Emerging roles of PAR-1 and PAFR in melanoma metastasis

Abstract

Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor-ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1 and PAFR, contribute to the acquisition of the metastatic phenotype of melanoma is presented and discussed.

Fig. 1

Schematic representation of molecules involved in cell invasion and angiogenesis via activation of PAR-1 which is overexpressed in metastatic melanoma cells. Thrombin from the microenvironment cleaves the N-terminus of PAR-1 to activate the receptor. The tumor-promoting signals transduced by PAR-1 through G-proteins upregulate molecules involved in angiogenesis and invasion

Fig. 2

A model for the stimulation of MMP-2 and MT1-MMP by PAF via activation of CREB/ATF-1. We propose that melanoma cells, regardless of their metastatic potential, express PAFR and secrete basal levels of MMP-2 and MT1-MMP. However, within the melanoma tumor microenvironment, melanoma cells come into contact with platelets, endothelial cells, and inflammatory cells that secrete PAF. PAF, through the activity of its receptor on tumor cells and a signaling cascade involving pertussis-toxin-insensitive Gα_q protein, adenylate cyclase, p38 MAPK and PKA, phosphorylates CREB and ATF-1. Activation of this and possibly other signaling mechanisms results in overexpression and secretion of MMP-2 and MT1-MMP. However, since only metastatic melanoma cells overexpress CREB and ATF-1, they are better equipped to respond to the stimulatory effect of PAF within the tumor microenvironment