Squamous cell carcinoma (SCC) of the oral cavity spreads by local extension and by lymphatic metastasis. Tumor invasion requires cell locomotion, which in turn requires motility factors. One such factor is hepatocyte growth factor (HGF), a strong stimulator of cell motility and invasion in oral SCC cells. The binding of HGF to its receptor, Met, triggers downstream signaling events that induce disruption of intercellular cadherin junctions, activate integrin-ECM binding, mobilizes the associated cytoskeleton, and finally initiates cell movement. The overall goal of the proposed studies is to understand, at the molecular and cellular levels, how HGF/Met governs the motile and invasive response of oral SCC cells. The hypothesis to be addressed is that the invasive response elicited by HGF via Met is regulated through cadherin- and integrin-mediated adhesion.
The aims are: 1) to analyze how intercellular adhesion contacts modulate HGF-induced motility; 2) to define the mechanisms that regulate HGF-mediated dispersion of multicellular colonies; and 3) to determine whether HGF receptor and integrin receptors have synergistic roles in disrupting cadherin/catenin function during HGF-induced cell motility.
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