Multiple effects of EPCR on cancer. In the vasculature, the EPCR-APC–mediated signaling pathway on the endothelium provides an antimetastatic effect by inhibiting the extravasation of tumor cells through down-regulation of vascular adhesion molecules on the endothelium that are involved in tumor cell adhesion and by enhancing barrier integrity of the endothelium. EPCR on tumor cells may increase the metastatic potential as EPCR-APC signaling promotes tumor cell survival, migration, and invasion. In the tumor compartment, EPCR, in general, promotes tumor growth and burden through its survival benefits. However, in malignant pleural mesothelioma (MPM), EPCR suppresses tumor growth by promoting tumor cell apoptosis and/or inhibiting tumor cell proliferation. At present, it is unclear whether specific receptor(s) present on MPM cells or the pleural microenvironment is responsible for the EPCR-mediated tumor cell apoptosis in MPM. TF, tissue factor; PAR1, protease activated receptor-1.