About this Journal Submit a Manuscript Table of Contents
ISRN Dermatology
Volume 2013 (2013), Article ID 597927, 26 pages
http://dx.doi.org/10.1155/2013/597927
Review Article

Transforming Growth Factor-Beta and Urokinase-Type Plasminogen Activator: Dangerous Partners in Tumorigenesis—Implications in Skin Cancer

Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Dr. Subotića 4, 11129 Belgrade, Serbia

Received 26 May 2013; Accepted 18 June 2013

Academic Editors: M. Clelia and E. Nagore

Copyright © 2013 Juan F. Santibanez. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. S. A. Brooks, H. J. Lomax-Browne, T. M. Carter, C. E. Kinch, and D. M. S. Hall, “Molecular interactions in cancer cell metastasis,” Acta Histochemica, vol. 112, no. 1, pp. 3–25, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. A. B. Roberts and L. M. Wakefield, “The two faces of transforming growth factor β in carcinogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 15, pp. 8621–8623, 2003. View at Publisher · View at Google Scholar · View at Scopus
  3. C. Caulin, F. G. Scholl, P. Frontelo, C. Gamallo, and M. Quintanilla, “Chronic exposure of cultured transformed mouse epidermal cells to transforming growth factor-β1 induces an epithelial-mesenchymal transdifferentiation and a spindle tumoral phenotype,” Cell Growth and Differentiation, vol. 6, no. 8, pp. 1027–1035, 1995. View at Scopus
  4. J. P. Their, “Epithelial-mesenchymal transitions in tumor progression,” Nature Reviews Cancer, vol. 2, no. 6, pp. 442–454, 2002. View at Scopus
  5. L. M. Wakefield and A. B. Roberts, “TGF-β signaling: positive and negative effects on tumorigenesis,” Current Opinion in Genetics and Development, vol. 12, no. 1, pp. 22–29, 2002. View at Publisher · View at Google Scholar · View at Scopus
  6. P. Wikstrom, P. Stattin, I. Franck-Lissbrant, J. E. Damber, and A. Bergh, “Transforming growth factor β1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer,” Prostate, vol. 37, no. 1, pp. 19–29, 1998. View at Publisher · View at Google Scholar
  7. R. Derynck and Y. E. Zhang, “Smad-dependent and Smad-independent pathways in TGF-β family signalling,” Nature, vol. 425, no. 6958, pp. 577–584, 2003. View at Publisher · View at Google Scholar · View at Scopus
  8. M. J. Duffy, P. M. McGowan, and W. M. Gallagher, “Cancer invasion and metastasis: changing views,” Journal of Pathology, vol. 214, no. 3, pp. 283–293, 2008. View at Publisher · View at Google Scholar · View at Scopus
  9. M. J. Duffy, “Urokinase-type plasminogen activator: a potent marker of metastatic potential in human cancers,” Biochemical Society Transactions, vol. 30, no. 2, pp. 207–210, 2002. View at Scopus
  10. M. Jo, K. S. Thomas, N. Marozkina et al., “Dynamic assembly of the urokinase-type plasminogen activator signaling receptor complex determines the mitogenic activity of urokinase-type plasminogen activator,” The Journal of Biological Chemistry, vol. 280, no. 17, pp. 17449–17457, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. E. Planus, G. Barlovatz-Meimon, R. A. Rogers, S. Bonavaud, D. E. Ingber, and N. Wang, “Binding of urokinase to plasminogen activator inhibitor type-1 mediates cell adhesion and spreading,” Journal of Cell Science, vol. 110, no. 9, pp. 1091–1098, 1997. View at Scopus
  12. D. Q. Seetoo, P. J. Crowe, P. J. Russell, and J. L. Yang, “Quantitative expression of protein markers of plasminogen activation system in prognosis of colorectal cancer,” Journal of Surgical Oncology, vol. 82, no. 3, pp. 184–193, 2003. View at Publisher · View at Google Scholar · View at Scopus
  13. N. Harbeck, R. E. Kates, M. Schmitt et al., “Urokinase-type plasminogen activator and its inhibitor type 1 predict disease outcome and therapy response in primary breast cancer,” Clinical Breast Cancer, vol. 5, no. 5, pp. 348–352, 2004. View at Scopus
  14. J. F. S. Santibañez, M. Quintanilla, and C. Bernabeu, “TGF-β/TGF-β receptor system and its role in physiological and pathological conditions,” Clinical Science, vol. 121, no. 6, pp. 233–251, 2011. View at Publisher · View at Google Scholar · View at Scopus
  15. J. F. Santibanez and J. Kocic, “Transforming growth factor-β superfamily, implications in development and differentiation of stem cells,” Biomolecular Concepts, vol. 5, pp. 429–445, 2012.
  16. M. A. Anzano, A. B. Roberts, J. M. Smith, M. B. Sporn, and J. E. de Larco, “Sarcoma growth factor from conditioned medium of virally transformed cells is composed of both type α and type β transforming growth factors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 80, no. 20 I, pp. 6264–6268, 1983. View at Scopus
  17. R. Govinden and K. D. Bhoola, “Genealogy, expression, and cellular function of transforming growth factor-β,” Pharmacology and Therapeutics, vol. 98, no. 2, pp. 257–265, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. M. C. Birchenall-Roberts, F. W. Ruscetti, J. Kasper et al., “Transcriptional regulation of the transforming growth factor β1 promoter by v-src gene products is mediated through the AP-1 complex,” Molecular and Cellular Biology, vol. 10, no. 9, pp. 4978–4983, 1990. View at Scopus
  19. A. B. Roberts, “Molecular and cell biology of TGF-β,” Mineral and Electrolyte Metabolism, vol. 24, no. 2-3, pp. 111–119, 1998. View at Publisher · View at Google Scholar · View at Scopus
  20. C. Bernabeu, J. M. Lopez-Novoa, and M. Quintanilla, “The emerging role of TGF-β superfamily coreceptors in cancer,” Biochimica et Biophysica Acta, vol. 1792, no. 10, pp. 954–973, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. G. M. Di Guglielmo, C. le Roy, A. F. Goodfellow, and J. L. Wrana, “Distinct endocytic pathways regulate TGF-β receptor signalling and turnover,” Nature Cell Biology, vol. 5, no. 5, pp. 410–421, 2003. View at Publisher · View at Google Scholar · View at Scopus
  22. T. Ebisawa, M. Fukuchi, G. Murakami et al., “Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation,” The Journal of Biological Chemistry, vol. 276, no. 16, pp. 12477–12480, 2001. View at Publisher · View at Google Scholar · View at Scopus
  23. S. Souchelnytskyi, P. ten Dijke, K. Miyazono, and C. Heldin, “Phosphorylation of ser165 in TGF-β type I receptor modulates TGF-β1-induced cellular responses,” EMBO Journal, vol. 15, no. 22, pp. 6231–6240, 1996. View at Scopus
  24. M. Huse, T. W. Muir, L. Xu, Y. Chen, J. Kuriyan, and J. Massagué, “The TGFβ receptor activation process: an inhibitor- to substrate-binding switch,” Molecular Cell, vol. 8, no. 3, pp. 671–682, 2001. View at Publisher · View at Google Scholar · View at Scopus
  25. L. Attisano and S. T. Lee-Hoefl ich, “The Smads,” Genome Biology, vol. 2, no. 8, Article ID REVIEWS3010, 2001.
  26. Y. Shi and J. Massagué, “Mechanisms of TGF-β signaling from cell membrane to the nucleus,” Cell, vol. 113, no. 6, pp. 685–700, 2003. View at Publisher · View at Google Scholar · View at Scopus
  27. J. Massagué and Y. G. Chen, “Controlling TGF-β signaling,” Genes and Development, vol. 14, no. 6, pp. 627–644, 2000. View at Scopus
  28. K. Miyazono, S. Maeda, and T. Imamura, “BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk,” Cytokine and Growth Factor Reviews, vol. 16, no. 3, pp. 251–263, 2005. View at Publisher · View at Google Scholar · View at Scopus
  29. K. M. Mulder and S. L. Morris, “Activation of p21(ras) by transforming growth factor β in epithelial cells,” The Journal of Biological Chemistry, vol. 267, no. 8, pp. 5029–5031, 1992. View at Scopus
  30. M. K. Lee, C. Pardoux, M. C. Hall et al., “TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcA,” EMBO Journal, vol. 26, no. 17, pp. 3957–3967, 2007. View at Publisher · View at Google Scholar · View at Scopus
  31. A. Sorrentino, N. Thakur, S. Grimsby et al., “The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner,” Nature Cell Biology, vol. 10, no. 10, pp. 1199–1207, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. M. Yamashita, K. Fatyol, C. Jin, X. Wang, Z. Liu, and Y. E. Zhang, “TRAF6 mediates smad-independent activation of JNK and p38 by TGF-β,” Molecular Cell, vol. 31, no. 6, pp. 918–924, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. J. Xu, S. Lamouille, and R. Derynck, “TGF-Β-induced epithelial to mesenchymal transition,” Cell Research, vol. 19, no. 2, pp. 156–172, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. R. H. Chen, Y. H. Su, R. L. C. Chuang, and T. Y. Chang, “Suppression of transforming growth factor-β-induced apoptosis through a phosphatidylinositol 3-kinase/Akt-dependent pathway,” Oncogene, vol. 17, no. 15, pp. 1959–1968, 1998. View at Scopus
  35. H. W. Smith and C. J. Marshall, “Regulation of cell signalling by uPAR,” Nature Reviews Molecular Cell Biology, vol. 11, no. 1, pp. 23–36, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. S. D. Mason and J. A. Joyce, “Proteolytic networks in cancer,” Trends in Cell Biology, vol. 21, no. 4, pp. 228–237, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. J. D.. Vassalli, D. Baccino, and D. Belin, “A cellular binding site for the M(r) 55,000 form of the human plasminogen activator, urokinase,” Journal of Cell Biology, vol. 100, no. 1, pp. 86–92, 1985. View at Scopus
  38. E. Appella, E. A. Robinson, S. J. Ullrich et al., “The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases,” The Journal of Biological Chemistry, vol. 262, no. 10, pp. 4437–4440, 1987. View at Scopus
  39. A. Poliakov, V. Tkachuk, T. Ovchinnikova, N. Potapenko, S. Bagryantsev, and V. Stepanova, “Plasmin-dependent elimination of the growth-factor-like domain in urokinase causes its rapid cellular uptake and degradation,” Biochemical Journal, vol. 355, no. 3, pp. 639–645, 2001. View at Scopus
  40. F. Blasi and P. Carmeliet, “uPAR: a versatile signalling orchestrator,” Nature Reviews Molecular Cell Biology, vol. 3, no. 12, pp. 932–943, 2002. View at Publisher · View at Google Scholar · View at Scopus
  41. V. Ellis and K. Dano, “Potentiation of plasminogen activation by an anti-urokinase monoclonal antibody due to ternary complex formation. A mechanistic model for receptor-mediated plasminogen activation,” The Journal of Biological Chemistry, vol. 268, no. 7, pp. 4806–4813, 1993. View at Scopus
  42. D. C. Rijken and H. R. Lijnen, “New insights into the molecular mechanisms of the fibrinolytic system,” Journal of Thrombosis and Haemostasis, vol. 7, no. 1, pp. 4–13, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. C. Barinka, G. Parry, J. Callahan et al., “Structural basis of interaction between urokinase-type plasminogen activator and its receptor,” Journal of Molecular Biology, vol. 363, no. 2, pp. 482–495, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. G. Sotiropoulou, G. Pampalakis, and E. P. Diamandis, “Functional roles of human Kallikrein-related peptidases,” The Journal of Biological Chemistry, vol. 284, no. 48, pp. 32989–32994, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. E. Skrzydlewska, M. Sulkowska, M. Koda, and S. Sulkowski, “Proteolytic-antiproteolytic balance and its regulation in carcinogenesis,” World Journal of Gastroenterology, vol. 11, no. 9, pp. 1251–1266, 2005. View at Scopus
  46. P. A. Madureira, P. A. O'Connell, A. P. Surette, V. A. Miller, and D. M. Waisman, “The biochemistry and regulation of S100A10: a multifunctional plasminogen receptor involved in oncogenesis,” Journal of Biomedicine and Biotechnology, vol. 2012, Article ID 353687, 21 pages, 2012. View at Publisher · View at Google Scholar
  47. S. Ye and E. J. Goldsmith, “Serpins and other covalent protease inhibitors,” Current Opinion in Structural Biology, vol. 11, no. 6, pp. 740–745, 2001. View at Publisher · View at Google Scholar · View at Scopus
  48. P. Carmeliet, L. Moons, R. Lijnen et al., “Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation,” Nature Genetics, vol. 17, no. 4, pp. 439–444, 1997. View at Scopus
  49. Y. He, X. D. Liu, Z. Y. Chen et al., “Interaction between cancer cells and stromal fibroblasts is required for activation of the uPAR-uPA-MMP-2 cascade in pancreatic cancer metastasis,” Clinical Cancer Research, vol. 13, no. 11, pp. 3115–3124, 2007. View at Publisher · View at Google Scholar · View at Scopus
  50. H. M. Zhou, A. Nichols, P. Meda, and J. D. Vassalli, “Urokinase-type plasminogen activator and its receptor synergize to promote pathogenic proteolysis,” EMBO Journal, vol. 19, no. 17, pp. 4817–4826, 2000. View at Scopus
  51. A. Estreicher, J. Muhlhauser, J. L. Carpentier, L. Orci, and J. D. Vassalli, “The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes,” Journal of Cell Biology, vol. 111, no. 2, pp. 783–792, 1990. View at Publisher · View at Google Scholar · View at Scopus
  52. K. A. Houck, D. W. Leung, A. M. Rowland, J. Winer, and N. Ferrara, “Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms,” The Journal of Biological Chemistry, vol. 267, no. 36, pp. 26031–26037, 1992. View at Scopus
  53. R. M. Lyons, L. E. Gentry, A. F. Purchio, and H. L. Moses, “Mechanism of activation of latent recombinant transforming growth factor β1 by plasmin,” Journal of Cell Biology, vol. 110, no. 4, pp. 1361–1367, 1990. View at Scopus
  54. S. S. Okada, S. R. Grobmyer, and E. S. Barnathan, “Contrasting effects of plasminogen activators, urokinase receptor, and LDL receptor-related protein on smooth muscle cell migration and invasion,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 16, no. 10, pp. 1269–1276, 1996. View at Scopus
  55. N. Wang, E. Planus, M. Pouchelet, J. J. Fredberg, and G. Barlovatz-Meimon, “Urokinase receptor mediates mechanical force transfer across the cell surface,” The American Journal of Physiology, vol. 268, no. 4, pp. C1062–C1066, 1995. View at Scopus
  56. C. L. Jackson and M. A. Reidy, “The role of plasminogen activation in smooth muscle cell migration after arterial injury,” Annals of the New York Academy of Sciences, vol. 667, pp. 141–150, 1992. View at Publisher · View at Google Scholar · View at Scopus
  57. A. W. Clowes, M. M. Clowes, T. R. Kirkman, C. L. Jackson, Y. P. T. Au, and R. Kenagy, “Heparin inhibits the expression of tissue-type plasminogen activator by smooth muscle cells in injured rat carotid artery,” Circulation Research, vol. 70, no. 6, pp. 1128–1136, 1992. View at Scopus
  58. P. A. Andreasen, L. Kjoller, L. Christensen, and M. J. Duffy, “The urokinase-type plasminogen activator system in cancer metastasis: a review,” International Journal of Cancer, vol. 72, no. 1, pp. 1–22, 1997. View at Publisher · View at Google Scholar
  59. M. C. Kugler, Y. Wei, and H. A. Chapman, “Urokinase receptor and integrin interactions,” Current Pharmaceutical Design, vol. 9, no. 19, pp. 1565–1574, 2003. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Resnati, M. Guttinger, S. Valcamonica, N. Sidenius, F. Blasi, and F. Fazioli, “Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect,” EMBO Journal, vol. 15, no. 7, pp. 1572–1582, 1996. View at Scopus
  61. D. Liu, J. A. Aguirre-Ghiso, Y. Estrada, and L. Ossowski, “EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma,” Cancer Cell, vol. 1, no. 5, pp. 445–457, 2002. View at Publisher · View at Google Scholar · View at Scopus
  62. J. Guerrero, J. F. Santibañez, A. González, and J. Martínez, “EGF receptor transactivation by urokinase receptor stimulus through a mechanism involving Src and matrix metalloproteinases,” Experimental Cell Research, vol. 292, no. 1, pp. 201–208, 2004. View at Publisher · View at Google Scholar
  63. M. Jo, K. S. Thomas, D. M. O'Donnell, and S. L. Gonias, “Epidermal growth factor receptor-dependent and -independent cell-signaling pathways originating from the urokinase receptor,” The Journal of Biological Chemistry, vol. 278, no. 3, pp. 1642–1646, 2003. View at Publisher · View at Google Scholar · View at Scopus
  64. N. Juretic, J. F. Santibáñez, C. Hurtado, and J. Martínez, “ERK 1,2 and p38 pathways are involved in the proliferative stimuli mediated by urokinase in osteoblastic SaOS-2 cell line,” Journal of Cellular Biochemistry, vol. 83, no. 1, pp. 92–98, 2001. View at Publisher · View at Google Scholar · View at Scopus
  65. J. A. Aguirre-Ghiso, “Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo,” Oncogene, vol. 21, no. 16, pp. 2513–2524, 2002. View at Publisher · View at Google Scholar · View at Scopus
  66. E. Vial, E. Sahai, and C. J. Marshall, “ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility,” Cancer Cell, vol. 4, no. 1, pp. 67–79, 2003. View at Publisher · View at Google Scholar · View at Scopus
  67. L. Kjøller and A. Hall, “Rac mediates cytoskeletal rearrangements and increased cell motility induced by urokinase-type plasminogen activator receptor binding to vitronectin,” Journal of Cell Biology, vol. 152, no. 6, pp. 1145–1158, 2001. View at Publisher · View at Google Scholar · View at Scopus
  68. Y. Koshelnick, M. Ehart, P. Hufnagl, P. C. Heinrich, and B. R. Binder, “Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598,” The Journal of Biological Chemistry, vol. 272, no. 45, pp. 28563–28567, 1997. View at Publisher · View at Google Scholar · View at Scopus
  69. A. R. Nusrat and H. A. Chapman Jr., “An autocrine role for urokinase in phorbol ester-mediated differentiation of myeloid cell lines,” Journal of Clinical Investigation, vol. 87, no. 3, pp. 1091–1097, 1991. View at Scopus
  70. Q. Huai, A. Zhou, L. Lin et al., “Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes,” Nature Structural and Molecular Biology, vol. 15, no. 4, pp. 422–423, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. Y. Wei, D. A. Waltz, N. Rao, R. J. Drummond, S. Rosenberg, and H. A. Chapman, “Identification of the urokinase receptor as an adhesion receptor for vitronectin,” The Journal of Biological Chemistry, vol. 269, no. 51, pp. 32380–32388, 1994. View at Scopus
  72. C. D. Madsen, G. M. S. Ferraris, A. Andolfo, O. Cunningham, and N. Sidenius, “uPAR-induced cell adhesion and migration: vitronectin provides the key,” Journal of Cell Biology, vol. 177, no. 5, pp. 927–939, 2007. View at Publisher · View at Google Scholar · View at Scopus
  73. H. W. Smith, P. Marra, and C. J. Marshall, “uPAR promotes formation of the p130Cas-Crk complex to activate Rac through DOCK180,” Journal of Cell Biology, vol. 182, no. 4, pp. 777–790, 2008. View at Publisher · View at Google Scholar · View at Scopus
  74. P. Chaurasia, J. A. Aguirre-Ghiso, O. D. Liang, H. Gardsvoll, M. Ploug, and L. Ossowski, “A region in urokinase plasminogen receptor domain III controlling a functional association with α5β1 integrin and tumor growth,” The Journal of Biological Chemistry, vol. 281, no. 21, pp. 14852–14863, 2006. View at Publisher · View at Google Scholar · View at Scopus
  75. F. Zhang, C. C. Tom, M. C. Kugler et al., “Distinct ligand binding sites in integrin α3β1 regulate matrix adhesion and cell-cell contact,” Journal of Cell Biology, vol. 163, no. 1, pp. 177–188, 2003. View at Publisher · View at Google Scholar · View at Scopus
  76. M. Conese, A. Nykjær, C. M. Petersen et al., “α-2 macroglobulin receptor/Ldl receptor-related protein(Lrp)-dependent internalization of the urokinase receptor,” Journal of Cell Biology, vol. 131, no. 6 I, pp. 1609–1622, 1995. View at Publisher · View at Google Scholar · View at Scopus
  77. R. P. Czekay, T. A. Kuemmel, R. A. Orlando, and M. G. Farquhar, “Direct binding of occupied urokinase receptor (uPAR) to LDL receptor-related protein is required for endocytosis of uPAR and regulation of cell surface urokinase activity,” Molecular Biology of the Cell, vol. 12, no. 5, pp. 1467–1479, 2001. View at Scopus
  78. G. W. Prager, J. M. Breuss, S. Steurer et al., “Vascular endothelial growth factor receptor-2-induced initial endothelial cell migration depends on the presence of the urokinase receptor,” Circulation Research, vol. 94, no. 12, pp. 1562–1570, 2004. View at Publisher · View at Google Scholar · View at Scopus
  79. N. Behrendt, O. N. Jensen, L. H. Engelholm, E. Mørtz, M. Mann, and K. Danø, “A urokinase receptor-associated protein with specific collagen binding properties,” The Journal of Biological Chemistry, vol. 275, no. 3, pp. 1993–2002, 2000. View at Publisher · View at Google Scholar · View at Scopus
  80. J. Sturge, D. Wienke, L. East, G. E. Jones, and C. M. Isacke, “GPI-anchored uPAR requires Endo180 for rapid directional sensing during chemotaxis,” Journal of Cell Biology, vol. 162, no. 5, pp. 789–794, 2003. View at Publisher · View at Google Scholar · View at Scopus
  81. Z. Ma, K. S. Thomas, D. J. Webb et al., “Regulation of Rac1 activation by the low density lipoprotein receptor-related protein,” Journal of Cell Biology, vol. 159, no. 6, pp. 1061–1070, 2002. View at Publisher · View at Google Scholar · View at Scopus
  82. D. J. Webb, D. H. D. Nguyen, and S. L. Gonias, “Extracellular signal-regulated kinase functions in the urokinase receptor-dependent pathway by which neutralization of low density lipoprotein receptor-related protein promotes fibrosarcoma cell migration and Matrigel invasion,” Journal of Cell Science, vol. 113, no. 1, pp. 123–134, 2000. View at Scopus
  83. V. A. Tkachuk, O. S. Plekhanova, and Y. V. Parfyonova, “Regulation of arterial remodeling and angiogenesis by urokinase-type plasminogen activator,” Canadian Journal of Physiology and Pharmacology, vol. 87, no. 4, pp. 231–251, 2009. View at Publisher · View at Google Scholar · View at Scopus
  84. L. A. Miles, S. Lighvani, N. Baik et al., “The plasminogen receptor, Plg-R(KT), and macrophage function,” Journal of Biomedicine and Biotechnology, vol. 2012, Article ID 250464, 14 pages, 2012. View at Publisher · View at Google Scholar
  85. A. Díaz-Ramos, A. Roig-Borrellas, A. García-Melero, and R. López-Alemany, “α-enolase, a multifunctional protein: its role on pathophysiological situations,” Journal of Biomedicine and Biotechnology, vol. 2012, Article ID 156795, 12 pages, 2012. View at Publisher · View at Google Scholar
  86. S. Ulisse, E. Baldini, S. Sorrenti, and M. D'Armiento, “The urokinase plasminogen activator system: a target for anti-cancer therapy,” Current Cancer Drug Targets, vol. 9, no. 1, pp. 32–71, 2009. View at Publisher · View at Google Scholar · View at Scopus
  87. T. Syrovets, M. Jendrach, A. Rohwedder, A. Schüle, and T. Simmet, “Plasmin-induced expression of cytokines and tissue factor in human monocytes involves AP-1 and IKKβ-mediated NF-κB activation,” Blood, vol. 97, no. 12, pp. 3941–3950, 2001. View at Publisher · View at Google Scholar · View at Scopus
  88. L. Burysek, T. Syrovets, and T. Simmet, “The serine protease plasmin triggers expression of MCP-1 and CD40 in human primary monocytes via activation of p38 MAPK and Janus kinase (JAK)/STAT signaling pathways,” The Journal of Biological Chemistry, vol. 277, no. 36, pp. 33509–33517, 2002. View at Publisher · View at Google Scholar · View at Scopus
  89. N. Montuori, G. Rossi, and P. Ragno, “Post-transcriptional regulation of gene expression in the plasminogen activation system,” Biological Chemistry, vol. 383, no. 1, pp. 47–53, 2002. View at Publisher · View at Google Scholar · View at Scopus
  90. J. Nagamine, J. S. Lee, P. A. Menoud, and R. Nanbu, “Structure, and function of the urokinase-type plasminogen activator gene,” in Fibrinolysis in Disease, P. Glas-Greenvalt, Ed., pp. 10–120, CRC Press, Boca Raton, Fla, USA, 1995.
  91. A. Riccio, G. Grimaldi, P. Verde, G. Sebastio, S. Boast, and F. Blasi, “The human urokinase-plasminogen activator gene and its promoter,” Nucleic Acids Research, vol. 13, no. 8, pp. 2759–2771, 1985. View at Publisher · View at Google Scholar · View at Scopus
  92. I. Ibañez-Tallon, G. Caretti, F. Blasi, and M. P. Crippa, “In vivo analysis of the state of the human uPA enhancer following stimulation by TPA,” Oncogene, vol. 18, no. 18, pp. 2836–2845, 1999. View at Publisher · View at Google Scholar · View at Scopus
  93. I. Ibañez-Tallon, C. Ferrai, E. Longobardi, I. Facetti, F. Blasi, and M. P. Crippa, “Binding of Sp1 to the proximal promoter links constitutive expression of the human uPA gene and invasive potential of PC3 cells,” Blood, vol. 100, no. 9, pp. 3325–3332, 2002. View at Publisher · View at Google Scholar · View at Scopus
  94. M. P. Crippa, “Urokinase-type plasminogen activator,” International Journal of Biochemistry and Cell Biology, vol. 39, no. 4, pp. 690–694, 2007. View at Publisher · View at Google Scholar · View at Scopus
  95. J. P. Irigoyen, P. Muñoz-Cánoves, L. Montero, M. Koziczak, and Y. Nagamine, “The plasminogen activator system: biology and regulation,” Cellular and Molecular Life Sciences, vol. 56, no. 1-2, pp. 104–132, 1999. View at Scopus
  96. E. Benasciutti, G. Pagès, O. Kenzior, W. Folk, F. Blasi, and M. P. Crippa, “MAPK and JNK transduction pathways can phosphorylate Sp1 to activate the uPA minimal promoter element and endogenous gene transcription,” Blood, vol. 104, no. 1, pp. 256–262, 2004. View at Publisher · View at Google Scholar · View at Scopus
  97. P. Verde, S. Boast, A. Franze, F. Robbiati, and F. Blasi, “An upstream enhancer and a negative element in the 5′ flanking region of the human urokinase plasminogen activator gene,” Nucleic Acids Research, vol. 16, no. 22, pp. 10699–10716, 1988. View at Scopus
  98. D. D'Orazio, D. Besser, R. Marksitzer et al., “Cooperation of two PEA3/AP1 sites in uPA gene induction by TPA and FGF-2,” Gene, vol. 201, no. 1-2, pp. 179–187, 1997. View at Publisher · View at Google Scholar · View at Scopus
  99. S. K. Hansen, C. Nerlov, U. Zabel et al., “A novel complex between the p65 subunit of NF-κB and c-Rel binds to a DNA element involved in the phorbol ester induction of the human urokinase gene,” EMBO Journal, vol. 11, no. 1, pp. 205–213, 1992. View at Scopus
  100. W. Wang, J. L. Abbruzzese, D. B. Evans, and P. J. Chiao, “Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA,” Oncogene, vol. 18, no. 32, pp. 4554–4563, 1999. View at Publisher · View at Google Scholar · View at Scopus
  101. P. Pakneshan, B. Têtu, and S. A. Rabbani, “Demethylation of urokinase promoter as a prognostic marker in patients with breast carcinoma,” Clinical Cancer Research, vol. 10, no. 9, pp. 3035–3041, 2004. View at Publisher · View at Google Scholar · View at Scopus
  102. V. Villar, J. Kocic, D. Bugarski, G. Jovcic, and J. F. Santibanez, “SKIP is required for TGF-β1-induced epithelial mesenchymal transition and migration in transformed keratinocytes,” FEBS Letters, vol. 584, no. 22, pp. 4586–4592, 2010. View at Publisher · View at Google Scholar · View at Scopus
  103. M. Koziczak, W. Krek, and Y. Nagamine, “Pocket protein-independent repression of urokinase-type plasminogen activator and plasminogen activator inhibitor 1 gene expression by E2F1,” Molecular and Cellular Biology, vol. 20, no. 6, pp. 2014–2022, 2000. View at Publisher · View at Google Scholar · View at Scopus
  104. H. Allgayer, “Molecular regulation of an invasion-related molecule—options for tumour staging and clinical strategies,” European Journal of Cancer, vol. 42, no. 7, pp. 811–819, 2006. View at Publisher · View at Google Scholar · View at Scopus
  105. H. Wang, J. Skibber, J. Juarez, and D. Boyd, “Transcriptional activation of the urokinase receptor gene in invasive colon cancer,” International Journal of Cancer, vol. 58, no. 5, pp. 650–657, 1994. View at Scopus
  106. E. Soravia, A. Grebe, P. de Luca et al., “A conserved TATA-less proximal promoter drives basal transcription from the urokinase-type plasminogen activator receptor gene,” Blood, vol. 86, no. 2, pp. 624–635, 1995. View at Scopus
  107. R. Gum, J. Juarez, H. Allgayer, A. Mazar, Y. Wang, and D. Boyd, “PMA requires JNK1-dependent and -independent signaling modules,” Oncogene, vol. 17, no. 2, pp. 213–225, 1998. View at Scopus
  108. E. Lengyel, H. Wang, E. Stepp et al., “Requirement of an upstream AP-1 motif for the constitutive and phorbol ester-inducible expression of the urokinase-type plasminogen activator receptor gene,” The Journal of Biological Chemistry, vol. 271, no. 38, pp. 23176–23184, 1996. View at Publisher · View at Google Scholar · View at Scopus
  109. B. Krishnamachary, S. Berg-Dixon, B. Kelly et al., “Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1,” Cancer Research, vol. 63, no. 5, pp. 1138–1143, 2003. View at Scopus
  110. J. Rius, M. Guma, C. Schachtrup et al., “NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α,” Nature, vol. 453, no. 7196, pp. 807–811, 2008. View at Publisher · View at Google Scholar · View at Scopus
  111. Y. Wang, J. Dang, H. Wang, H. Allgayer, G. A. C. Murrell, and D. Boyd, “Identification of a novel nuclear factor-κB sequence involved in expression of urokinase-type plasminogen activator receptor,” European Journal of Biochemistry, vol. 267, no. 11, pp. 3248–3254, 2000. View at Publisher · View at Google Scholar · View at Scopus
  112. H. Wang, L. Yang, S. Jamaluddin, and D. D. Boyd, “The Kruppel-like KLF4 transcription factor, a novel regulator of urokinase receptor expression, drives synthesis of this binding site in colonic crypt luminal surface epithelial cells,” The Journal of Biological Chemistry, vol. 279, no. 21, pp. 22674–22683, 2004. View at Publisher · View at Google Scholar · View at Scopus
  113. B. Mann, M. Gelos, A. Siedow et al., “Target genes of β-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 4, pp. 1603–1608, 1999. View at Publisher · View at Google Scholar · View at Scopus
  114. K. Rother, C. Johne, K. Spiesbach et al., “Identification of Tcf-4 as a transcriptional target of p53 signalling,” Oncogene, vol. 23, no. 19, pp. 3376–3384, 2004. View at Publisher · View at Google Scholar · View at Scopus
  115. M. Kida, S. Wakabayashi, and A. Ichinose, “Characterization of the 5′-flanking regions of plasminogen-related genes A and B,” FEBS Letters, vol. 404, no. 1, pp. 95–99, 1997. View at Publisher · View at Google Scholar · View at Scopus
  116. G. Meroni, G. Buraggi, R. Mantovani, and R. Taramelli, “Motifs resembling hepatocyte nuclear factor 1 and activator protein 3 mediate the tissue specificity of the human plasminogen gene,” European Journal of Biochemistry, vol. 236, no. 2, pp. 373–382, 1996. View at Scopus
  117. G. R. Jenkins, D. Seiffert, R. J. Parmer, and L. A. Miles, “Regulation of plasminogen gene expression by interleukin-6,” Blood, vol. 89, no. 7, pp. 2394–2403, 1997. View at Scopus
  118. F. G. Bannach, A. Gutierrez-Fernandez, R. J. Parmer, and L. A. Miles, “Interleukin-6-induced plasminogen gene expression in murine hepatocytes is mediated by transcription factor CCAAT/enhancer binding protein β (C/EBPβ),” Journal of Thrombosis and Haemostasis, vol. 2, no. 12, pp. 2205–2212, 2004. View at Publisher · View at Google Scholar · View at Scopus
  119. A. Gutiérrez-Fernández, R. J. Parmer, and L. A. Miles, “Plasminogen gene expression is regulated by nerve growth factor,” Journal of Thrombosis and Haemostasis, vol. 5, no. 8, pp. 1715–1725, 2007. View at Publisher · View at Google Scholar · View at Scopus
  120. J. Keski-Oja, F. Blasi, E. B. Leof, and H. L. Moses, “Regulation of the synthesis and activity of urokinase plasminogen activator in A549 human lung carcinoma cells by transforming growth factor-β,” Journal of Cell Biology, vol. 106, no. 2, pp. 451–459, 1988. View at Scopus
  121. B. I. Gerwin, J. Keski-Oja, M. Seddon, L. F. Lechner, and C. C. Harris, “TGF-β1 modulation of urokinase and PAI-1 expression in human bronchial epithelial cells,” The American Journal of Physiology, vol. 259, no. 4, pp. L262–L269, 1990. View at Scopus
  122. E. H. Allan, R. Zeheb, T. D. Gelehrter et al., “Transforming growth factor β inhibits plasminogen activator (PA) activity and stimulates production of urokinase-type PA, PA inhibitor-1 mRNA, and protein in rat osteoblast-like cells,” Journal of Cellular Physiology, vol. 149, no. 1, pp. 34–43, 1991. View at Scopus
  123. F. W. Fawthrop, B. O. Oyajobi, R. A. D. Bunning, and R. G. G. Russell, “The effect of transforming growth factor β on the plasminogen activator activity of normal human osteoblast-like cells and a human osteosarcoma cell line MG-63,” Journal of Bone and Mineral Research, vol. 7, no. 12, pp. 1363–1371, 1992. View at Scopus
  124. D. J. Falcone, T. A. McCaffrey, A. Haimovitz-Friedman, and M. Garcia, “Transforming growth factor-β1 stimulates macrophage urokinase expression and release of matrix-bound basic fibroblast growth factor,” Journal of Cellular Physiology, vol. 155, no. 3, pp. 595–605, 1993. View at Publisher · View at Google Scholar · View at Scopus
  125. S. S. Park, L. Li, T. S. Korn, M. M. Mitra, and J. Y. Niederkorn, “Effect of transforming growth factor-β on plasminogen activator production of cultured human uveal melanoma cells,” Current Eye Research, vol. 15, no. 7, pp. 755–763, 1996. View at Scopus
  126. C. H. Graham, “Effect of transforming growth factor-β on the plasminogen activator system in cultured first trimester human cytotrophoblasts,” Placenta, vol. 18, no. 2-3, pp. 137–143, 1997. View at Publisher · View at Google Scholar · View at Scopus
  127. A. R. Farina, A. Coppa, A. Tiberio et al., “Transforming growth factor-β1 enhances the invasiveness of human MDA-MB-231 breast cancer cells by up-regulating urokinase activity,” International Journal of Cancer, vol. 75, no. 5, pp. 721–730, 1998. View at Publisher · View at Google Scholar
  128. J. F. Santibáñez, P. Frontelo, M. Iglesias, J. Martínez, and M. Quintanilla, “Urokinase expression and binding activity associated with the transforming growth factor β1-induced migratory and invasive phenotype of mouse epidermal keratinocytes,” Journal of Cellular Biochemistry, vol. 74, no. 1, pp. 61–73, 1999. View at Publisher · View at Google Scholar
  129. J. F. Santibáñez, M. Iglesias, P. Frontelo, J. Martínez, and M. Quintanilla, “Involvement of the Ras/MAPK signaling pathway in the modulation of urokinase production and cellular invasiveness by transforming growth factor-β1 in transformed keratinocytes,” Biochemical and Biophysical Research Communications, vol. 273, no. 2, pp. 521–527, 2000. View at Publisher · View at Google Scholar · View at Scopus
  130. J. F. Santibañez, “JNK mediates TGF-β1-induced epithelial mesenchymal transdifferentiation of mouse transformed keratinocytes,” FEBS Letters, vol. 580, no. 22, pp. 5385–5391, 2006. View at Publisher · View at Google Scholar · View at Scopus
  131. N. Tobar, V. Villar, and J. F. Santibanez, “ROS-NFκΒ mediates TGF-β1-induced expression of urokinase-type plasminogen activator, matrix metalloproteinase-9 and cell invasion,” Molecular and Cellular Biochemistry, vol. 340, no. 1-2, pp. 195–202, 2010. View at Publisher · View at Google Scholar · View at Scopus
  132. J. Kocic, D. Bugarski, and J. F. Santibanez, “SMAD3 is essential for transforming growth factor-β1-induced urokinase type plasminogen activator expression and migration in transformed keratinocytes,” European Journal of Cancer, vol. 48, no. 10, pp. 1550–1557, 2012. View at Publisher · View at Google Scholar · View at Scopus
  133. S. R. Shiou, P. K. Datta, P. Dhawan et al., “Smad4-dependent regulation of urokinase plasminogen activator secretion and RNA stability associated with invasiveness by autocrine and paracrine transforming growth factor-β,” The Journal of Biological Chemistry, vol. 281, no. 45, pp. 33971–33981, 2006. View at Publisher · View at Google Scholar · View at Scopus
  134. I. Schwarte-Waldhoff, S. Klein, S. Blass-Kampmann et al., “DPC4/SMAD4 mediated tumor suppression of colon carcinoma cells is associated with reduced urokinase expression,” Oncogene, vol. 18, no. 20, pp. 3152–3158, 1999. View at Publisher · View at Google Scholar · View at Scopus
  135. Y. Nagamine, R. L. Medcaf, and P. Muñoz-Cánoves, “Transcriptional and posttranscriptional regulation of the plasminogen activator system,” Thrombosis and Haemostasis, vol. 93, pp. 661–675, 2005.
  136. M. R. Hassler and G. Egger, “Epigenomics of cancer—emerging new concepts,” Biochimie, vol. 94, no. 11, pp. 2219–2230, 2012. View at Publisher · View at Google Scholar
  137. P. A. Marks, R. A. Rifkind, V. M. Richon, and R. Breslow, “Inhibitors of histone deacetylase are potentially effective anticancer agents,” Clinical Cancer Research, vol. 7, no. 4, pp. 759–760, 2001. View at Scopus
  138. S. M. K. Pulukuri, N. Estes, J. Patel, and J. S. Rao, “Demethylation-linked activation of urokinase plasminogen activator is involved in progression of prostate cancer,” Cancer Research, vol. 67, no. 3, pp. 930–939, 2007. View at Publisher · View at Google Scholar · View at Scopus
  139. S. M. K. Pulukuri, B. Gorantla, and J. S. Rao, “Inhibition of histone deacetylase activity promotes invasion of human cancer cells through activation of urokinase plasminogen activator,” The Journal of Biological Chemistry, vol. 282, no. 49, pp. 35594–35603, 2007. View at Publisher · View at Google Scholar · View at Scopus
  140. S. Chauhan and D. D. Boyd, “Regulation of u-PAR gene expression by H2A.Z is modulated by the MEK-ERK/AP-1 pathway,” Nucleic Acids Research, vol. 40, no. 2, pp. 600–613, 2012. View at Publisher · View at Google Scholar · View at Scopus
  141. P. Papageorgis, A. W. Lambert, S. Ozturk et al., “Smad signaling is required to maintain epigenetic silencing during breast cancer progression,” Cancer Research, vol. 70, no. 3, pp. 968–978, 2010. View at Publisher · View at Google Scholar · View at Scopus
  142. M. Blumenberg, S. Gao, K. Dickman, A. P. Grollman, E. P. Bottinger, and J. Zavadil, “Chromatin structure regulation in transforming growth factor-β-directed epithelial-mesenchymal transition,” Cells Tissues Organs, vol. 185, no. 1-3, pp. 162–174, 2007. View at Publisher · View at Google Scholar · View at Scopus
  143. J. P. Annes, J. S. Munger, and D. B. Rifkin, “Making sense of latent TGFβ activation,” Journal of Cell Science, vol. 116, part 2, pp. 217–224, 2003. View at Publisher · View at Google Scholar · View at Scopus
  144. M. Quintanilla, G. del Castillo, J. Kocic, and J. F. Santibanez, “TGF-B and MMPs: a complex regulatory loop involved in tumor progression,” in Matrix Metalloproteinases: Biology, Functions and Clinical Implications, N. Oshiro and E. Miyagi, Eds., Nova Science, New York, NY, USA, 2012.
  145. K. Janssens, P. ten Dijke, S. Janssens, and W. van Hul, “Transforming growth factor-β1 to the bone,” Endocrine Reviews, vol. 26, no. 6, pp. 743–774, 2005. View at Publisher · View at Google Scholar · View at Scopus
  146. J. Taipale, K. Miyazono, C. H. Heldin, and J. Keski-Oja, “Latent transforming growth factor-β1 associates to fibroblast extracellular matrix via latent TGF-β binding protein,” Journal of Cell Biology, vol. 124, no. 1-2, pp. 171–181, 1994. View at Scopus
  147. Q. Yu and I. Stamenkovic, “Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis,” Genes and Development, vol. 14, no. 2, pp. 163–176, 2000. View at Scopus
  148. S. L. Dallas, J. L. Rosser, G. R. Mundy, and L. F. Bonewald, “Proteolysis of latent transforming growth factor-β (TGF-β)-binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-β from bone matrix,” The Journal of Biological Chemistry, vol. 277, no. 24, pp. 21352–21360, 2002. View at Publisher · View at Google Scholar · View at Scopus
  149. M. Hyytiäinen, C. Penttinen, and J. Keski-Oja, “Latent TGF-β binding proteins: extracellular matrix association and roles in TGF-β activation,” Critical Reviews in Clinical Laboratory Sciences, vol. 41, no. 3, pp. 233–264, 2004. View at Publisher · View at Google Scholar · View at Scopus
  150. D. B. Rifkin, “Latent transforming growth factor-β (TGF-β) binding proteins: orchestrators of TGF-β availability,” The Journal of Biological Chemistry, vol. 280, no. 9, pp. 7409–7412, 2005. View at Publisher · View at Google Scholar · View at Scopus
  151. P. D. Brown, L. M. Wakefield, A. D. Levinson, and M. B. Sporn, “Physicochemical activation of recombinant latent transforming growth factor-β's 1,2 and 3,” Growth Factors, vol. 3, no. 1, pp. 35–43, 1990. View at Scopus
  152. P. Jullien, T. M. Berg, and D. A. Lawrence, “Acidic cellular environments: activation of latent TGF-β and sensitization of cellular responses to TGF-β and EGF,” International Journal of Cancer, vol. 43, no. 5, pp. 886–891, 1989. View at Scopus
  153. M. H. Barcellos-Hoff and T. A. Dix, “Redox-mediated activation of latent transforming growth factor-β1,” Molecular Endocrinology, vol. 10, no. 9, pp. 1077–1083, 1996. View at Publisher · View at Google Scholar · View at Scopus
  154. M. Horiguchi, M. Ota, and D. B. Rifkin, “Matrix control of transforming growth factor-β function,” Journal of Biochemistry, vol. 152, no. 4, pp. 321–329, 2012.
  155. Y. Sato, R. Tsuboi, R. Lyons, H. Moses, and D. B. Rifkin, “Characterization of the activation of latent TGF-β by co-cultures of endothelial cells and pericytes or smooth muscle cells: a self-regulating system,” Journal of Cell Biology, vol. 111, no. 2, pp. 757–763, 1990. View at Publisher · View at Google Scholar · View at Scopus
  156. I. Nunes, R. L. Shapiro, and D. B. Rifkin, “Characterization of latent TGF-β activation by murine peritoneal macrophages,” Journal of Immunology, vol. 155, no. 3, pp. 1450–1459, 1995. View at Scopus
  157. P. A. Dennis and D. B. Rifkin, “Cellular activation of latent transforming growth factor β requires binding to the cation-independent mannose 6-phosphate/insulin-like growth factor type II receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 2, pp. 580–584, 1991. View at Publisher · View at Google Scholar · View at Scopus
  158. S. Godár, V. Hořejší, U. H. Weidle, B. R. Binder, C. Hansmann, and H. Stockinger, “M6P/IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-β1,” European Journal of Immunology, vol. 29, no. 3, pp. 1004–1013, 1999. View at Scopus
  159. L. E. Odekon, F. Blasi, and D. B. Rifkin, “Requirement for receptor-bound urokinase in plasmin-dependent cellular conversion of latent TGF-β to TGF-β,” Journal of Cellular Physiology, vol. 158, no. 3, pp. 398–407, 1994. View at Scopus
  160. G. Jenkins, “The role of proteases in transforming growth factor-β activation,” International Journal of Biochemistry and Cell Biology, vol. 40, no. 6-7, pp. 1068–1078, 2008. View at Publisher · View at Google Scholar · View at Scopus
  161. S. Launay, E. Maubert, N. Lebeurrier et al., “HtrA1-dependent proteolysis of TGF-β controls both neuronal maturation and developmental survival,” Cell Death and Differentiation, vol. 15, no. 9, pp. 1408–1416, 2008. View at Publisher · View at Google Scholar · View at Scopus
  162. J. P. Thiery, “Epithelial-mesenchymal transitions in development and pathologies,” Current Opinion in Cell Biology, vol. 15, no. 6, pp. 740–746, 2003. View at Publisher · View at Google Scholar · View at Scopus
  163. S. A. Mani, W. Guo, M. J. Liao et al., “The epithelial-mesenchymal transition generates cells with properties of stem cells,” Cell, vol. 133, no. 4, pp. 704–715, 2008. View at Publisher · View at Google Scholar · View at Scopus
  164. C. H. Heldin, M. Vanlandewijck, and A. Moustakas, “Regulation of EMT by TGFβ in cancer,” FEBS Letters, vol. 586, no. 14, pp. 1959–1970, 2012. View at Publisher · View at Google Scholar · View at Scopus
  165. A. Moustakas and C. H. Heldin, “The regulation of TGFβ signal transduction,” Development, vol. 136, no. 22, pp. 3699–3714, 2009. View at Publisher · View at Google Scholar · View at Scopus
  166. P. Juárez and T. A. Guise, “TGF-β in cancer and bone: implications for treatment of bone metastases,” Bone, vol. 48, no. 1, pp. 23–29, 2011. View at Publisher · View at Google Scholar · View at Scopus
  167. J. P. Thiery, H. Acloque, R. Y. J. Huang, and M. A. Nieto, “Epithelial-mesenchymal transitions in development and disease,” Cell, vol. 139, no. 5, pp. 871–890, 2009. View at Publisher · View at Google Scholar · View at Scopus
  168. G. Moreno-Bueno, H. Peinado, P. Molina et al., “The morphological and molecular features of the epithelial-to-mesenchymal transition,” Nature Protocols, vol. 4, no. 11, pp. 1591–1613, 2009. View at Scopus
  169. K. Garber, “Epithelial-to-mesenchymal transition is important to metastasis, but questions remain,” Journal of the National Cancer Institute, vol. 100, no. 4, pp. 232–239, 2008. View at Publisher · View at Google Scholar · View at Scopus
  170. A. Voulgari and A. Pintzas, “Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic,” Biochimica et Biophysica Acta, vol. 1796, no. 2, pp. 75–90, 2009. View at Publisher · View at Google Scholar · View at Scopus
  171. T. Masaki, A. Goto, M. Sugiyama et al., “Possible contribution of CD44 variant 6 and nuclear β-catenin expression to the formation of budding tumor cells in patients with T1 colorectal carcinoma,” Cancer, vol. 92, no. 10, pp. 2539–2546, 2001. View at Publisher · View at Google Scholar
  172. M. Iwatsuki, K. Mimori, T. Yokobori et al., “Epithelial-mesenchymal transition in cancer development and its clinical significance,” Cancer Science, vol. 101, no. 2, pp. 293–299, 2010. View at Publisher · View at Google Scholar · View at Scopus
  173. R. Kalluri and R. A. Weinberg, “The basics of epithelial-mesenchymal transition,” Journal of Clinical Investigation, vol. 119, no. 6, pp. 1420–1428, 2009. View at Publisher · View at Google Scholar · View at Scopus
  174. P. Juárez and T. A. Guise, “TGF-β in cancer and bone: implications for treatment of bone metastases,” Bone, vol. 48, no. 1, pp. 23–29, 2011. View at Publisher · View at Google Scholar · View at Scopus
  175. J. Zavadil and E. P. Böttinger, “TGF-β and epithelial-to-mesenchymal transitions,” Oncogene, vol. 24, no. 37, pp. 5764–5774, 2005. View at Publisher · View at Google Scholar · View at Scopus
  176. M. Deckers, M. van Dinther, J. Buijs et al., “The tumor suppressor Smad4 is required for transforming growth factor β-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells,” Cancer Research, vol. 66, no. 4, pp. 2202–2209, 2006. View at Publisher · View at Google Scholar · View at Scopus
  177. A. B. Roberts, F. Tian, S. D. Byfield et al., “Smad3 is key to TGF-β-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis,” Cytokine and Growth Factor Reviews, vol. 17, no. 1-2, pp. 19–27, 2006. View at Publisher · View at Google Scholar · View at Scopus
  178. K. E. Hoot, J. Lighthall, G. Han et al., “Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression,” Journal of Clinical Investigation, vol. 118, no. 8, pp. 2722–2732, 2008. View at Publisher · View at Google Scholar · View at Scopus
  179. J. F. Santibáñez, J. Kocić, A. Fabra, A. Cano, and M. Quintanilla, “Rac1 modulates TGF-β1-mediated epithelial cell plasticity and MMP9 production in transformed keratinocytes,” FEBS Letters, vol. 584, no. 11, pp. 2305–2310, 2010. View at Publisher · View at Google Scholar · View at Scopus
  180. A. Cano, M. A. Pérez-Moreno, I. Rodrigo et al., “The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression,” Nature Cell Biology, vol. 2, no. 2, pp. 76–83, 2000. View at Publisher · View at Google Scholar · View at Scopus
  181. A. Boutet, C. A. de Frutos, P. H. Maxwell, M. J. Mayol, J. Romero, and M. A. Nieto, “Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney,” EMBO Journal, vol. 25, no. 23, pp. 5603–5613, 2006. View at Publisher · View at Google Scholar · View at Scopus
  182. J. G. Lyons, V. Patel, N. C. Roue et al., “Snail up-regulates proinflammatory mediators and inhibits differentiation in oral keratinocytes,” Cancer Research, vol. 68, no. 12, pp. 4525–4530, 2008. View at Publisher · View at Google Scholar · View at Scopus
  183. M. Jo, S. Takimoto, V. Montel, and S. L. Gonias, “The urokinase receptor promotes cancer metastasis independently of urokinase-type plasminogen activator in mice,” The American Journal of Pathology, vol. 175, no. 1, pp. 190–200, 2009. View at Publisher · View at Google Scholar · View at Scopus
  184. R. D. Lester, M. Jo, V. Montel, S. Takimoto, and S. L. Gonias, “uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells,” Journal of Cell Biology, vol. 178, no. 3, pp. 425–436, 2007. View at Publisher · View at Google Scholar · View at Scopus
  185. R. Gupta, C. Chetty, P. Bhoopathi et al., “Downregulation of uPA/uPAR inhibits intermittent hypoxia-induced epithelial-mesenchymal transition (EMT) in DAOY and D283 medulloblastoma cells,” International Journal of Oncology, vol. 38, no. 3, pp. 733–744, 2011. View at Publisher · View at Google Scholar · View at Scopus
  186. M. Jo, B. M. Eastman, D. L. Webb, K. Stoletov, R. Klemke, and S. L. Gonias, “Cell signaling by urokinase-type plasminogen activator receptor induces stem cell-like properties in breast cancer cells,” Cancer Research, vol. 70, no. 21, pp. 8948–8958, 2010. View at Publisher · View at Google Scholar · View at Scopus
  187. J. F. Santibáñez, P. Frontelo, M. Iglesias, J. Martínez, and M. Quintanilla, “Urokinase expression and binding activity associated with the transforming growth factor β1-induced migratory and invasive phenotype of mouse epidermal keratinocytes,” Journal of Cellular Biochemistry, vol. 74, no. 1, pp. 61–73, 1999. View at Publisher · View at Google Scholar
  188. V. R. Gogineni, R. Gupta, A. K. Nalla, K. K. Velpula, and J. S. Rao, “uPAR and cathepsin B shRNA impedes TGF-β1-driven proliferation and invasion of meningioma cells in a XIAP-dependent pathway,” Cell Death and Disease, vol. 3, article e439, 2012. View at Publisher · View at Google Scholar
  189. M. Chovanec, K. Smetana Jr., J. Betka et al., “Correlation of expression of nuclear proteins pKi67 and p63 with lectin histochemical features in head and neck squamous cell cancer,” International Journal of Oncology, vol. 27, no. 2, pp. 409–415, 2005. View at Scopus
  190. J. J. Christiansen and A. K. Rajasekaran, “Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis,” Cancer Research, vol. 66, no. 17, pp. 8319–8326, 2006. View at Publisher · View at Google Scholar · View at Scopus
  191. S. Geng, Y. Guo, Q. Wang, L. Li, and J. Wang, “Cancer stem-like cells enriched with CD29 and CD44 markers exhibit molecular characteristics with epithelial-mesenchymal transition in squamous cell carcinoma,” Archives of Dermatological Research, vol. 305, no. 1, pp. 35–47, 2013. View at Publisher · View at Google Scholar
  192. H. Iwata, Y. Aoyama, H. Kamiya, Y. Ichiki, and Y. Kitajima, “Spindle cell squamous cell carcinoma showing epithelial-mesenchymal transition,” Journal of the European Academy of Dermatology and Venereology, vol. 23, no. 2, pp. 214–215, 2009. View at Publisher · View at Google Scholar · View at Scopus
  193. M. Nakamura, K. Sugita, and Y. Tokura, “Expression of Snail1 in the vimentin-expressing squamous cell carcinoma mimicking atypical fibroxanthoma: possible involvement of an epithelial-mesenchymal transition,” Journal of the European Academy of Dermatology and Venereology, vol. 24, no. 11, pp. 1365–1366, 2010. View at Publisher · View at Google Scholar · View at Scopus
  194. H. Chen, M. Takahara, L. Xie et al., “Levels of the EMT-related protein Snail/Slug are not correlated with p53/p63 in cutaneous squamouscell carcinoma,” Journal of Cutaneous Pathology, vol. 40, no. 7, pp. 651–656, 2013. View at Publisher · View at Google Scholar
  195. T. J. Jang, “Epithelial to mesenchymal transition in cutaneous squamous cell carcinoma is correlated with COX-2 expression but not with the presence of stromal macrophages or CD10-expressing cells,” Virchows Archiv, vol. 460, no. 5, pp. 481–487, 2012. View at Publisher · View at Google Scholar · View at Scopus
  196. L. Chin, L. A. Garraway, and D. E. Fisher, “Malignant melanoma: genetics and therapeutics in the genomic era,” Genes and Development, vol. 20, no. 16, pp. 2149–2182, 2006. View at Publisher · View at Google Scholar · View at Scopus
  197. A. J. Miller and M. C. Mihm Jr., “Melanoma,” The New England Journal of Medicine, vol. 355, no. 1, pp. 51–65, 2006. View at Publisher · View at Google Scholar · View at Scopus
  198. M. Y. Hsu, F. E. Meier, M. Nesbit et al., “E-cadherin expression in melanoma cells restores keratinocyte-mediated growth control and down-regulates expression of invasion-related adhesion receptors,” The American Journal of Pathology, vol. 156, no. 5, pp. 1515–1525, 2000. View at Scopus
  199. K. Hoek, D. L. Rimm, K. R. Williams et al., “Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas,” Cancer Research, vol. 64, no. 15, pp. 5270–5282, 2004. View at Publisher · View at Google Scholar · View at Scopus
  200. R. Bauer, R. Hein, and A. K. Bosserhoff, “A secreted form of P-cadherin is expressed in malignant melanoma,” Experimental Cell Research, vol. 305, no. 2, pp. 418–426, 2005. View at Publisher · View at Google Scholar · View at Scopus
  201. S. Kuphal, A. C. Martyn, J. Pedley et al., “H-Cadherin expression reduces invasion of malignant melanoma,” Pigment Cell and Melanoma Research, vol. 22, no. 3, pp. 296–306, 2009. View at Publisher · View at Google Scholar · View at Scopus
  202. N. Fenouille, M. Tichet, M. Dufies et al., “The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion,” PLoS ONE, vol. 7, no. 7, Article ID e40378, 2012.
  203. S. H. Shirley, V. R. Greene, L. M. Duncan, C. A. T. Cabala, E. A. Grimm, and D. F. Kusewitt, “Slug expression during melanoma progression,” The American Journal of Pathology, vol. 180, no. 6, pp. 2479–2489, 2012. View at Publisher · View at Google Scholar
  204. N. K. Haass and M. Herlyn, “Normal human melanocyte homeostasis as a paradigm for understanding melanoma,” The Journal of Investigative Dermatology, Symposium Proceedings, vol. 10, no. 2, pp. 153–163, 2005. View at Scopus
  205. N. Bonitsis, A. Batistatou, S. Karantima, and K. Charalabopoulos, “The role of cadherin/catenin complex in malignant melanoma,” Experimental Oncology, vol. 28, no. 3, pp. 187–193, 2006. View at Scopus
  206. S. R. Alonso, L. Tracey, P. Ortiz et al., “A high-throughput study in melanoma identifies epithelial-mesenchymal transition as a major determinant of metastasis,” Cancer Research, vol. 67, no. 7, pp. 3450–3460, 2007. View at Publisher · View at Google Scholar · View at Scopus
  207. S. Barrientos, O. Stojadinovic, M. S. Golinko, H. Brem, and M. Tomic-Canic, “Growth factors and cytokines in wound healing,” Wound Repair and Regeneration, vol. 16, no. 5, pp. 585–601, 2008. View at Publisher · View at Google Scholar · View at Scopus
  208. C. J. M. Kane, P. A. Hebda, J. N. Mansbridge, and P. C. Hanawalt, “Direct evidence for spatial and temporal regulation of transforming growth factor β1 expression during cutaneous wound healing,” Journal of Cellular Physiology, vol. 148, no. 1, pp. 157–173, 1991. View at Scopus
  209. R. A. F. Clark, Ed., The Molecular and Cellular Biology of Wound Repair, Plenum Press, New York, NY, USA, 2nd edition, 1996.
  210. S. Tsunawaki, M. Sporn, A. Ding, and C. Nathan, “Deactivation of macrophages by transforming growth factor-β,” Nature, vol. 334, no. 6179, pp. 260–262, 1988. View at Scopus
  211. A. Juncker-Jensen and L. R. Lund, “Phenotypic overlap between MMP-13 and the plasminogen activation system during wound healing in mice,” PLoS ONE, vol. 6, no. 2, Article ID e16954, 2011. View at Publisher · View at Google Scholar · View at Scopus
  212. J. W. Tyrone, J. R. Marcus, S. R. Bonomo, J. E. Mogford, Y. Xia, and T. A. Mustoe, “Transforming growth factor β3 promotes fascial wound healing in a new animal model,” Archives of Surgery, vol. 135, no. 10, pp. 1154–1159, 2000. View at Scopus
  213. C. Moali and D. J. S. Hulmes, “Extracellular and cell surface proteases in wound healing: new players are still emerging,” European Journal of Dermatology, vol. 19, no. 6, pp. 552–564, 2009. View at Publisher · View at Google Scholar · View at Scopus
  214. P. Carmeliet, L. Schoonjans, L. Kieckens et al., “Physiological consequences of loss of plasminogen activator gene function in mice,” Nature, vol. 368, no. 6470, pp. 419–424, 1994. View at Publisher · View at Google Scholar · View at Scopus
  215. L. R. Lund, K. A. Green, A. A. Stoop et al., “Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice,” EMBO Journal, vol. 25, no. 12, pp. 2686–2697, 2006. View at Publisher · View at Google Scholar · View at Scopus
  216. P. L. Leopold, J. Vincent, and H. Wang, “A comparison of epithelial-to-mesenchymal transition and re-epithelialization,” Seminars in Cancer Biology, vol. 22, no. 5-6, pp. 471–483, 2012. View at Publisher · View at Google Scholar
  217. E. L. Abel, J. M. Angel, K. Kiguchi, and J. DiGiovanni, “Multi-stage chemical carcinogenesis in mouse skin: fundamentals and applications,” Nature Protocols, vol. 4, no. 9, pp. 1350–1362, 2009. View at Publisher · View at Google Scholar · View at Scopus
  218. M. Schwarz, P. A. Münzel, and A. Braeuning, “Non-melanoma skin cancer in mouse and man,” Archives of Toxicology, vol. 87, no. 5, pp. 783–798, 2013. View at Publisher · View at Google Scholar
  219. E. Pérez-Gómez, G. Del Castillo, J. F. Santibanez, J. M. López-Novoa, C. Bernabéu, and M. Quintanilla, “The role of the TGF-β coreceptor endoglin in cancer,” The Scientific World Journal, vol. 10, pp. 2367–2384, 2010. View at Publisher · View at Google Scholar
  220. M. Quintanilla, K. Brown, M. Ramsden, and A. Balmain, “Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis,” Nature, vol. 322, no. 6074, pp. 78–80, 1986. View at Scopus
  221. A. G. Li, S. L. Lu, M. X. Zhang, C. Deng, and X. J. Wang, “Smad3 knockout mice exhibit a resistance to skin chemical carcinogenesis,” Cancer Research, vol. 64, no. 21, pp. 7836–7845, 2004. View at Publisher · View at Google Scholar · View at Scopus
  222. B. Patamalai, D. L. Burrow, I. Gimenez-Conti et al., “Altered expression of transforming growth factor-β1 mRNA and protein in mouse skin carcinogenesis,” Molecular Carcinogenesis, vol. 9, no. 4, pp. 220–229, 1994. View at Publisher · View at Google Scholar · View at Scopus
  223. W. Cui, D. J. Fowlis, S. Bryson et al., “TGFβ1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice,” Cell, vol. 86, no. 4, pp. 531–542, 1996. View at Publisher · View at Google Scholar · View at Scopus
  224. B. H. Weeks, W. He, K. L. Olson, and X. J. Wang, “Inducible expression of transforming growth factor β1 in papillomas causes rapid metastasis,” Cancer Research, vol. 61, no. 20, pp. 7435–7443, 2001. View at Scopus
  225. R. J. Akhurst and A. Balmain, “Genetic events and the role of TGF-β in epithelial tumour progression,” Journal of Pathology, vol. 187, no. 1, pp. 82–90, 1999. View at Publisher · View at Google Scholar
  226. P. J. Jensen and R. M. Lavker, “Urokinase is a positive regulator of epidermal proliferation in vivo,” Journal of Investigative Dermatology, vol. 112, no. 2, pp. 240–244, 1999. View at Publisher · View at Google Scholar · View at Scopus
  227. R. Mazzieri and F. Blasi, “The urokinase receptor and the regulation of cell proliferation,” Thrombosis and Haemostasis, vol. 93, no. 4, pp. 641–646, 2005. View at Publisher · View at Google Scholar · View at Scopus
  228. L. R. Lund, J. Eriksen, E. Ralfkiær, and J. Rømer, “Differential expression of urokinase-type plasminogen activator, its receptor, and inhibitors in mouse skin after exposure to a tumor-promoting phorbol ester,” Journal of Investigative Dermatology, vol. 106, no. 4, pp. 622–630, 1996. View at Scopus
  229. J. Berkelhammer and R. W. Oxenhandler, “Evaluation of premalignant and malignant lesions during the induction of mouse melanomas,” Cancer Research, vol. 47, no. 5, pp. 1251–1254, 1987. View at Scopus
  230. R. L. Shapiro, J. G. Duquette, D. F. Roses et al., “Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals,” Cancer Research, vol. 56, no. 15, pp. 3597–3604, 1996. View at Scopus
  231. Y. Drabsch and P. ten Dijke, “TGF-β signalling and its role in cancer progression and metastasis,” Cancer and Metastasis Reviews, vol. 31, no. 3-4, pp. 553–568, 2012. View at Publisher · View at Google Scholar
  232. P. C. Smith and J. Martínez, “Differential uPA expression by TGF-β1 in gingival fibroblasts,” Journal of Dental Research, vol. 85, no. 2, pp. 150–155, 2006. View at Publisher · View at Google Scholar · View at Scopus
  233. L. M. Coussens and Z. Werb, “Inflammation and cancer,” Nature, vol. 420, no. 6917, pp. 860–867, 2002. View at Publisher · View at Google Scholar · View at Scopus
  234. V. O. Melnikova and H. N. Ananthaswamy, “Cellular and molecular events leading to the development of skin cancer,” Mutation Research, vol. 571, no. 1-2, pp. 91–106, 2005. View at Publisher · View at Google Scholar · View at Scopus
  235. S. Bornstein, K. Hoot, G. W. Han, S. L. Lu, and X. J. Wang, “Distinct roles of individual Smads in skin carcinogenesis,” Molecular Carcinogenesis, vol. 46, no. 8, pp. 660–664, 2007. View at Publisher · View at Google Scholar · View at Scopus
  236. C. L. Green and P. A. Khavari, “Targets for molecular therapy of skin cancer,” Seminars in Cancer Biology, vol. 14, no. 1, pp. 63–69, 2004. View at Publisher · View at Google Scholar · View at Scopus
  237. G. Saldanha, A. Fletcher, and D. N. Slater, “Basal cell carcinoma: a dermatopathological and molecular biological update,” The British Journal of Dermatology, vol. 148, no. 2, pp. 195–202, 2003. View at Publisher · View at Google Scholar · View at Scopus
  238. P. Schmid, P. Itin, and T. H. Rufli, “In situ analysis of transforming growth factors-β (TGF-β1, TGF-β2, TGF-β3) and TGF-β type II receptor expression in basal cell carcinomas,” The British Journal of Dermatology, vol. 134, no. 6, pp. 1044–1051, 1996. View at Scopus
  239. M. E. J. M. Verhaegh, J. Arends, I. M. L. Majoie, R. Hoekzema, and H. A. M. Neumann, “Transforming growth factor-β and bcl-2 distribution patterns distinguish trichoepithelioma from basal cell carcinoma,” Dermatologic Surgery, vol. 23, no. 8, pp. 695–700, 1997. View at Scopus
  240. M. Furue, M. Kato, K. Nakamura et al., “Dysregulated expression of transforming growth factor b and its type-I and type-II receptors in basal-cell carcinoma,” International Journal of Cancer, vol. 71, no. 4, pp. 505–509, 1997. View at Publisher · View at Google Scholar
  241. T. Gambichler, M. Skrygan, J. M. Kaczmarczyk et al., “Increased expression of TGF-β/Smad proteins in basal cell carcinoma,” European Journal of Medical Research, vol. 12, no. 10, pp. 509–514, 2007. View at Scopus
  242. Y. Shao, J. Zhang, R. Zhang, J. Wan, W. Zhang, and B. Yu, “Examination of Smad2 and Smad4 copy-number variations in skin cancers,” Clinical and Translational Oncology, vol. 14, no. 2, pp. 138–142, 2012. View at Publisher · View at Google Scholar
  243. D. Javelaud, M. J. Pierrat, and A. Mauviel, “Crosstalk between TGF-β and hedgehog signaling in cancer,” FEBS Letters, vol. 586, no. 14, pp. 2016–2025, 2012. View at Publisher · View at Google Scholar
  244. A. P. Sappino, D. Belin, J. Huarte, S. Hirschel-Scholz, J. H. Saurat, and J. D. Vassalli, “Differential protease expression by cutaneous squamous and basal cell carcinomas,” Journal of Clinical Investigation, vol. 88, no. 4, pp. 1073–1079, 1991. View at Scopus
  245. T. Maguire, D. Chin, D. Soutar, and M. J. Duffy, “Low levels of urokinase plasminogen activator components in basal cell carcinoma of the skin,” International Journal of Cancer, vol. 85, no. 4, pp. 457–459, 2000. View at Publisher · View at Google Scholar
  246. E. M. Spiers, G. S. Lazarus, and B. Lyons-Giordano, “Expression of plasminogen activators in basal cell carcinoma,” Journal of Pathology, vol. 178, no. 3, pp. 290–296, 1996. View at Publisher · View at Google Scholar
  247. M. Quintanilla, E. Pérez-Gómez, D. Romero, M. Pons, and J. Renart, “TGF-β pathway and cancerogenesis of epithelial skin tumours,” in Molecular Mechanisms of Basal Cell and Squamous Cell Carcinomas, J. Reichrath, Ed., pp. 80–93, Landes Bioscience and Springer Science, Business Media, New York, NY, USA, 2006.
  248. A. G. Li, S. L. Lu, G. W. Han, M. Kulesz-Martin, and X. J. Wang, “Current view of the role of transforming growth factor β 1 in skin carcinogenesis,” The Journal of Investigative Dermatology, Symposium Proceedings, vol. 10, no. 2, pp. 110–117, 2005. View at Scopus
  249. M. Davies, S. S. Prime, J. W. Eveson et al., “Transforming growth factor-β enhances invasion and metastasis in Ras-transfected human malignant epidermal keratinocytes,” International Journal of Experimental Pathology, vol. 93, no. 2, pp. 148–156, 2012. View at Publisher · View at Google Scholar · View at Scopus
  250. A. Ganapathy, I. C. Paterson, S. S. Prime et al., “TGF-β inhibits metastasis in late stage human squamous cell carcinoma of the skin by a mechanism that does not involve Id1,” Cancer Letters, vol. 298, no. 1, pp. 107–118, 2010. View at Publisher · View at Google Scholar · View at Scopus
  251. K. Dano, J. Romer, B. S. Nielsen et al., “Cancer invasion and tissue remodelling-cooperation of protease systems and cell types,” in Acta Pathologica, Microbiologica et Immunologica Scandinavica, vol. 107, no. 1–6, pp. 120–127, 1999. View at Publisher · View at Google Scholar
  252. J. Rømer, C. Pyke, L. R. Lund, E. Ralfkiær, and K. Danø, “Cancer cell expression of urokinase-type plasminogen activator receptor mRNA in squamous cell carcinomas of the skin,” Journal of Investigative Dermatology, vol. 116, no. 3, pp. 353–358, 2001. View at Publisher · View at Google Scholar · View at Scopus
  253. J. Keski-Oja and K. Koli, “Enhanced production of plasminogen activator activity in human and murine keratinocytes by transforming growth factor-β1,” Journal of Investigative Dermatology, vol. 99, no. 2, pp. 193–200, 1992. View at Scopus
  254. K. Räsänen and A. Vaheri, “TGF-β1 causes epithelial-mesenchymal transition in HaCaT derivatives, but induces expression of COX-2 and migration only in benign, not in malignant keratinocytes,” Journal of Dermatological Science, vol. 58, no. 2, pp. 97–104, 2010. View at Publisher · View at Google Scholar · View at Scopus
  255. K. T. Flaherty and D. E. Fisher, “New strategies in metastatic melanoma: oncogene-defined taxonomy leads to therapeutic advances,” Clinical Cancer Research, vol. 17, no. 15, pp. 4922–4928, 2011. View at Publisher · View at Google Scholar · View at Scopus
  256. D. Javelaud, V. Alexaki, and A. Mauviel, “Transforming growth factor-β in cutaneous melanoma,” Pigment Cell and Melanoma Research, vol. 21, no. 2, pp. 123–132, 2008. View at Publisher · View at Google Scholar · View at Scopus
  257. R. S. Lo and O. N. Witte, “Transforming growth factor-β activation promotes genetic context-dependent invasion of immortalized melanocytes,” Cancer Research, vol. 68, no. 11, pp. 4248–4257, 2008. View at Publisher · View at Google Scholar · View at Scopus
  258. P. Schmid, P. Itin, and T. Rufli, “In situ analysis of transforming growth factor-βs (TGF-β1, TGF-β2, TGF-β3), and TGF-β type II receptor expression in malignant melanoma,” Carcinogenesis, vol. 16, no. 7, pp. 1499–1503, 1995. View at Scopus
  259. K. Krasagakis, D. Thölke, B. Farthmann, J. Eberle, U. Mansmann, and C. E. Orfanos, “Elevated plasma levels of transforming growth factor (TGF)-β1 and TGF-β2 in patients with disseminated malignant melanoma,” The British Journal of Cancer, vol. 77, no. 9, pp. 1492–1494, 1998. View at Scopus
  260. K. S. Mohammad, D. Javelaud, P. G. J. Fournier et al., “TGF-β-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases,” Cancer Research, vol. 71, no. 1, pp. 175–184, 2011. View at Publisher · View at Google Scholar · View at Scopus
  261. D. Javelaud, V. I. Alexaki, S. Dennler, K. S. Mohammad, T. A. Guise, and A. Mauviel, “TGF-β/SMAD/GLI2 signaling axis in cancer progression and metastasis,” Cancer Research, vol. 71, no. 17, pp. 5606–5610, 2011. View at Publisher · View at Google Scholar · View at Scopus
  262. R. Besch, C. Berking, C. Kammerbauer, and K. Degitz, “Inhibition of urokinase-type plasminogen activator receptor induces apoptosis in melanoma cells by activation of p53,” Cell Death and Differentiation, vol. 14, no. 4, pp. 818–829, 2007. View at Publisher · View at Google Scholar · View at Scopus
  263. S. D'Alessio, F. Margheri, M. Pucci et al., “Antisense oligodeoxynucleotides for urokinase-plasminogen activator receptor have anti-invasive and anti-proliferative effects in vitro and inhibit spontaneous metastases of human melanoma in mice,” International Journal of Cancer, vol. 110, no. 1, pp. 125–133, 2004. View at Publisher · View at Google Scholar · View at Scopus
  264. A. Teti, A. de Giorgi, M. T. Spinella et al., “Transforming growth factor-β enhances adhesion of melanoma cells to the endothelium in vitro,” International Journal of Cancer, vol. 72, no. 6, pp. 1013–1020, 1997. View at Publisher · View at Google Scholar
  265. L. Humbert and J. J. Lebrun, “TGF-β inhibits human cutaneous melanoma cell migration and invasion through regulation of the plasminogen activator system,” Cellular Signalling, vol. 25, no. 2, pp. 490–500, 2013. View at Publisher · View at Google Scholar
  266. L. Ramont, S. Pasco, W. Hornebeck, F. Maquart, and J. C. Monboisse, “Transforming growth factor-β1 inhibits tumor growth in a mouse melanoma model by down-regulating the plasminogen activation system,” Experimental Cell Research, vol. 291, no. 1, pp. 1–10, 2003. View at Publisher · View at Google Scholar · View at Scopus
  267. H. Allgayer, “Translational research on u-PAR,” European Journal of Cancer, vol. 46, no. 7, pp. 1241–1251, 2010. View at Publisher · View at Google Scholar · View at Scopus
  268. http://clinicaltrials.gov/.
  269. M. A. Glaire, E. M. El-Omar, T. C. Wang, and D. L. Worthley, “The mesenchyme in malignancy: a partner in the initiation, progression and dissemination of cancer,” Pharmacology and Therapeutics, vol. 136, no. 2, pp. 131–141, 2012. View at Publisher · View at Google Scholar