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: Karla C S Queiroz, Kun Shi, JanWillem Duitman, Hella L Aberson, Johanna W Wilmink, Carel J M van Noesel, Dick J Richel, C Arnold Spek
• Journal: International journal of cancer (Int J Cancer) Vol. 135 Issue 10 Pg. 2294-304 (Nov 15 2014) ISSN: 1097-0215 [Electronic] United States
• PMID: 24436106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 UICC.

Chemical References

• Antimetabolites, Antineoplastic
• Receptor, PAR-1
• Deoxycytidine
• Gemcitabine

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Cell Movement
• Cell Proliferation
• Cell Survival
• Deoxycytidine (analogs & derivatives, pharmacology)
• Disease Models, Animal
• Disease Progression
• Drug Resistance, Neoplasm
• Humans
• Immunoenzyme Techniques
• Liver Neoplasms (drug therapy, genetics, secondary)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neovascularization, Pathologic
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Prognosis
• Receptor, PAR-1 (physiology)
• Signal Transduction
• Stromal Cells (metabolism, pathology)
• Tumor Cells, Cultured
• Gemcitabine