Despite abundant evidence demonstrating that platelets foster metastasis, anti-platelet agents have low therapeutic potential 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 subject 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 via immune suppression. Genetic depletion and pharmacological targeting of the glycoprotein VI (GPVI) platelet-specific receptor in humanized mouse models efficiently reduce the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study demonstrates therapeutic efficacy when targeting animals bearing growing metastases. It further identifies GPVI as a molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations.

尽管大量证据表明血小板促进转移，但由于出血风险，抗血小板药物的治疗潜力较低。此外，血小板是否可以调节疾病晚期的转移仍不清楚。在这项研究中，我们将同基因转移模型应用于各种血小板减少方案，以表明血小板对转移提供双相贡献。虽然血小板与肿瘤细胞的有效血管内结合有效促进了转移，但血小板通过免疫抑制进一步支持已形成转移的生长。在人源化小鼠模型中，基因耗竭和糖蛋白 VI (GPVI) 血小板特异性受体的药理学靶向可有效减少已形成转移瘤的生长，而与活性血小板与血流中肿瘤细胞的结合无关。我们的研究证明了针对具有生长转移的动物的治疗效果。它进一步将 GPVI 确定为一个分子靶标，其抑制可以损害转移而不引起附带的止血干扰。