Grant: Operating Grant - PA: Inst of Nutrition, Metabolism and Diabetes -Bridge Funding

Colorectal cancer is a disease of defective Wnt signaling which is the third most common cause of cancer-deaths in Canada. Inflammation of the intestine increases the risk for colorectal cancer. Increases in dietary calcium reduce the onset of colonic polyposis and recurrence of colonic adenomas. The molecular basis of this chemoprotective effect of calcium are unknown. We have discovered that the extracellular calcium-sensing receptor is present on both the cells that line the gut as well as the cells which sit under them. We find that when we stimulate this receptor with calcium we cause these cells to produce powerful inhibitors of defective Wnt signaling, which result in the inhibition of colon cancer cell growth and the stimulation of differentiation. If we treat these cells with inflammatory mediators, the calcium-mediated production of inhibitors is lost. Our results suggest existence of a novel pathway which may be stimulated to inhibit development of colon cancer and explain how inflammation increases the risk for this cancer.