METASTATIS--BIOLOGICAL PHENOTYPE AND MODELS FOR THERAPY

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Human skin reconstructs in vitro and human skin grafts on athymic nude or SCID mice represent new tools for studying invasion and metastasis because they mimic the complex interactions of human melanoma cells with surrounding normal cells. These newly developed orthotopic models will be characterized for the expression of mRNA and antigens using in situ hybridization and antibody binding techniques. Invasion and metastasis models, will also be used to delineate the functional roles during invasion and metastasis of two tumor cell surface structures and one tumor-derived extracellular matrix protein. Each of these cellular components was chosen based on its selective expression on malignant cells from invasive lesions. The role for vitronectin receptor in melanoma invasion and metastasis will be investigated by selecting with monoclonal antibodies variant cells that do not express either the beta3 or the alphav subunits. Alternatively, antisense RNA constructs will be transfected into metastatic cells. The function of the cell surface metalloproteinase aminopeptidase N in invasion and metastasis will be determined using monoclonal antibodies and a specific inhibitor and the hypothesis will be tested that aminopeptidase N is involved either in the activation of matrix-degrading collagenases or in disrupting cell-cell adhesion. To investigate the role of the extracellular matrix protein tenascin in invasion and metastasis, monoclonal antibodies to five distinct determinants will be used to delineate with ultrastructural and biochemical techniques those epitopes on the tenascin molecule that are involved in tumor cell motility. The systematic investigations of tumor-derived components related to invasion and metastasis will help to understand the mechanisms of metastasis and to develop novel strategies for therapy.