TUMOR CELL ADHESIVE GLYCOPROTEINS AND METASTASIS

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Numerous investigators in both the clinical and basic sciences have postulated that platelets, platelet thrombi, and/or the coagulation cascade play a role in the metastasis of tumor cells. One proposed mechanism is that platelets enhance tumor cell adhesion to endothelial cells or subendothelial matrix during the arrest phase of the metastatic cascade. However, a causal relationship between tumor cells and platelets in the above interactions has not been established. Considerable information does exist for the role of platelet glycoproteins in platelet adhesion to the vessel wall. A causal role for platelet glycoprotein lb and glycoprotein llb/llla and platelet adhesion to the subendothelial matrix is firmly established. We have recently obtained evidence for the presence of immunologically related glycoproteins (lR GP) on the surface of several tumor cell lines. In the present proposal, we will test the following working hypothesis. First, that platelet glycoproteins lb and llb/llla (Gpllb/llla) play a major role in tumor cell-platelet interactions such as tumor cell induced platelet aggregation and platelet enhanced tumor cell adhesion to endothelial cells, extracellular matrix and/or its individual components. Second, that tumor cells possess surface glycoproteins which are lR, if not identical, to platelet GpIB and Gpllb/llla and that these tumor cell glycoproteins (lR Gplb; lR Gpllb/llla) play a major role in tumor cell induced platelet aggregation, tumor cell adhesion to endothelial cells, and tumor cell adhesion to endothelial cell extracellular matrix and/or its individual components. Preliminary data indicate the presence of these glycoproteins on the tumor cell surface by immunofluorescence and immunoelectron microscopic analysis. In addition, a role for the platelet glycoproteins and tumor cell glycoproteins in the interaction between the two cell types and in their subsequent interactions has been obtained. Other evidence suggests the tumor cell cytoskeleton may regulate the expression and function of these tumor cell membrane glycoproteins. In this proposal we will determine the role of lR Gpib and Gpllb/llla in tumor cell adhesion to endothelial cells, extracellular matrix, and its individual components under static conditions and under flow conditions exhibiting different shear rates. In addition, we will determine the role of platelet GpIB and Gpllb/llla in platelet tumor cell interaction and platelet facilitated tumor cell adhesion to biologically relevant substrata. The role of the tumor cell cytoskeleton in these processes will also be examined. Platelet Gpib serves as receptor for thrombin. Therefore, we will determine if tumor cell lR Gplb will function as a thrombin receptor and if thrombin can influence the expression of tumor cell lR Gpllb/llla and affect its functional relationship with the extracellular matrix. Finally we will determine if these tumor cell glycoproteins are heterogenously expressed on cells of different metastatic capabilities and transiently expressed on cells exposed to different environmental conditions. This proposal will therefore seek to establish functional significance for these glycoproteins in biological processes (i.e., adhesion, etc.) relevant to tumor metastasis.