Targeting glycoprotein VI to disrupt platelet-mediated tumor cell extravasation

Activated platelets coat circulating tumor cells, protecting them from shear stress in the blood stream and promoting their evasion from immune surveillance. Platelets promote tumor cell dissemination to distant organs by releasing transforming growth factor-β1 (TGF-β1) into the tumor microenvironment, which induces phenotypic changes to the epithelial-mesenchymal transition. This process facilitates tumor cell transendothelial extravasation and formation of early metastatic niches. Development of antiplatelet agents that interrupt the platelet-tumor cell axis but do not interfere with physiological hemostatic mechanisms is critical. The glycoprotein VI (GPVI), a member of the immunoreceptor family that is co-expressed with the fragment crystallizable (Fc) receptor γ-chain, is exclusively expressed in platelets and megakaryocytes, and blocking the receptor or genetic deficiency has minimal impact on bleeding. Tumor cell-expressed galectin-3, which contains a collagen-like peptide domain, binds to platelet GPVI-dimers, and the receptor-ligand activates platelets to form a protective heteroaggregate coat around tumor cells. This review highlights the potential of targeting the GPVI/FcR γ-chain complex to inhibit platelet activation by galectin-3 expressing tumor cells, disrupting the platelet-tumor cell amplification loop while maintaining the function of platelets in hemostasis.