Platelet Glycoprotein 1b-1X in Hemostasis and Malignancy.

The platelet paradigm in hemostasis and thrombosis involves an initiation step dependent upon platelet membrane receptors binding to ligands on a damaged or inflamed vascular surface. Once bound to the surface, platelets provide a unique microenvironment supporting the accumulation of more platelets and the elaboration of a fibrin-rich network produced by coagulation factors. This paradigm has been established from decades of research. The platelet-specific receptor, glycoprotein (GP) Ib-IX, is critical in this process and can initiate the formation of a platelet-rich thrombus by tethering the platelet to a thrombogenic surface. Several ligands binding to GP Ib-IX have been identified, but von Willebrand factor (vWF) and the resultant GP Ib-IX/vWF axis has emerged as a major initiator of platelet thrombus formation in the arterial circulation. Newer, emerging data supports a role for platelets in pathological events beyond the prevention of blood loss. We have obtained data supporting the hypothesis that platelet GP Ib-IX contributes to malignancy. Knockout and transgenic mouse colonies have been generated in our laboratory and bred to C57BL/6J animals to generate several congenic strains (> 10 generation backcrosses) with dysfunctional platelet GP Ib-IX. These colonies have been used to characterize tumor metastasis and primary tumor growth in syngeneic models where the host animals are immunocompetent. The results demonstrate platelet GP Ib-IX contributes to tumorigenesis, as a functional absence of GP Ib-IX correlates with a significant reduction in the number of metastatic foci using models of experimental metastasis. In addition, an absence of GP Ib-IX significantly reduces primary tumor burden. A second series of experiments has determined that platelet GP VI, a key activation receptor on the surface of platelets also contributes to progression of experimental metastasis. The importance of metastasis in the prognosis for recovery from cancer can not be over-emphasized. Indeed, the spread of metastatic disease represents a fundamental change in significantly shortening the lifespan of patients with breast cancer. Thus, understanding the molecules that regulate metastasis identifies potential targets for therapeutic intervention that could significantly improve the prognosis for the breast cancer patient. Several decades of prior work in hemostasis and thrombosis has placed this project in a position to quickly provide new information and understanding on the links between hemostasis and cancer.