Research Synopsis
Colorectal cancer risk has been related to diet and lifestyle factors in many ecological, case control and cohort studies. My goal is to understand the mechanisms responsible for these association with the expectation that such an understanding will suggest efficient approaches to colon cancer prevention.

At present, three basic mechanisms appear to be involved in colon carcinogenesis. First, high risk diets result in the consumption of excess calories, and the development of hyperinsulinemia and insulin resistance. The increased insulin acts as a growth factor, promoting the growth of cells with defective growth control mechanisms. Second, high risk diets can result in decreased epithelial membrane integrity and increased permeability. This results in the possible exposure of epithelial cells to luminal toxins, products of inflammation and also luminal growth hormones. This will also provide a proliferative stimulus. Third, high risk diets increase the mutation frequency in epithelial cells either because they contain genotoxic compounds such as heterocyclic amines or because they lead to the endogenous formation of genotoxic compounds such as advanced glycation end-products or reactive oxygen species. The combination of proliferation stimuli and genotoxins results in the accumulation of the mutations characteristic of colorectal cancer.

The importance of the three mechanisms can be evaluated in animal models and clinical studies with the use of experimentally modified diets and biomarkers of epithelial exposure and cancer risk. Typical dietary intervention might include increased dietary calcium, folic acid and n-3 fatty acids; exposure biomarkers, plasma insulin, insulin-like growth factors, markers of inflammation and direct chemical assessment of genotoxins and their products; and disease biomarkers the putative colon cancer precursor lesions aberrant crypt foci (ACF) and colonic polyps. With consistent hypotheses and simple methods for testing them we should be able to define the factors relating diet and colorectal cancer.