Marc B. Bissonnette, M.D.

Nutrition as it Relates to Colonic Carcinogenesis

Research Summary

1. Investigation of the roles of bile acids in the promotion or inhibition of colon cancer. In the azoxymethane (AOM) model of experimental colon cancer, cholic acid potently enhances colon cancer, whereas ursodeoxycholic acid (UDCA) inhibits tumorigenesis. Similar actions are strongly suggested in humans, in whom high fat diets that are associated with increased cholic acid, enhance colon tumor risk. In contrast, UDCA appears to block the development of colonic dysplasia and adenomas in patients with conditions predisposing to this malignancy. We are investigating the effects of these bile acids on regulators of cell proliferation and cell death that are involved in the ability of these agents to alter tumor development. We have recently found, for example, that cholic acid significantly enhances cyclooxygenase II (Cox-2) expression, whereas UDCA inhibits this induction in AOM tumors. We have also observed that growth-promoting cyclin D1 is up-regulated, whereas growth-inhibiting E-cadherin is down-regulated in aberrant crypt foci (ACF) in this model. ACF are the earliest visible putative precursors of colon cancer.

2. Role of wild type activated Ras in colonic carcinogenesis. We are also characterizing signal transduction elements involved in activating wild type Ras in colon cancers. We have found that some human and AOM colonic tumors have wild type Ras with activation levels comparable to those of mutant Ras. These tumors have a “survival” phenotype in contrast to the “proliferative” phenotype characterizing tumors with mutant Ras. We are currently investigating the mechanisms activating wild type Ras and the biological consequences of this activation.

3. Identification of early molecular changes driving colonic carcinogenesis at the ACF stage. In the area of translational clinical research, we have begun to characterize human aberrant crypt foci (ACF) isolated by image magnification chromoendoscopy. In our preliminary studies by real time PCR we find that cyclin D1, Cox-2 and iNOS are increased in ACF, compared to normal mucosa. These enzymes and cell cycle regulators (cyclin D1) are expected to increase proliferation and potentially, thereby, enhance the risk of colon cancer. We will be examining ACF for alterations in gene expression using DNA microarray technology as well. These studies will be useful to elucidate premalignant events at an early stage of colonic carcinogenesis. They will also help identify potential biomarkers for individuals “at risk” for colon cancer, and to monitor the efficacy of chemopreventive agents in these patients.

Selected Papers

Chen A, Davis BH, Sitrin MD, Brasitus TA and Bissonnette M. (2002). Transforming growth factor-b1 signaling is involved in Caco-2 Cell growth inhibition induced by 1,25-dihydroxyvitamin D3 Am. J. Physiol. 283: G864-G874.

Wang H, Wang J, Xiao S-Y, Haydon R, Debra Stoiber D, He T-C, Bissonnette M, and Hart J. (2002). Elevated protein expression of cyclin D1 and Fra-1, but decreased expression of c-Myc, in human colorectal adenocarcinomas overexpressing? b-catenin. Int. J. Cancer 101: 301-310.

Wali R, Khare S, Tretiakova M, Cohen G, Nguyen L, Hart J, Wang J, Wen M, Joseph L, Ramaswamy A, Sitrin M, Brasitus T and Bissonnette M. (2002). Ursodeoxycholic acid and F6-D3 inhibit aberrant crypt proliferation in the rat AOM model of colon cancer: roles of cyclin D1 and E-cadherin. Cancer Epidemiology Biomarkers and Prevention 11: 1653-1662.

Wali R, Stoiber D, Nguyen L, Hart J, Sitrin M, Brasitus T and Bissonnette M. (2002). Ursodeoxycholic acid inhibits the initiation and post-initiation phases of azoxymethane-induced colonic tumor development. Cancer Epidemiology Biomarkers and Preventions, 11: 1316-1321.

Wali R, Kong J, Sitrin M, Bissonnette M and Li Y. (2003). The vitamin D receptor is not required for the rapid actions of 1,25-dihydroxyvitamin D3 in mouse osteoblasts. J Cellular Biochemistry, 88: 794-801.

Khare S, Cerda S, Wali RK, Von Lintig FC, Tretiakova M, Joseph L, Stoiber D, Cohen G, Nimmagadda K, Hart J, Sitrin MD, Boss GR and Bissonnette M. (2003). Ursodeoxycholic Acid Inhibits Ras Mutations, Wild-type Ras Activation, and Cyclooxygenase-2 Expression in Colon Cancer. Cancer Res. 63: 3517-3523.

Roy HK, Gulizia J, DiBaise JK, Karolski WJ, Ansari S, Madugula M, Hart J, Bissonnette M, and Wali RK. (2004). Polyethylene glycol inhibits intestinal neoplasia and induces epithelial apoptosis in Apc (min) mice. Cancer Lett, 215: 35-42.