Regulation of Melanoma Progression by the Tumor Microenvironment: The Roles of PAR-1 and PAFR
The interaction of tumor cells and the host stroma (microenvironment) is essential for tumor progression and metastasis. The melanoma tumor microenvironment has emerged within the last decade as a significant player in melanoma progression from the radial growth phase to the vertical growth phase by providing the necessary elements for growth, invasion and survival. Two receptors involved in this transition that are not only activated by factors from the tumor microenvironment but also in turn secrete factors into the microenvironment are the Protease Activated Receptor 1 (PAR-1) and the Platelet Activating Factor Receptor (PAFR). Thrombin, which is abundant in the microenvironment milieu, activates PAR-1 causing cell signaling via G-proteins resulting in upregulation and secretion of gene products involved in adhesion (integrins), invasion (MMP-2) and angiogenesis (IL-8, VEGF, PDGF, bFGF). PAF, which is secreted by platelets, macrophages, neutrophils, endothelial cells and keratinocytes within the tumor microenvironment, will activate PAFR and signal through p38 MAPK to phosphorylate the CREB/ATF-1 transcription factors. Phosphorylation of CREB/ATF-1 results in overexpression and secretion of MMP-2 and MT1-MMP. Since only metastatic melanoma cells express activated CREB/ATF-1, we propose that they are better equipped to respond to PAF than their non-metastatic counterparts. These two G-protein coupled receptors that play major roles in melanoma progression highlight the crucial interactions between the tumor microenvironment and melanoma cells in the acquisition of the metastatic phenotype.
KeywordsMelanoma progression Metastasis Invasion Angiogenesis Thrombin Protease activated receptor-1 Platelet activating factor Tumor microenvironment Transcription factors Metalloproteinase G-protein coupled receptor
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