Regulation of Melanoma Progression by the Tumor Microenvironment: The Roles of PAR-1 and PAFR

  • Gabriel J. Villares
  • Menashe Bar-Eli
Part of the TTME book series (TTME, volume 2)

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.


Melanoma 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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  1. 1.
    Lee, J.T., Herlyn, M., Microenvironmental influences in melanoma progression. J Cell Biochem 101: 862–872, 2007.CrossRefPubMedGoogle Scholar
  2. 2.
    Postovit, L.M., Seftor, E.A., Seftor, R.E., Hendrix, M.J., Influence of the microenvironment on melanoma cell fate determination and phenotype. Cancer Res 66: 7833–7836, 2006.CrossRefPubMedGoogle Scholar
  3. 3.
    Melnikova, V., Bar-Eli, M., Inflammation and melanoma growth and metastasis: the role of platelet-activating factor (PAF) and its receptor. Cancer Metastasis Rev 26: 359–371, 2007.CrossRefPubMedGoogle Scholar
  4. 4.
    Hsu, M.Y., Meier, F., Herlyn, M., Melanoma development and progression: a conspiracy between tumor and host. Differentiation 70: 522–536, 2002.CrossRefPubMedGoogle Scholar
  5. 5.
    Tellez, C., Bar-Eli, M., Role and regulation of the thrombin receptor (PAR-1) in human melanoma. Oncogene 22: 3130–3137, 2003.CrossRefPubMedGoogle Scholar
  6. 6.
    Ruf, W., Tissue factor and PAR signaling in tumor progression. Thromb Res 120(Suppl 2): S7–S12, 2007.CrossRefGoogle Scholar
  7. 7.
    Bromberg, M.E., Konigsberg, W.H., Madison, J.F., Pawashe, A., Garen, A., Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci USA 92: 8205–8209, 1995.CrossRefPubMedGoogle Scholar
  8. 8.
    Fischer, E.G., Ruf, W., Mueller, B.M., Tissue factor-initiated thrombin generation activates the signaling thrombin receptor on malignant melanoma cells. Cancer Res 55: 1629–1632, 1995.PubMedGoogle Scholar
  9. 9.
    Nierodzik, M.L., Bain, R.M., Liu, L.X., Shivji, M., Takeshita, K., Karpatkin, S., Presence of the seven transmembrane thrombin receptor on human tumour cells: effect of activation on tumour adhesion to platelets and tumor tyrosine phosphorylation. Br J Haematol 92: 452–457, 1996.CrossRefPubMedGoogle Scholar
  10. 10.
    Haralabopoulos, G.C., Grant, D.S., Kleinman, H.K., Maragoudakis, M.E., Thrombin promotes endothelial cell alignment in Matrigel in vitro and angiogenesis in vivo. Am J Physiol 273: C239–C245, 1997.PubMedGoogle Scholar
  11. 11.
    Shimizu, S., Gabazza, E.C., Hayashi, T., Ido, M., Adachi, Y., Suzuki, K., Thrombin stimulates the expression of PDGF in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 279: L503–L510, 2000.PubMedGoogle Scholar
  12. 12.
    Even-Ram, S.C., Maoz, M., Pokroy, E., Reich, R., Katz, B.Z., Gutwein, P., Altevogt, P., Bar-Shavit, R., Tumor cell invasion is promoted by activation of protease activated receptor-1 in cooperation with the alpha vbeta 5 integrin. J Biol Chem 276: 10952–10962, 2001.CrossRefPubMedGoogle Scholar
  13. 13.
    Wojtukiewicz, M.Z., Tang, D.G., Nelson, K.K., Walz, D.A., Diglio, C.A., Honn, K.V., Thrombin enhances tumor cell adhesive and metastatic properties via increased alpha IIb beta 3 expression on the cell surface. Thromb Res 68: 233–245, 1992.CrossRefPubMedGoogle Scholar
  14. 14.
    Senger, D.R., Ledbetter, S.R., Claffey, K.P., Papadopoulos-Sergiou, A., Peruzzi, C.A., Detmar, M., Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin. Am J Pathol 149: 293–305, 1996.PubMedGoogle Scholar
  15. 15.
    Zucker, S., Conner, C., DiMassmo, B.I., Ende, H., Drews, M., Seiki, M., Bahou, W.F., Thrombin induces the activation of progelatinase A in vascular endothelial cells: physiologic regulation of angiogenesis. J Biol Chem 270: 23730–23738, 1995.CrossRefPubMedGoogle Scholar
  16. 16.
    Ueno, A., Murakami, K., Yamanouchi, K., Watanabe, M., Kondo, T., Thrombin stimulates production of interleukin-8 in human umbilical vein endothelial cells. Immunology 88: 76–81, 1996.CrossRefPubMedGoogle Scholar
  17. 17.
    Huang, Y.Q., Li, J.J., Hu, L., Lee, M., Karpatkin, S., Thrombin induces increased expression and secretion of VEGF from human FS4 fibroblasts, DU145 prostate cells and CHRF megakaryocytes. Thromb Haemost 86: 1094–1098, 2001.PubMedGoogle Scholar
  18. 18.
    Cucina, A., Borrelli, V., Di Carlo, A., Pagliei, S., Corvino, V., Santoro-D’Angelo, L., Cavallaro, A., Sterpetti, A.V., Thrombin induces production of growth factors from aortic smooth muscle cells. J Surg Res 82: 61–66, 1999.CrossRefPubMedGoogle Scholar
  19. 19.
    O’Brien, P.J., Molino, M., Kahn, M., Brass, L.F., Protease activated receptors: theme and variations. Oncogene 20: 1570–1581, 2001.CrossRefPubMedGoogle Scholar
  20. 20.
    Ruf, W., Mueller, B.M., Thrombin generation and the pathogenesis of cancer. Semin Thromb Hemost 32(Suppl 1): 61–68, 2006.Google Scholar
  21. 21.
    Hansen, K.K., Saifeddine, M., Hollenberg, M.D., Tethered ligand-derived peptides of proteinase-activated receptor 3 (PAR3) activate PAR1 and PAR2 in Jurkat T cells. Immunology 112: 183–190, 2004.CrossRefPubMedGoogle Scholar
  22. 22.
    Even-Ram, S., Uziely, B., Cohen, P., Grisaru-Granovsky, S., Maoz, M., Ginzburg, Y., Reich, R., Vlodavsky, I., Bar-Shavit, R., Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med 4: 909–914, 1998.CrossRefPubMedGoogle Scholar
  23. 23.
    Henrikson, K.P., Salazar, S.L., Fenton, J.W., II, Pentecost, B.T., Role of thrombin receptor in breast cancer invasiveness. Br J Cancer 79: 401–406, 1999.CrossRefPubMedGoogle Scholar
  24. 24.
    Rudroff, C., Schafberg, H., Nowak, G., Weinel, R., Scheele, J., Kaufmann, R., Characterization of functional thrombin receptors in human pancreatic tumor cells (MIA PACA-2). Pancreas 16: 189–194, 1998.CrossRefPubMedGoogle Scholar
  25. 25.
    Wojtukiewicz, M.Z., Tang, D.G., Ben-Josef, E., Renaud, C., Walz, D.A., Honn, K.V., Solid tumor cells express functional “tethered ligand” thrombin receptor. Cancer Res 55: 698–704, 1995.PubMedGoogle Scholar
  26. 26.
    Kaushal, V., Kohli, M., Dennis, R.A., Siegel, E.R., Chiles, W.W., Mukunyadzi, P., Thrombin receptor expression is upregulated in prostate cancer. Prostate 66: 273–282, 2006.CrossRefPubMedGoogle Scholar
  27. 27.
    Boire, A., Covic, L., Agarwal, A., Jacques, S., Sherifi, S., Kuliopulos, A., PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120: 303–313, 2005.CrossRefPubMedGoogle Scholar
  28. 28.
    Tellez, C., McCarty, M., Ruiz, M., Bar-Eli, M., Loss of activator protein-2alpha results in overexpression of protease-activated receptor-1 and correlates with the malignant phenotype of human melanoma. J Biol Chem 278: 46632–46642, 2003.CrossRefPubMedGoogle Scholar
  29. 29.
    Massi, D., Naldini, A., Ardinghi, C., Carraro, F., Franchi, A., Paglierani, M., Tarantini, F., Ketabchi, S., Cirino, G., Hollenberg, M.D., Geppetti, P., Santucci, M., Expression of protease-activated receptors 1 and 2 in melanocytic nevi and malignant melanoma. Hum Pathol 36: 676–685, 2005.CrossRefPubMedGoogle Scholar
  30. 30.
    Tellez, C.S., Davis, D.W., Prieto, V.G., Gershenwald, J.E., Johnson, M.M., McCarty, M.F., Bar-Eli, M., Quantitative analysis of melanocytic tissue array reveals inverse correlation between activator protein-2alpha and protease-activated receptor-1 expression during melanoma progression. J Invest Dermatol 127: 387–393, 2007.CrossRefPubMedGoogle Scholar
  31. 31.
    Balkwill, F., Mantovani, A., Inflammation and cancer: back to Virchow? Lancet 357: 539–545, 2001.Google Scholar
  32. 32.
    Coussens, L.M., Werb, Z., Inflammation and cancer. Nature 420: 860–867, 2002.CrossRefPubMedGoogle Scholar
  33. 33.
    Mantovani, A., Cancer: inflammation by remote control. Nature 435: 752–753, 2005.CrossRefPubMedGoogle Scholar
  34. 34.
    Pikarsky, E., Porat, R.M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E., Ben-Neriah, Y., NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431: 461–466, 2004.CrossRefPubMedGoogle Scholar
  35. 35.
    Coffer, P.J., Schweizer, R.C., Dubois, G.R., Maikoe, T., Lammers, J.W., Koenderman, L., Analysis of signal transduction pathways in human eosinophils activated by chemoattractants and the T-helper 2-derived cytokines interleukin-4 and interleukin-5. Blood 91: 2547–2557, 1998.PubMedGoogle Scholar
  36. 36.
    Franklin, R.A., Mazer, B., Sawami, H., Mills, G.B., Terada, N., Lucas, J.J., Gelfand, E.W., Platelet-activating factor triggers the phosphorylation and activation of MAP-2 kinase and S6 peptide kinase activity in human B cell lines. J Immunol 151: 1802–1810, 1993.PubMedGoogle Scholar
  37. 37.
    Honda, Z., Takano, T., Gotoh, Y., Nishida, E., Ito, K., Shimizu, T., Transfected platelet-activating factor receptor activates mitogen-activated protein (MAP) kinase and MAP kinase kinase in Chinese hamster ovary cells. J Biol Chem 269: 2307–2315, 1994.PubMedGoogle Scholar
  38. 38.
    Ishii, S., Nagase, T., Shimizu, T., Platelet-activating factor receptor. Prostaglandins Other Lipid Mediat 68–69: 599–609, 2002.CrossRefGoogle Scholar
  39. 39.
    Melnikova, V.O., Mourad-Zeidan, A.A., Lev, D.C., Bar-Eli, M., Platelet-activating factor mediates MMP-2 expression and activation via phosphorylation of cAMP-response element-binding protein and contributes to melanoma metastasis. J Biol Chem 281: 2911–2922, 2006.CrossRefPubMedGoogle Scholar
  40. 40.
    Landis, M., Yi, Q., Hyatt, A.M., Travers, A.R., Lewis, D.A., Travers, J.B., Involvement of P38 MAP kinase in the augmentation of UVB-mediated apoptosis via the epidermal platelet-activating factor receptor. Arch Dermatol Res 299: 263–266, 2007.CrossRefPubMedGoogle Scholar
  41. 41.
    Nick, J.A., Avdi, N.J., Young, S.K., Knall, C., Gerwins, P., Johnson, G.L., Worthen, G.S., Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP. J Clin Invest 99: 975–986, 1997.CrossRefPubMedGoogle Scholar
  42. 42.
    Ishii, S., Nagase, T., Tashiro, F., Ikuta, K., Sato, S., Waga, I., Kume, K., Miyazaki, J., Shimizu, T., Bronchial hyperreactivity, increased endotoxin lethality and melanocytic tumorigenesis in transgenic mice overexpressing platelet-activating factor receptor. Embo J 16: 133–142, 1997.CrossRefPubMedGoogle Scholar
  43. 43.
    Sato, S., Kume, K., Ito, C., Ishii, S., Shimizu, T., Accelerated proliferation of epidermal keratinocytes by the transgenic expression of the platelet-activating factor receptor. Arch Dermatol Res 291: 614–621, 1999.CrossRefPubMedGoogle Scholar
  44. 44.
    Travers, J.B., Huff, J.C., Rola-Pleszczynski, M., Gelfand, E.W., Morelli, J.G., Murphy, R.C., Identification of functional platelet-activating factor receptors on human keratinocytes. J Invest Dermatol 105: 816–823, 1995.CrossRefPubMedGoogle Scholar
  45. 45.
    Darst, M., Al-Hassani, M., Li, T., Yi, Q., Travers, J.M., Lewis, D.A., Travers, J.B., Augmentation of chemotherapy-induced cytokine production by expression of the platelet-activating factor receptor in a human epithelial carcinoma cell line. J Immunol 172: 6330–6335, 2004.PubMedGoogle Scholar
  46. 46.
    Rutberg, S.E., Goldstein, I.M., Yang, Y.M., Stackpole, C.W., Ronai, Z., Expression and transcriptional activity of AP-1, CRE, and URE binding proteins in B16 mouse melanoma subclones. Mol Carcinog 10: 82–87, 1994.CrossRefPubMedGoogle Scholar
  47. 47.
    Axelrad, T.W., Deo, D.D., Ottino, P., Van Kirk, J., Bazan, N.G., Bazan, H.E., Hunt, J.D., Platelet-activating factor (PAF) induces activation of matrix metalloproteinase 2 activity and vascular endothelial cell invasion and migration. Faseb J 18: 568–570, 2004.PubMedGoogle Scholar
  48. 48.
    van Kempen, L.C., van Muijen, G.N., Ruiter, D.J., Stromal responses in human primary melanoma of the skin. Front Biosci 10: 2922–2931, 2005.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Gabriel J. Villares
  • Menashe Bar-Eli
    • 1
  1. 1.Department of Cancer BiologyThe University of Texas, MD Anderson Cancer CenterHoustonUSA

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