Role of phytochemicals in colon cancer prevention. A nutrigenomics approach

Specific food compounds, especially from fruits and vegetables, may protect against development of colon cancer. In this thesis effects and mechanisms of various phytochemicals in relation to colon cancer prevention were studied through application of large-scale gene expression profiling. Expression measurement of thousands of genes can yield a more complete and in-depth insight into the mode of action of the compounds. Effects of quercetin (a flavonoid present in e.g. apples and onions), curcumin (a spice used e.g. in curries) and resveratrol (present e.g. in grapes) were studied in cultured colon cancer cells. These studies confirmed some hypothesized mechanisms of action of these compounds (e.g. effects on cell cycle) and yielded new interesting leads (e.g. effects on proteasome genes, DNA repair genes, tubulin genes). In addition, expression profiles of a panel of 14 human cell lines derived from colonic tissue were compared and related to expression profiles of human colon biopsies from normal and tumor tissue. Changes in expression profiles of a subset of colon cancer-specific genes (as a biomarker set) in cultured colon cancer cells could be useful to translate in vitro results to the in vivo situation. In addition to the in vitro studies, effects of wheat bran, curcumin,rutinand benzyl isothiocyanate on colon carcinogenesis were studied in a rat model. Wheat bran and curcuminshoweda protective effect (lower tumor multiplicity after 8 months compared to the control group). Expression profiles of differentially expressed genes in small intestinal tissue at intermediate time points were predictive of colon tumor development at the end of the study, confirming a correlation between effects in small intestine and colon. In summary, the studies in this thesis demonstrate the potential of large-scale expression profiling in nutrition studies. These studies also demonstrated that although the technological advancements in large-scale gene expression analysis allow for the collection of 'whole genome' results, the challenge for the coming years will be to further exploit these data. Only when advances in the bioinformatics field lead to easier interpretation of large amounts of data from nutrigenomics studies, the large potential of nutrigenomics can become reality.