Inflammation and melanoma growth and metastasis: the role of platelet-activating factor (PAF) and its receptor.
An inflammatory tumor microenvironment fosters tumor growth, angiogenesis and metastatic progression. Platelet-activating factor (PAF) is an inflammatory biolipid produced from membrane glycerophospholipids. Through the activity of its G-protein coupled receptor, PAF triggers a variety of pathological reactions including tumor neo-angiogenesis. Several groups have demonstrated that inhibiting PAF-PAF receptor pathway at the level of a ligand or receptor results in an effective inhibition of experimental tumor growth and metastasis. In particular, our group has recently demonstrated that PAF receptor antagonists can effectively inhibit the metastatic potential of human melanoma cells in nude mice. Furthermore, we showed that PAF stimulated the phosphorylation of CREB and ATF-1 in metastatic melanoma cells, which resulted in overexpression of MMP-2 and MT1-MMP. Our data indicate that PAF acts as a promoter of melanoma metastasis in vivo. Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that these cells are better equipped to respond to PAF within the tumor microenvironment when compared to their non-metastatic counterparts.
Melnikova
Vladislava
V
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, P.O. Box 173, Houston, TX 77030, USA.
Bar-Eli
Menashe
M
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004095:Dihydropyridines / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000150:complications*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology* / Q000556:secondary*; D009389:Neovascularization, Pathologic / Q000209:etiology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction
D017362:Cyclic AMP Response Element-Binding Protein; D004095:Dihydropyridines; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C066024:PCA 4248; C079238:alcohol O-acetyltransferase; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14