The metastatic tumor cell differs from its nonmetastatic counterpart by distinct phenotypic qualities. Among the traits considered important for metastatic behavior are changes in the adhesiveness and motility of the tumor cells. Distinct changes in the cell surface (and hence adhesiveness) of well-defined high and low metastatic variants have been described in the literature. The migration of tumor cells can be directly influenced by isolated extracellular matrix components in vitro. At present, the role that matrix-mediated migration might play in promoting metastatic tumor spread is poorly understood. The current proposal is designed to attempt to better elucidate the role of this potential relationship. The proposal can be divided into several specific aims and approaches. Initially, migration of murine tumor lines (1735 and B16 melanomas and UV2237 fibrosarcomas) with well-established metastatic potentials will be compared for attachment and motility responses to laminin, cellular fibronectin, and serum-spreading factor. Alternatively, subclones of these metastatic tumors will be grown and selected for high or low attachment activities to each protein and the metastatic potential for each subclone will be determined. Additionally, attachment/motility promoting fragments will be isolated from proteolytic digests of two of the proteins: fibronectin and laminin. Fragments from these proteolytic digests will be identified and purified on the basis of additional ligand-binding activities, including collagen, proteoglycans, and monoclonal antibodies. Monoclonal antibodies will be made and used to specifically block matrix-mediated tumor cell attachment or motility. Certain basic biochemical characterizations on the isolated fragments will also be performed. Additionally, the role of matrix-mediated tumor cell interactions will be studied using an in vitro amnion invasion assay. This point will be addressed through the use of specific subclones of metastatic tumor cell lines. It is the intent of these proposed studies to elucidate the biochemical nature of tumor cell/matrix interactions that potentiate metastatic tumor spread in vivo. (L)
