Scatter factor (SF) or hepatocyte growth factor (HGF) is a cytokine implicated in diverse biological processes, including carcinogenesis, epithelial morphogenesis and organ repair. The applicant has found that SF can protect cultured breast cancer cells and non-tumor epithelial cells against apoptosis induced by multiple DNA damaging agents, including x-ray, UV irradiation and adriamycin leading to an increased cell survival. Protection was dependent on the expression of the c-Met proto-oncogene, the receptor for SF, but did not require functional p53. The protection seen against adriamycin may result from changes in the levels of different apoptosis regulatory proteins. The investigators hypothesize that SF mediated protection of target cells results from the transduction of a specific signal from the activated c-Met distinct from signals for motility and morphogenesis. This signal leads to downstream alterations in the levels of apoptosis regulatory proteins. By enhancing the survival of cells with genetic damage, SF may promote carcinogenesis and/or chemoradioresistance of established tumors. The applicant proposes to test these hypotheses in specific aims 1 and 2 by examining the mechanism by which SF protects epithelial and carcinoma cells against apoptosis at the levels of signal transduction from the c-Met receptor and modulation of pathways involved in apoptosis, cell cycle progression and DNA repair.
In specific aim 3, an experimental animal model will be used to determine if SF can protect tumors against apoptosis.
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