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.

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

“…To determine whether PAR-2 activation in OSCC cell lines induces expression of candidate mRNAs known to be associated with inflammation in OSCC, expression of three pro-inflammatory genes known to be regulated downstream of PAR-2 activation was evaluated (27,39,40). Interleukin 8 (CXCL8 gene, IL8 protein) is a member of the pro-inflammatory CXC chemokine gene family.…”

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

“…For example, recognition of fibrinogen by thrombin is directly mediated by active site and exosite I interactions, while platelet PAR-1 and PAR-4 cleavage involves both exosite I and II [30][31][32]. Thrombin activates cells through a unique proteolytic mechanism [3,33]. Namely, it exposes its receptor active site by cleavage of a key extracellular domain (residues LDPR/S).…”

“…Detachment from the primary tumor and intravasation, surviving in vessels, overcoming mechanical flow and immune system components of the blood, transendothelial migration, stabilization within distant vascular beds, growth, and the establishment of a new supportive vasculature are major challenges tumor cells must confront to effectively metastasize [1]. Nearly every move of malignant cells is accompanied by some function of thrombin, a major player in cancer dissemination that can modify tumor cell behavior either directly through its receptors (protease-activated receptors, PARs) or indirectly by generating fibrin matrices [2,3]. Thrombin enhances tumor invasive potential locally and contributes to cancer cell relocation and seeding [4][5][6][7][8][9][10][11][12][13][14][15].…”

“…Since then, biologically functional receptor has been identified in several human cancer cell types [reviewed in 3, [22][23][24] as well as on metastatic tumors [22]. The thrombin receptor appears to control myelination in development [23], which suggests a potential link to perineural invasion [reviewed in 3,24].…”

Anti-tumor effect of licochalcone-E is mediated by caspase-dependent apoptosis through extrinsic and intrinsic apoptotic signaling pathways in KB cancer cells

“…Cancer is a disease with high mortality due to the invasion or metastasis of abnormal cells to other parts of the body [1]. Worldwide, the most commonly reported types of cancer are breast cancer, colorectal cancer, lung cancer, cervical cancer, and oral cancer [2].…”