? ? In ovarian cancer, as in most other solid tumor, metastatic disease rather than the primary lesion is the most common cause of death of the majority of patients. Dysregulated HGF/c-Met signaling of cell migration has been suggested to contribute to tumor invasion and metastasis. Specific inhibitors against HGF/c-Met signaling, therefore, may have important therapeutic potential for the treatment of cancers in which Met activity contributes to the invasive/metastatic phenotype. Recently, several c-Met receptor antagonists have been developed. The goal of the proposed research is to investigate the effects of a c-Met specific ATP-competitive small-molecule SU11274 on human ovarian carcinoma cell motility and transendothelial invasion. We hypothesize that c-Met- mediated signals affect cell motility by altering specific physical processes which provide the actual means for movement. Moreover, we suspect that although the role of c-Met varies from cell type to cell type, inhibition of c-Met may significantly inhibit motility and invasive activity in ovarian cancer cells expressing high levels of activated c-Met. The project will be facilitated by the use of electric cell-substrate impedance sensing (ECIS), a novel cell-based biosensor that monitors morphological changes of cells adherent on small gold electrodes. This approach will be combined with our established ability in fluorescence imaging, ECM coated polyacrylamide substrate, and digital image analysis to characterize a variety of cellular responses to SU11274.
The specific aims are: 1. To determine the effect of activated c-Met on cell migration speed and/or directional persistence. 2. To determine the effect of activated c-Met on cell contractile force and morphology. 3. To determine the effect of c-Met inactivation by SU11274 on the transendothelial invasion of ovarian cancer cells. The proposed research will provide new information regarding the functional role of activated c- Met in metastatic behaviors of human ovarian carcinoma cells. The results will contribute to a broader goal of developing a new molecularly targeted anti-cancer therapy for ovarian cancer and possibly other forms of cancer. ? ? ?
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