Malignant melanoma of the oral cavity is almost always fatal. The proposed work focuses on two stages in melanoma progression: invasion and metastasis, during which melanoma cells interact with the extracellular matrix primarily through integrin receptors. The vitronectin receptor alphavbeta3 is expressed by vertically invasive and metastatic cutaneous melanoma but is absent from superficial spreading melanoma and normal melanocytes in vivo. In the murine K1735 melanoma, highly metastatic cells express alphavbeta3, but not the alphavbeta5 vitronectin receptor, while poorly metastatic cells express alphavbeta5 but not alphavbeta3. Adhesion of alphavbeta3, but not alphavbeta5, to vitronectin results in the activation of FAK, c-Src, and pMAP kinase-signaling molecules implicated in cell motility and gene expression - and in increased expression of matrix metalloproteinase-2 (MMP-2). This study addresses the following questions: 1) Does expression of alphavbeta3 or alphaVbeta5 correlate with oral melanoma metastasis? Human biopsy specimens will be evaluated by immunohistochemistry and in situ hybridization for expression of alphavbeta3 or alphavbeta5. 2) Does expression of alphavbeta3 correlate with metastatic potential in murine melanoma cells? K1735 cells with differing metastatic potential will be used to generate additional metastatic variants by both transoral and hind-flank injection. The resulting tumors and variant cell lines will be evaluated for expression of alphavbeta3 and for activation of FAK, pMAP kinase, and expression of MMP-2. 3) Will overexpression of alphavbeta3 confer the metastatic phenotype to poorly metastatic melanoma cells? Poorly metastatic cells expressing beta3 by retroviral transduction will be evaluated for invasive and metastatic behavior. The effect on metastasis of expressing a constitutively active Src will also be evaluated. 4) Will decreasing alphavbeta3 receptor expression, or suppressing its function, alter the invasive and metastatic potential of melanoma cells? beta3 expression in highly metastatic cells will be reduced by both antisense and dominant negative strategies. Also, human beta3 will be expressed in poorly invasive melanoma cells, and its function suppressed by function-blocking antibody to human beta3. Finally, whether expression of a dominant-negative c-Src in a highly metastatic cell line decreases metastasis will be determined. Understanding the role beta3 plays in oral melanoma invasion and metastasis may lead to novel prognostic indicators and development of new treatment strategies.
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