METASTASIS INHIBITION BY FIBRONECTIN-TUMOR INTERACTIONS

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Tumor metastasis is a multistep process that involves a variety of tumor and host factors which are related in a complex manner. Recent efforts in cancer research have largely been concentrated in the areas of identifying phenotypic traits which contribute to metastatic behavior, on understanding mechanisms by which tumor heterogeneity is generated, and on understanding host factors which contribute to metastatic disease. The rationale behind these efforts is that an understanding of the biology of tumor metastasis will spawn new strategies that might prove useful in improving therapeutic schemes. Fibronectin, a major noncollagenous cell adhesion glycoprotein of tissues and plasma, is a key candidate as a host factor which is involved in mediating the metastasis of solid tissue neoplasms. The expression of fibronectin on cell surfaces changes as a result of transformation. Furthermore, fibronectin has been shown to promote the adhesion and migration of metastatic tumor cells in vitro, and it is deposited early in the stroma which surrounds newly forming metastatic foci. Plasma fibronectin could also participate in thromboembolus formation during homotypic/heterotypic aggregation when tumor cells are in the circulatory system. Fibronectin within these emboli could promote tumor growth and facilitate the migration of cells out of the vasculature during extravasation. Cell adhesion to fibronectin has a complex molecular basis and is mediated by several classes of cell surface receptors, including cell surface glycoproteins, glycolipids, and cell surface proteoglycans. We present evidence that experimental metastasis can be inhibited in mice by ex vivo pretreatment of tumor cells with a purified proteolytic fragment of fibronectin which binds to cell surface associated heparan sulfate proteoglycans (HSPGs). Isolation and partial characterization of these proteoglycans demonstrates that there are at least two distinct cell surface HSPGs, one which can be extracted from the cell surface by exogenous heparin, and a second class which requires trypsinization for extraction. These two classes of HSPGs have distinctly different side chains and hydrodynamic properties, and they are metabolized at different rates. Both populations of HSPGs bind to fibronectin and laminin (a noncollagenous glycoprotein of basement membranes) thus both are candidates as potential cell surface receptors for extracellular matrix adhesion proteins. The studies proposed within this grant are designed to isolate and characterize these proteoglycans, and to generate antibodies against the HSPGs which inhibit the interaction of these molecules with fibronectin and laminin. These antibodies will be used to study the biological significance of HSPG mediated tumor cell adhesion to the extracellular matrix. These studies will include an examination of the effects of these antibodies on tumor cell adhesion, motility, and invasion in vitro, and they will also be tested for the ability to inhibit experimental metastasis in vivo.