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. Inhibiting such interactions by targeting PAR-1 could potentially be a useful therapeutic modality for melanoma patients.

Figure 1

Thrombin and PAR-1 promote melanoma progression by inducing cross-talk between tumor cells and the microenvironment. PAR-1 expression on melanoma and stromal cells induces downstream signaling that regulate the expression of genes such as Cx-43, maspin, VEGF, IL-8, PAFR, and PAF which in turn affect the metastatic phenotype of melanoma. Cx-43 promotes interaction with vascular endothelial cells, while IL-8 serves as a survival factor for vascular endothelial cells and acts in a autocrine fashion to induce MMP-2 secretion by the melanoma cells.