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Emerging roles of PAR-1 and PAFR in melanoma metastasis.

Melnikova VO, Villares GJ, Bar-Eli M - Cancer Microenviron (2008)

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

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.

No MeSH data available.


Related in: MedlinePlus

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
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Fig1: 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

Mentions: In tumor cells, PAR-1 stimulates expression of adhesion molecules such as integrins αIIbβ3, αvβ5, and αvβ3 [45–47]. Indeed, thrombin-treated melanoma cells enhance their adhesion to platelets and fibronectin in vitro [48]. In various types of cells, including vascular endothelial cells, PAR-1 activation results in upregulation of gene products involved in invasion (MMP-2) [49], and angiogenesis (IL-8, VEGF, bFGF, PDGF) [50–53]. In human melanoma cells, thrombin acts as a growth factor and is mitogenic [32]. Overall, thrombin and PAR-1 contribute to the acquisition of the metastatic phenotype of melanoma by facilitating tumor invasion and metastasis through the induction of cell adhesion molecules, matrix degrading proteases, and stimulating the secretion of angiogenic factors into the melanoma tumor microenvironment (Fig. 1).Fig. 1


Emerging roles of PAR-1 and PAFR in melanoma metastasis.

Melnikova VO, Villares GJ, Bar-Eli M - Cancer Microenviron (2008)

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
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654348&req=5

Fig1: 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
Mentions: In tumor cells, PAR-1 stimulates expression of adhesion molecules such as integrins αIIbβ3, αvβ5, and αvβ3 [45–47]. Indeed, thrombin-treated melanoma cells enhance their adhesion to platelets and fibronectin in vitro [48]. In various types of cells, including vascular endothelial cells, PAR-1 activation results in upregulation of gene products involved in invasion (MMP-2) [49], and angiogenesis (IL-8, VEGF, bFGF, PDGF) [50–53]. In human melanoma cells, thrombin acts as a growth factor and is mitogenic [32]. Overall, thrombin and PAR-1 contribute to the acquisition of the metastatic phenotype of melanoma by facilitating tumor invasion and metastasis through the induction of cell adhesion molecules, matrix degrading proteases, and stimulating the secretion of angiogenic factors into the melanoma tumor microenvironment (Fig. 1).Fig. 1

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

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.

No MeSH data available.


Related in: MedlinePlus