Platelets favor the outgrowth of established metastases

Abstract

Despite abundant evidence demonstrating that platelets foster metastasis, a therapeutic approach based on anti-platelet agents is not an option due to the risk of hemorrhages. In addition, whether platelets can regulate metastasis at the late stages of the disease remains unknown. In this study, we subjected syngeneic models of metastasis to various thrombocytopenic regimes to show that platelets provide a biphasic contribution to metastasis. While potent intravascular binding of platelets to tumor cells efficiently promotes metastasis, platelets further support the outgrowth of established metastases. Genetic depletion and pharmacological targeting of the platelet-specific receptor GPVI in humanized mouse models efficiently reduced the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study is the first to demonstrate therapeutic efficacy when targeting animals carrying growing metastases. It further identifies GPVI as the first molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations.

Platelet Contributions to the (Pre)metastatic Tumor Microenvironment

“…Garcia-Leon et al recently addressed this limitation and proposed that platelet GPVI is important not only for platelet-tumor cell binding but also the subsequent proliferative outgrowth of experimental lung metastases. 67 Unlike aspirin and P2Y 12 inhibitors, therapeutic approaches that target GPVI have minimal impact on hemostasis and may offer a novel adjuvant approach to limit the outgrowth of metastatic tumors. 8,68 Platelet lysophosphatidic acid has also been implicated in the progression of osteolytic bone metastasis in mice with mammary tumors, suggesting several underlying mechanisms of action.…”

“…74,75 Another important consideration is that experimental metastasis models typically do not account for the systemic effects of a primary tumor, which has been shown to restrain metastatic tumors in a dormant state, thereby preventing the outgrowth of macrometastases. 76 Extravascular platelets can be found within both primary tumors and metastases, 67 and therefore have the potential to contribute to the long-term characteristics of the primary and metastatic TME. Whether platelets extravasate bound to invade tumor cells or exit the vasculature in isolation remains to be investigated, as does whether platelets extravasate by chance due to permeabilized vasculature or through active migratory processes.…”