Abstract
Thrombin activates its G‐coupled seven transmembrane protease‐activated receptor (PAR‐1) by cleaving the receptor's N‐terminal end. In several human cancers, PAR1 expression and activation correlates with tumor progression and metastatization. This provides compelling evidence for the effectiveness of an appropriate antithrombin agent for the adjuvant treatment of patients with cancer. Dabigatran is a selective direct thrombin inhibitor that reversibly binds to thrombin. In this study, we aimed to explore if dabigatran may affect mechanisms favoring tumor growth by interfering with thrombin‐induced PAR‐1 activation.We confirmed that exposure of tumor cells to thrombin significantly increased cell proliferation and this was coupled with downregulation of p27 and concomitant induction of cyclin D1. Dabigatran was consistently effective in antagonizing thrombin‐induced proliferation as well as it restored the baseline pattern of cell cycle protein expression. Thrombin significantly upregulated the expression of proangiogenetic proteins like Twist and GRO‐α in human umbilical vascular endothelial cells (HUVEC) cells and their expression was significantly brought down to control levels when dabigatran was added to culture. We also found that the chemoattractant effect of thrombin on tumor cells was lost in the presence of dabigatran, and that the thrombin antagonist was effective in dampening vascular tube formation induced by thrombin. Our data support a role of thrombin in inducing the proliferation, migration, and proangiogenetic effects of tumor cells in vitro. Dabigatran has activity in antagonizing all these effects, thereby impairing tumor growth and progression. In vivo models may help to understand the relevance of this pathway.
Highlights
Advanced malignancy often correlates with activation of the coagulation system, termed cancer coagulopathy, which is associated with increased mortality rates [1]
The data presented in this study corroborate the ability of thrombin to increase proliferation, migration as well as to modulate neoangiogenesis of glioblastoma and breast cancer cells in an in vitro system
In agreement with previous findings from different experimental models, we found that proliferation of breast cancer and glioblastoma cells is coupled with the induction of cyclin D1, an activator of kinases driving progression through the G1 phase of the cell cycle, and with downregulation of p27, a negative regulator of the cell cycle
Summary
Advanced malignancy often correlates with activation of the coagulation system, termed cancer coagulopathy, which is associated with increased mortality rates [1]. Several coagulation factors play a pathogenetic role in the induction of such a hypercoagulable state of cancer [2]. Besides increasing the risk of thrombosis of cancer patients, the hypercoagulable state fuels critical cellular events in the tumor microenvironment, including cell proliferation, cell adhesion, angiogenesis, and invasion. Based on this two-w ay relationship between cancer and venous thromboembolism, preclinical studies have addressed the question whether anticoagulants like heparin may have antineoplastic properties, in aggressive cancers like glioblastoma and breast carcinomas [3, 4]. Mechanisms like prevention of tube-like structure formation in glioblastomas
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