title: Protease-activated receptor-1 drives pancreatic cancer progression and chemoresistance.
abstract: Protease activated receptor (PAR)-1 expression in tumor cells is associated with disease progression and overall survival in a variety of cancers of epithelial origin; however, the importance of PAR-1 in the tumor microenvironment remains unexplored. Utilizing an orthotopic pancreatic cancer model in which tumor cells are PAR-1 positive whereas stromal cells are PAR-1 negative, we show that PAR-1 expression in the microenvironment drives progression and induces chemoresistance of pancreatic cancer. PAR-1 enhances monocyte recruitment into the tumor microenvironment by regulating monocyte migration and fibroblast dependent chemokine production thereby inducing chemoresistance. Overall, our data identify a novel role of PAR-1 in the pancreatic tumor microenvironment and suggest that PAR-1 may be an attractive target to reduce drug resistance in pancreatic cancer.
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Karla C S
authors.initials: KC
authors.lastname: Queiroz
authors.forename: Kun
authors.initials: K
authors.lastname: Shi
authors.forename: JanWillem
authors.initials: J
authors.lastname: Duitman
authors.forename: Hella L
authors.initials: HL
authors.lastname: Aberson
authors.forename: Johanna W
authors.initials: JW
authors.lastname: Wilmink
authors.forename: Carel J M
authors.initials: CJ
authors.lastname: van Noesel
authors.forename: Dick J
authors.initials: DJ
authors.lastname: Richel
authors.forename: C Arnold
authors.initials: CA
authors.lastname: Spek
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D044463:Receptor, PAR-1 / Q000502:physiology*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D044463:Receptor, PAR-1; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: chemoresistance; macrophage; microenvironment; protease activated receptors