title: Endothelial cell protein C receptor opposes mesothelioma growth driven by tissue factor.
abstract: The procoagulant protein tissue factor (F3) is a powerful growth promoter in many tumors, but its mechanism of action is not well understood. More generally, it is unknown whether hemostatic factors expressed on tumor cells influence tissue factor-mediated effects on cancer progression. In this study, we investigated the influence of tissue factor, endothelial cell protein C receptor (EPCR, PROCR), and protease activated receptor-1 (PAR1, F2R) on the growth of malignant pleural mesothelioma (MPM), using human MPM cells that lack or express tissue factor, EPCR or PAR1, and an orthotopic nude mouse model of MPM. Intrapleural administration of MPM cells expressing tissue factor and PAR1 but lacking EPCR and PAR2 (F2RL1) generated large tumors in the pleural cavity. Suppression of tissue factor or PAR1 expression in these cells markedly reduced tumor growth. In contrast, tissue factor overexpression in nonaggressive MPM cells that expressed EPCR and PAR1 with minimal levels of tissue factor did not increase their limited tumorigenicity. More importantly, ectopic expression of EPCR in aggressive MPM cells attenuated their growth potential, whereas EPCR silencing in nonaggressive MPM cells engineered to overexpress tissue factor increased their tumorigenicity. Immunohistochemical analyses revealed that EPCR expression in tumor cells reduced tumor cell proliferation and enhanced apoptosis. Overall, our results enlighten the mechanism by which tissue factor promotes tumor growth through PAR1, and they show how EPCR can attenuate the growth of tissue factor-expressing tumor cells.
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA.
authors.forename: Shiva
authors.initials: S
authors.lastname: Keshava
authors.forename: Sanghamitra
authors.initials: S
authors.lastname: Sahoo
authors.forename: Torry A
authors.initials: TA
authors.lastname: Tucker
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
authors.forename: L Vijaya Mohan
authors.initials: LV
authors.lastname: Rao
authors.forename: Usha R
authors.initials: UR
authors.lastname: Pendurthi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000074283:Endothelial Protein C Receptor; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010997:Pleural Neoplasms / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D044463:Receptor, PAR-1 / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D018180:Thrombomodulin / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D008074:Lipoproteins; C478370:PROCR protein, human; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface; C546931:THBD protein, human; D018180:Thrombomodulin; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin
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