? Colorectal cancer, the third leading cause of cancer death in men and women in the U.S., results from the interaction of genetic and dietary susceptibility elements. Since colorectal cancer is caused by failure of terminal cell differentiation, dietary factors that promote cell migration, a required phenotype for cell differentiation, can be expected to decrease colorectal cancer risk. Our long-term goal of this research is to identify mechanisms by which specific dietary compounds mediate the development of phenotypes associated with cell differentiation including migration, cell-cell communication and apoptosis. The objective of this application is to identify the intracellular signaling pathways induced by flavonoids that contribute to cell migration. Our central hypothesis is that specific flavonoids, present in the diet in foods and beverages, will elicit the migratory phenotype in non-tumorigenic colon epithelial cells by activating specific intracellular signaling pathways. Wild-type adenomatous polyposis coil (APC) is a gatekeeper gene for inherited and sporadic colorectal cancer in rodents and humans. The migratory phenotype is dependent upon wild-type APC expression since full length APC protein mediates directed cell migration in the colon. We will use non-tumorigenic colon epithelial cell lines with normal Apc genotype (called YAMC) and mutant Apc genotype (called IMCE) to identify biological determinants of cell migration relevant to the early stages of colon tumorigenesis. To test our hypothesis and achieve our objectives, we propose to address three specific aims. First, we will identify specific flavonoids that induce migration in YAMC and IMCE cells by performing dose-response studies of flavonoid-dependent cell migration using twelve (12) compounds representing five (5) flavonoid families. Second, we will quantify the ability of migration-inducing flavonoids to activate relevant cell signaling pathways associated with cell migration by co-treating YAMC and IMCE cells with flavonoids and receptor- and signaling pathway-specific antagonists or inhibitors. Third, we will quantify the ability of selected migration-inducing flavonoids to modulate gene expression in YAMC and IMCE cells using cDNA microarrays constructed from the 15K mouse set of the National Institute of Aging. These analyses will identify genes and clusters of gene families whose transcription is increased or decreased in response to these flavonoids. The identification of dietary compounds which could stimulate migration, and hence, cell differentiation, in cells expressing mutant Apc (IMCE cells) could define a new strategy for prevention of colon cancer by diet-derived compounds. Ultimately, this research will provide critical information necessary for specific and rational dietary recommendations to decrease colon cancer risk in humans. ? ?
| Fenton, Jenifer I; Hord, Norman G (2004) Flavonoids promote cell migration in nontumorigenic colon epithelial cells differing in Apc genotype: implications of matrix metalloproteinase activity. Nutr Cancer 48:182-8 |
