Inhibition of Platelet GPVI Induces Intratumor Hemorrhage and Increases Efficacy of Chemotherapy in Mice
ISTH Academy. Volz J. Jul 10, 2019; 274053; OC 79.3 Topic: Platelets Beyond Hemostasis
Julia Volz
Julia Volz
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OC 79.3

Inhibition of Platelet GPVI Induces Intratumor Hemorrhage and Increases Efficacy of Chemotherapy in Mice

J. Volz1,2, E. Mammadova-Bach1,2, J. Gil-Pulido3, R. Nandigama4, K. Remer1,2, L. Sorokin5, A. Zernecke3, S.I. Abrams6, S. Ergün4, E. Henke4, B. Nieswandt1,2
1University Hospital Würzburg, Institute of Experimental Biomedicine I, Würzburg, Germany, 2University of Würzburg, Rudolf Virchow Center, Würzburg, Germany, 3University Hospital Würzburg, Institute of Experimental Biomedicine II, Würzburg, Germany, 4University of Würzburg, Institute for Anatomy and Cell biology, Würzburg, Germany, 5University of Münster, Institute of Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Cluster of Excellence, Münster, Germany, 6Roswell Park Comprehensive Cancer Center, Department of Immunology, Buffalo, United States

Main Topic: Platelets and Megakaryocytes
Category: Platelets Beyond Hemostasis

Background: Platelets are small anucle­ated cells that play a central role in the arrest of bleeding. Previous studies have identified platelets as major regulators of tumor vascular integrity, since their depletion selectively renders tumor vessels highly permeable and causes massive intratumoral hemorrhage. While these results established platelets as potential targets for anti-tumor therapy, their depletion is not a treatment option due to their essential role in hemostasis. Thus, a detailed understanding of how platelets safeguard vascular integrity in tumors is urgently required.
Glycoprotein (GP) VI is a platelet-specific activating receptor, regulating multiple platelet functions including activation and pro-coagulant activity. GPVI has been proposed as a potentially safe anti-thrombotic target, since its blockade reduces arterial thrombosis without impairing hemostasis. GPVI also contributes to the maintenance of vessel integrity under conditions of inflammation. However, its role in the regulation of tumor vessel integrity remains unknown.
Aims: We investigated the role of GPVI in the maintenance of vascular integrity in primary tumors and studied the potential impact of GPVI-blockade on the efficacy of chemotherapy.
Methods: Primary tumors were induced by heterotopic and orthotopic implantation of prostate (TrampC1) and breast (AT-3) cancer cells. Tumor vascularization and growth were analyzed in wild-type and Gp6-/- mice and upon treatment with the GPVI-blocking antibody JAQ1 F(ab´)2 alone or combined with chemotherapeutic drugs.
Results: We show that blockade of GPVI induces tumor hemorrhage and reduces tumor growth with similar kinetics and to a comparable extent as platelet depletion. Moreover, GPVI blockade in mice increased intratumoral accumulation of co-administered chemotherapeutic drugs. Consequently, combination of GPVI-blockade with chemotherapy resulted in a profound and prolonged anti-tumor effect.
Conclusions: Our findings identify platelet GPVI as a key regulator of vascular integrity especially in growing tumors and could serve as a novel therapeutic target for the development of anti-tumor strategies that impede platelet function.

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