期刊
MOLECULAR MEDICINE
卷 23, 期 -, 页码 13-23出版社
FEINSTEIN INST MED RES
DOI: 10.2119/molmed.2016.00214
关键词
-
资金
- Dutch Cancer Foundation [2009-4324, 2014-6782]
Pancreatic cancer is one of the most lethal solid malignancies, with few treatment options. We have recently shown that expression of protease activated receptor (PAR)- 1 in the tumor microenvironment drives the progression and induces the chemoresistance of pancreatic cancer. As thrombin is the prototypical PAR-1 agonist, here we address the effects of the direct thrombin inhibitor dabigatran on pancreatic cancer growth and drug resistance in an orthotropic pancreatic cancer model. We show that dabigatran treatment did not affect primary tumor growth, whereas it significantly increased tumor dissemination throughout the peritoneal cavity. Increased dissemination was accompanied by intratumoral bleeding and increased numbers of aberrant and/or collapsed blood vessels in the primary tumors. In combination with gemcitabine, dabigatran treatment limited primary tumor growth, did not induce bleeding complications and prevented tumor cell dissemination. Dabigatran was, however, not as efficient as genetic ablation of PAR-1 in our previous study, suggesting that thrombin is not the main PAR-1 agonist in the setting of pancreatic cancer. Overall, we show that dabigatran potentiates gemcitabine-induced growth inhibition of pancreatic cancer but does not affect primary tumor growth when used as monotherapy.
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