specific stages of carcinogenesis. The interactions and synergies of dietary components require further studies and coupled with current gene array methodology may enable the precise roles of specific nutrients to be elucidated. Tumor incidence in the 48 contiguous United States can vary by a factor of four or more. What could be learned from comparison of diets among the states? There may be still enough regional dietary differences to make this approach interesting. Insofar as animal studies are concerned, the prevailing trend is to study nutritional approaches in experiments using specific carcinogens. In this type of study, different nutritional interventions at various stages of carcinogenesis could be informative. Studies of spontaneous carcinogenesis are now rarely carried out. Possibly this is due to the open-endedness of such studies, which may not appeal to granting agencies. However, spontaneous carcinogenesis would simplify the equation because the variable of carcinogen metabolism would have been removed.
The influence of obesity on carcinogenesis has been reviewed at length. In 1913 Hoffman (14) suggested that "erroneous diet" contributed to cancer risk. In 1927 he proposed that energy excess played a critical role in cancer development (15). Twenty years ago Garfinkel (16) demonstrated the effects of overweight on cancer at several sites. Although a fat-rich diet is probably the easiest way to achieve overweight, simply overeating and underexercising can also do the trick. Possibly, then, a large part of the dietary fat effect is due to excess weight rather than lipid metabolism. Almost a century ago energy restriction was found to inhibit growth of transplanted tumors (17); a similar effect on spontaneous tumors was reported a few years later (18). In experiments in which the tumors were chemically induced, diets high in energy and fat were twice as carcinogenic for rats as those that were high in fat and low in energy (19). Energy restriction by 10% does not affect dimethylbenzanthracene-induced tumor incidence in rats but reduces tumor size. At 30% energy restriction, tumor incidence, multiplicity, and burden are all reduced significantly (20). Energy restriction is effective even in the face of high fat diets (21). Energy restriction by 30% or 40% reduces plasma insulin levels and the role of insulin in carcinogenesis is beginning to attract attention (22). Energy restriction is effective even when instituted late in life (23,24). Ross and Bras (25) found that when the energy intake of rats was restricted for only the first 7 wk of life, incidence of spontaneous tumors fell by 40%. Energy restriction inhibits tumorigenesis irrespective of the means of achieving it (i.e., reduce total dietary intake or reduce calories by reducing dietary fat, proteins, or carbohydrates). Exercise, another form of energy restriction, lowers the incidence of dimethylhydrazine-induced colon tumors in rats by 50% (26) and also reduces significantly the growth of transplanted tumors by 50% (27). Vigorous occupational physical activity reduces the risk of colon cancer in men (28–30). It would be interesting to examine the effects of combining energy restriction with a dietary component known to affect carcinogenesis.
Dietary approaches to inhibition of carcinogenesis have focused on one compound or class of compounds at a time, which belies the complexity of the problem. The basic scientific alphabet has been established. We should start learning how to put it into words.
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FOOTNOTES |
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2 Supported in part by a Research Career Award (HL00734) from the National Institutes of Health and the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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1. Armstrong, B. & Doll, R. (1975) Environmental factors and cancer incidence in different countries, with special references to dietary practice. Int. J. Cancer 15: 617–631.[Medline]
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5. Boutron-Ruault, M. C., Senesse, P., Meance, S., Belghiti, C. & Faivre, J. (2001) Energy intake, body mass index, physical activity and the colorectal adenoma-carcinoma sequence. Nutr. Cancer 39: 50–57.[Medline]
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7. Faivre, J., Boutron, J. M., Hilton, B., Bedeane, L. & Klepping, C. (1985) Epidemiology of colorectal cancer In: Diet and Human Carcinogenesis (Joosens, J., Hill, M. & Geboers, J., eds.), pp. 123–136. Exerpta Medica, Amsterdam, The Netherlands.
8. Giovannucci, E., Stampfer, M. J., Colditz, G., Rimm, E. B. & Willett, W. C. (1992) Relationship of diet to risk of colorectal adenoma in men. J. Natl. Cancer Inst. 84: 91–98.
9. Giovannucci, E., Rimm, E. B., Stampfer, M. J., Colditz, G. A., Ascherio, A. & Willett, W. C. (1994) Intake of fat, meat and fiber in relation to risk of colon cancer in man. Cancer Res. 54: 2390–2397.
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13. The ATBC Cancer Prevention Study Group. (1994) The effect of Vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330: 1029–1035.
14. Hoffman, F. L. (1913) The menace of cancer. Am. J. Obstet. Dis. Women Child. 68: 88–91.
15. Hoffman, F. L. (1927) Cancer increase and overnutrition. Prudential Insurance Co., Newark, NJ.
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17. Moreschi, C. (1909) Beziehungen zwischen Ernährung u. Tumorwachstum. Z. Immunitätsforsh. 2: 651–675.
18. Ross, P. (1914) The influence of diet on transplanted and spontaneous tumors. J. Exp. Med. 20: 433–451.[Abstract]
19. Lavik, P. S. & Baumann, C. A. (1943) Further studies on the tumor promoting action of fat. Cancer Res. 3: 749–756.
20. Klurfeld, D. M., Welch, D. B., Davis, M. J. & Kritchevsky, D. (1989) Determination of degree of energy restriction necessary to reduce DMBA-induced mammary tumorigenesis in rats during the promotion phase. J. Nutr. 119: 286–291.
21. Klurfeld, D. M., Welch, C. B., Lloyd, L. M. & Kritchevsky, D. (1989) Inhibition of DMBA-induced mammary tumorigenesis by caloric restriction in rats fed high fat diets. Int. J. Cancer 43: 922–925.[Medline]
22. Giovannucci, E. (2001) Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J. Nutr. 131: 3109S–3120S.
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