PAR-1 and Thrombin: The Ties That Bind the Microenvironment to Melanoma Metastasis

Abstract

Progression of melanoma is dependent on cross-talk between tumor cells and the adjacent microenvironment. The thrombin receptor, Protease Activated Receptor-1 (PAR-1) plays a key role in exerting this function during melanoma progression. PAR-1 and its activating factors, which are expressed on tumor cells and the surrounding stroma, induce not only coagulation, but also cell signaling which promotes the metastatic phenotype. Several adhesion molecules, cytokines, growth factors and proteases have recently been identified as downstream targets of PAR-1 and have been shown to modulate interactions between tumor cells and the microenvironment in the process of melanoma growth and metastasis. Inhibition of these interactions by targeting PAR-1 could be utilized as a potential therapeutic modality for melanoma patients.

Novel Role for p21-activated Kinase 2 in Thrombin-induced Monocyte Migration

“…Thrombin, which is an extracellular protease, plays an important role in blood clotting by converting fibrinogen to fibrin (7). A large amount of literature suggests that thrombin, besides its pivotal role in clotting, acts as a mitogen and chemotactic factor to a variety of cell types, including smooth muscle cells (8,9). Thrombin mediates its effects via a family of G protein-coupled receptors (GPCRs), 2 namely, protease-activated receptors (PARs) (10,11).…”

The wound healing, chronic fibrosis, and cancer progression triad

“…PAR-1 is present in a variety of tumor types (89), and its activation promotes cancer cell proliferation and angiogenesis (95). In the clinic, PAR-1 signaling is suspected to facilitate melanoma metastasis (416), and it correlates with poor prognosis of gastric, prostate, and breast cancers (28, 100, 313). PAR-1 also facilitates pulmonary fibrosis (143), while PAR-1-deficient mice seem to resist bleomycin-induced pulmonary fibrosis (142).…”

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

“…Other studies suggest that thrombin-mediated cellular effects are triggered via long-lasting activation of the PTEN/ PI3K/AKT signaling pathway in lung cancer [78], activation of receptor tyrosine kinases Met, PDGFR, ROS1, and the inactivation of protein tyrosine phosphatase (PTP1B) in Hep3B liver carcinoma cells [79], as well as second messengers Erk1/2 in breast and colorectal cancer [80,81] or Akt/ PKB in melanoma [16].…”

“…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]. A prothrombotic state is characteristic for advanced and metastatic cancers [10,11,16,17], and enzymatically active thrombin is reportedly present on surgically excised tumor specimens, including malignant melanoma [reviewed in 3]. Additionally, hirudin, a highly specific thrombin inhibitor, markedly suppresses tumor seeding into the blood, implantation, and spontaneous metastasis in a mouse model, which prolongs survival [13,[18][19][20].…”