Thrombin-Activated Platelets Protect Vascular Endothelium against Tumor Cell Extravasation by Targeting Endothelial VCAM-1

Abstract

When activated by thrombin, the platelets release their granular store of factors. These thrombin-activated platelets (TAPLT) have been shown to be capable of ameliorating pro-inflammatory processes. In this study, we tested if TAPLT could also protect the endothelium against tumor-related pro-inflammatory changes that promote angiogenesis and metastasis. Using endothelial cell (EC) models in vitro, we demonstrated that TAPLT protected EC against tumor conditioned medium (TCM)-induced increases of reactive oxygen species (ROS) production, EC permeability and angiogenesis, and inhibited transendothelial migration that was critical for cancer cell extravasation and metastasis. In vivo observations of TAPLT-mediated inhibition of angiogenesis and pulmonary colonization in a BALB/c nude mouse model were consistent with the in vitro findings. Neutralization of vascular cell adhesion molecule-1 (VCAM-1) binding significantly inhibited the ability of TAPLT to interact with EC and abrogated the TAPLT-mediated protection of EC against tumor angiogenesis and metastasis. Taken together, these findings suggest that VCAM-1-mediated linkage to EC is required for TAPLT to confer protection of EC against tumor-induced permeation and angiogenesis, thereby resisting tumor extravasation and metastasis.

Emerging roles of platelets in cancer biology and their potential as therapeutic targets

“…Thrombin, ADP, and thromboxane A2 (TXA2) interact with G proteincoupled receptors P2Y1 and P2Y12 on the platelet surface and initiate specific downstream signaling cascades (13). Upon activation by thrombin, platelets can release granular factors that promote TCIPA and mediate immune responses (14). On the other hand, C-type lectin-like receptor (CLEC) -2, glycoprotein (GP) VI, and FcRgIIA are tyrosine-activated motif immunoreceptors on platelets.…”