Protease‐activated receptor‐1 impedes prostate and intestinal tumor progression in mice

Abstract

Essentials Protease activated receptor-1 (PAR-1) has been proposed to drive cancer progression. Surprisingly, PAR-1 deletion accelerated tumor progression in two distinct experimental settings. PAR-1 deletion was shown to limit the apoptosis of transformed epithelial cells. Thrombin- and activated protein C-mediated PAR-1 activation have unique effects on tumor cell biology. SUMMARY: Background Multiple studies have implicated protease-activated receptor-1 (PAR-1), a G-protein-coupled receptor activated by proteolytic cleavage of its N-terminus, as one target coupling thrombin-mediated proteolysis to tumor progression. Objective To analyze the role of PAR-1 in the setting of two distinct spontaneously developing tumor models in mice. Methods We interbred PAR-1-deficient mice with Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, which spontaneously develop prostate tumors, and adenomatous polyposis coli Min (APC ) mice, which spontaneously develop intestinal adenomas. Results Analyses of TRAMP mice with advanced disease (30 weeks) revealed that PAR-1 deficiency resulted in significantly larger and more aggressive prostate tumors. Prostates collected at an earlier time point (12 weeks of age) revealed that PAR-1 promotes apoptosis in transformed epithelia. In vitro analyses of TRAMP-derived cells revealed that activated protein C-mediated PAR-1 cleavage can induce tumor cell apoptosis, suggesting that tumor cell-intrinsic PAR-1 functions can limit tumor progression. Paralleling results in TRAMP mice, PAR-1-deficient APC mice developed three-fold more adenomas than PAR-1-expressing mice, and the adenomas that formed were significantly larger. Moreover, loss of PAR-1 expression was shown to limit apoptosis in transformed intestinal epithelial cells. Conclusions Together, these results demonstrate a previously unrecognized role for PAR-1 in impeding tumor progression in vivo. These results also offer a cautionary note suggesting that long-term PAR-1 inhibition could increase malignancy risk in some contexts.

Rivaroxaban does not affect growth of human pancreatic tumors in mice

“…However, growth of colonic adenocarcinoma tumors was reduced in PAR1 −/− mice . In contrast, spontaneous tumor growth in the TRAMP model and the adenomatous polyposis coli Min (APC Min/+ ) model was enhanced in PAR1 −/− mice . Silencing PAR1 expression in the human malignant pleural mesothelioma cell line REN reduced tumor growth in nude mice …”

“…16 In contrast, spontaneous tumor growth in the TRAMP model and the adenomatous polyposis coli Min (APC Min/+ ) model was enhanced in PAR1 −/− mice. 19 Silencing PAR1 expression in the human malignant pleural mesothelioma cell line REN reduced tumor growth in nude mice. 20 The role of PAR1 in the growth of pancreatic tumors in mice is complex, and conflicting results have been reported.…”

Protease‐activated receptor‐1 impedes prostate and intestinal tumor progression in mice: comment

“…Consistent with such clinical data hinting towards a tumor-promoting effect of PAR-1, experimental studies seem to provide solid evidence for activated PAR-1 as a driver of cancer progression. Indeed, PAR-1 activation induces proliferation, migration and invasion of cancer cells in different in vitro experiments (excellently reviewed in references [2]), whereas tumor cell-specific PAR-1 overexpression potentiates tumor growth in preclinical animal models of breast and prostate cancer (Table 1; [3,4]). In line with this, shRNA-mediated inhibition of tumor cell PAR-1, stromal PAR-1 depletion or pharmacological PAR-1 inhibition consistently suppress tumor growth in animal models (Table 1; [3,4]).…”

“…Indeed, PAR-1 activation induces proliferation, migration and invasion of cancer cells in different in vitro experiments (excellently reviewed in references [2]), whereas tumor cell-specific PAR-1 overexpression potentiates tumor growth in preclinical animal models of breast and prostate cancer (Table 1; [3,4]). In line with this, shRNA-mediated inhibition of tumor cell PAR-1, stromal PAR-1 depletion or pharmacological PAR-1 inhibition consistently suppress tumor growth in animal models (Table 1; [3,4]). As a consequence, the current paradigm dictates that PAR-1 promotes cancer progression based on which PAR-1 has been suggested as a promising target for the treatment of cancer [1].…”

“…In a recent issue of the Journal of Thrombosis and Haemostasis, Adams and colleagues elegantly addressed the importance of PAR-1 in spontaneously developing tumor models and showed that the genetic elimination of PAR-1 in fact aggravated tumor development [3]. Interbreeding PAR-1-deficient mice with TRAMP (transgenic adenocarcinoma of the mouse prostate) mice that spontaneously develop prostate tumors led to significantly larger tumors with features of aggressive growth.…”