Abstract
Although many studies have demonstrated that components of the hemostatic system may be involved in signaling leading to cancer progression, the potential mechanisms by which they contribute to cancer dissemination are not yet precisely understood. Among known coagulant factors, tissue factor (TF) and thrombin play a pivotal role in cancer invasion. They may be generated in the tumor microenvironment independently of blood coagulation and can induce cell signaling through activation of protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They play important roles in vascular physiology, neural tube closure, hemostasis, and inflammation. All of these agents (TF, thrombin, PARs—mainly PAR-1 and PAR-2) are thought to promote cancer invasion and metastasis at least in part by facilitating tumor cell migration, angiogenesis, and interactions with host vascular cells, including platelets, fibroblasts, and endothelial cells lining blood vessels. Here, we discuss the role of PARs and their activators in cancer progression, focusing on TF- and thrombin-mediated actions. Therapeutic options tailored specifically to inhibit PAR-induced signaling in cancer patients are presented as well.
Highlights
The association between blood coagulation, with respect to venous thrombosis and cancer development was first described in the nineteenth century by Drs Trousseau and Bouillaud [1]
Activation of distinct subtypes of protease-activated receptors (PARs) is cancer-specific, for example, gene regulation elicited by Tissue factor (TF)/factor VIIa (FVIIa) through PAR-2 in MDA-MB-231 cells may occur in glioblastoma cell lines through thrombin-mediated activation of PAR-1 [38]
Cleavage of the extracellular portion of the PAR-1 receptor by thrombin occurs at a canonical R41-S42 site, while matrix metalloproteases (MMPs)-1 cleaves PAR-1 at a novel site (D39-P40) resulting in a tethered ligand that is two amino acids longer (PR-SFLLRN) than that generated by thrombin
Summary
The association between blood coagulation, with respect to venous thrombosis and cancer development was first described in the nineteenth century by Drs Trousseau and Bouillaud [1]. Thrombin binds and cleaves PAR-3 in murine platelets without eliciting further cellular signaling from PAR3, but this facilitates activation of the low-affinity thrombin receptor, PAR-4 [30, 34] This exceptional mechanism of transactivation exists between PAR-1 and PAR-2, or PAR-1 and PAR-4 in human endothelial cells or platelets, respectively. Tethered ligand of one receptor, generated by thrombin-mediated proteolysis, can directly stimulate the active site of another PAR and effectively induce intracellular signaling [33, 35, 36]. It seems that PARs form physical heterodimers, especially after stimulation by cytokines during inflammation [33]. A/A), in pancreatic cancer (PAR-1 -506 Ins/Del) and in gastric cancer (PAR-1-505 Ins/Del) [17, 78, 79]
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