Abstract
PAR-1 is expressed not only in epithelium, neurons, astrocytes, immune cells, but also in cancer-associated fibroblasts, ECs (epithelial cells), myocytes of blood vessels, mast cells, and macrophages in tumor microenvironment, whereas PAR-1 stimulates macrophages to synthesize and secrete thrombin as well as other growth factors, resulting in enhanced cell proliferation, tumor growth and metastasis. Therefore, considerable effort has been devoted to the development of inhibitors targeting PAR-1. Here, we provide a comprehensive review of PAR-1’s role in cancer invasiveness and dissemination, as well as potential therapeutic strategies targeting PAR-1 signaling.
Highlights
PAR-1 was the first member of the PARs family, which was found simultaneously by both two independent laboratories in 1991, during the process of identifying GPCR (G proteincoupled receptors) that mediate thrombin signal pathway in both human and hamster cells [1,2,3]
Thrombin-induced PAR-1 activation breaks down extracellular matrix and basement membrane to increase Matrix www.impactjournals.com/oncotarget metalloprotease-1 (MMP-1)/-9 levels, which is closely related to nasopharyngeal carcinoma metastasis [106]
PAR-1 actively participates in steps of cancer cell proliferation, invasion and metastasis which involve complex mechanisms
Summary
PAR-1 was the first member of the PARs (protease-activated receptors) family, which was found simultaneously by both two independent laboratories in 1991, during the process of identifying GPCR (G proteincoupled receptors) that mediate thrombin signal pathway in both human and hamster cells [1,2,3]. PAR-1 is irreversibly activated by thrombin, tissue factor (TF), endothelial protein C receptor (EPCR), MMPs, and so on. Thrombin activates signaling pathways in tumor cells by interacting with PAR1 [33,34,35]. Leading to consistent activation of second messenger signaling [36,37], PAR-1 cooperates with growth factor receptor (EGFR) and ErbB / Her2 or MMP-1 derived from fibroblasts to mediate Ca2+ pathway in cancer [39,40].
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