Hedgehog (Hh) pathway activity is important for the growth of a significant fraction of human cancers and is also implicated in stem cell maintenance in postembryonic tissues. Our preliminary results suggest that the Hh pathway is activated during tissue repair in response to acute injury in adult pancreas. We hypothesize that injury-induced pathway activation results in the expansion of tissue stem cells, and that inappropriate continuation of pathway activity may initiate cancer growth by transforming these cells into cancer stem cells. This hypothesis will be evaluated by assessing the stem cell character of cells with pathway activity induced by tissue injury and by testing whether continuous pathway activity in these cells can induce tumor formation. Various approaches including immunohistochemistry, cell culture, flow cytometry and mouse models will be used. Completion of these studies will expand our understanding of the mechanism by which Hh pathway activity causes growth of injury-associated tumors and provide a basis for using Hh pathway blockade as a new approach in human cancer therapy. ? ? ?
