Protease-activated receptors (PARs)--biology and role in cancer invasion and metastasis

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.

Keywords: Cancer invasion; Metastasis; Microenvironment; PAR-1; PAR-2; Thrombin; Tissue factor.

Fig. 1

Structure and mechanism of protease-activated receptor (PAR) activation

Fig. 2

Protease-activated receptor 1 (PAR-1) activation and signaling. Protein RhoGEFs, Rho, Rac. MAP kinase mitogen-activated protein kinase, DAG diacylglycerol, PI3 inositol (1,4,5)-trisphosphate, GRKs G-protein-coupled receptor kinases