BIOCHEMICAL MECHANISM IN PLATELET-TUMOR CELL INTERACTION

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Platelets appear able to facilitate tumor metastasis, possibly by physically shielding tumor cells within a platelet embolus, by increasing attachment to the vessel wall and by providing platelet factors which can enhance tumor cell extravasation and growth. The following studies are proposed to elucidate biochemical mechanisms involved in the interaction of platelets with tumor cells and to evaluate their significance in the early stages of tumor metastasis using in vitro and in vivo model system: (i) determine the mechanism of tumor cellinduced platelet aggregation mediated by the ADPdependent and thrombindependent processes with regard to the possible role of surface proteases, complement and arachidonate metabolism, taking into account possibilities of cellular collaboration between platelets and tumor cells; (ii) examination of human tumor tissue to determine whether mechanisms other than the thrombindependent and ADPdependent systems can be detected; (iii) identification of plasma factors responsible for responder and nonresponder status in platelets from normal individuals challenged with tumors cells and microvesicles; (iv) evaluation of the role of ADP scavengers in reducing metastasis in murine modes; (v) characterization of the protein and glycoprotein composition of microvesicles from ADPdependent and thrombindependent lines to determine whether they arise from specialized areas of the tumor cell membrane; (vi) ADPdependent and thrombindependent microvesicles will be fused with unreactive tumor cells to determine whether this can confer the appropriate proaggregatory activity and can enhance tumor metastasis in a murine model; (viii) a new parallelplate perfusion model will be adapted to study the role of platelets in enhancing tumor cellinduced damage to endothelial cells and basement membrane and the biochemical bases for these changes.