The dissemination of malignant cells from the primary tumor to distant sites involves a sequence of steps in which the adhesion of tumor cells to extracellular matrix proteins, and to other cells, is an important component. The involvement of individual adhesion receptors in invasion and metastasis has been mostly studied through correlation of expression in pathological tissue sections. An experimental model of invasion and metastasis, which closely mimics the conditions in patients, has been developed in human/mouse chimeras. In this model, human melanoma cells proliferate orthotopically, i.e., in the same tissue as in patients. Melanoma cells are injected into human skin grafted to severe combined immunodeficient mice. The malignant cells then proliferate and invade the human dermis before they metastasize to the lymph nodes and lungs of the mouse. When melanoma cells are injected intraarterially in this model, they can localize (home) into human skin transplants. This model will be key in assessing the roles of the cell-substrate integrin alpha-v-beta-3 and the cell-cell adhesion receptor Mel-CAM in invasion into human skin, and in metastasis to mouse lungs or human dermis. These two receptors have been selected after preliminary studies because they are overexpressed on tumorigenic and metastatic melanoma cells with little or no expression on nonmalignant melanocytes. Antisense RNA constructs in adenovirus gene-transfer vectors will be used to determine whether the absence of Mel-CAM and of the beta3 subunit of the a-v-beta-3 integrin, either alone or in combination, will suppress tumor growth and invasion in the human dermis, and metastasis formation to mouse lymph nodes, lungs, and/or to noninjected human skin grafts. Sense constructs for both adhesion receptors will be transduced into biologically early melanoma cells which are nontumorigenic and which do not express either receptor), and it will be determined whether overexpression of these receptors leads to a biologically aggressive malignant phenotype. To identify the ligands to the alpha-v-beta-3 integrin that are functionally important for melanoma invasion and metastasis, in situ immunochemical and hybridization analyses will be performed. Once the ligands are identified, monoclonal antibodies that can specifically inhibit alpha-v-beta-3-mediated adhesion of melanoma cells will be developed as a first step in developing adhesion antagonists for melanoma metastasis intervention.
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