Platelets Protect Tumors from Hemorrhage Induced by Stroma-Infiltrating Leukocytes

In a recent study, we showed that platelets are crucial regulators of tumor vascular homeostasis in that they continuously prevent tumor hemorrhage through secretion of their granules. However, it remains unclear what platelets target to prevent tumor bleeding. Tumors are associated with inflammation, a cause of hemorrhage in thrombocytopenia. We hypothesized that platelets protect tumors from vascular damages induced by infiltrating inflammatory cells. Here, we report that thrombocytopenia-induced tumor hemorrhage preferentially occurs at the periphery of tumors, where massive accumulation of monocytes/macrophages and neutrophils was revealed by tumor histology. To further investigate the role of tumor-infiltrating leukocytes in the induction of tumor hemorrhage in thrombocytopenic mice, we used genetically-engineered mice with a deficiency in either beta2 or beta3 integrins, or in integrin activation. We show that these mice have decreased leukocyte infiltration in the tumor stroma and are protected from thrombocytopenia-induced tumor hemorrhage. Using a model of TNFa-induced skin inflammation, we demonstrate that releasates from collagen- and thrombin-stimulated platelets inhibit neutrophil-induced vascular damage. Our results show that platelets protect tumors from vascular leakage induced by infiltrating leukocytes and that releasate from activated platelets has potent in vivo healing properties needed after leukocyte transmigration.