title: Role of the protein C receptor in cancer progression.
abstract: The hemostatic system plays pleiotropic roles in cancer progression by shaping the tumor microenvironment and metastatic niches through thrombin-dependent fibrin deposition and platelet activation. Expanding experimental evidence implicates coagulation protease receptors expressed by tumor cells as additional players that directly influence tumor biology. Pro-angiogenic G protein-coupled signaling of TF through protease activated receptor 2 and regulation of tumor cell and vascular integrins through ligation by alternative spliced TF are established pathways driving tumor progression. Our recent work shows that the endothelial protein C receptor (EPCR), a stem cell marker in hematopoietic, neuronal and epithelial cells, is also crucial for breast cancer growth in the orthotopic microenvironment of the mammary gland. In aggressive triple-negative breast cancer cells, EPCR expression is a characteristic of cancer stem cell-like populations that have tumor initiating properties in vivo. Blocking antibodies to EPCR attenuate in vivo tumor growth and proliferation specifically of EPCR(+) cells on defined integrin matrices in vitro. We also showed that tumor-associated macrophages are a source for upstream coagulation proteases that can activate TF- and EPCR-dependent cellular responses, suggesting that tumor cells utilize the tumor microenvironment for tumor promoting coagulation protease signaling.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA; Center for Thrombosis and Hemostasis, Universitätsmedizin, Johannes Gutenberg University, Mainz, Germany. Electronic address: ruf@scripps.edu.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA; UMR CNRS 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Illkirch, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Schaffner
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001777:Blood Coagulation / Q000502:physiology*; D001943:Breast Neoplasms / Q000097:blood*; D018450:Disease Progression; D000074283:Endothelial Protein C Receptor; D005260:Female; D006801:Humans; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D011956:Receptors, Cell Surface
keywords: Cancer stem cell; Coagulation; Macrophage; Protease; Tumor microenvironment