Cancer and Metastasis Reviews

, Volume 27, Issue 1, pp 85–94 | Cite as

The Met tyrosine kinase receptor in development and cancer

  • Alessandra Gentile
  • Livio Trusolino
  • Paolo M. ComoglioEmail author


Met is a tyrosine kinase receptor, encoded by an oncogene, whose crucial role has been elucidated during the last two decades. The complex biological program triggered by Met has been dissected and its biological relevance in both physiology and pathology has been proven. Met supports a morphogenetic program, known as invasive growth, taking place both during embryogenesis and adulthood. In tumors Met is often aberrantly activated, giving rise to the pathological counterpart of the invasive growth program: cancer progression towards metastasis. Several approaches have been recently developed to interfere with the tumorigenic and metastatic processes triggered by Met.


Met HGF Tyrosine kinase receptor Metastasis “Invasive growth” 



We would like to thank Andrea Bertotti for micrographs. Work in the authors’ laboratory is supported by AIRC (Associazione Italiana per la Ricerca sul Cancro), MIUR (Ministero dell’Isruzione, Universita’ e Ricerca), Compagnia San Paolo, Fondazione Cassa di Risparmio di Torino. AG is supported by an AIRC fellowship.

Note added in Proof

During the revision of this review, another paper was published that demonstrated reduced proliferation, xenograft growth and experimental metastasis formation following shRNA-mediated down-regulation of MET in a gastric carcinoma cell line with amplification of MET gene [86].


  1. 1.
    Cooper, C. S., Park, M., Blair, D. G., Tainsky, M. A., Huebner, K., Croce, C. M., et al. (1984). Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature, 311, 29–33.PubMedCrossRefGoogle Scholar
  2. 2.
    Park, M., Testa, J. R., Blair, D. G., Parsa, N. Z., & Vande Woude, G. F. (1988). Two rearranged MET alleles in MNNG-HOS cells reveal the orientation of MET on chromosome 7 to other markers tightly linked to the cystic fibrosis locus. Proceedings of the National Academy of Sciences of the United States of America, 85, 2667–2671.PubMedCrossRefGoogle Scholar
  3. 3.
    Park, M., Dean, M., Cooper, C. S., Schmidt, M., O’Brien, S. J., Blair, D. G., et al. (1986). Mechanism of met oncogene activation. Cell, 45, 895–904.PubMedCrossRefGoogle Scholar
  4. 4.
    Soman, N. R., Wogan, G. N., & Rhim, J. S. (1990). TPR-MET oncogenic rearrangement: Detection by polymerase chain reaction amplification of the transcript and expression in human tumor cell lines. Proceedings of the National Academy of Sciences of the United States of America, 87, 738–742.PubMedCrossRefGoogle Scholar
  5. 5.
    Giordano, S., Ponzetto, C., Di Renzo, M. F., Cooper, C. S., & Comoglio, P. M. (1989). Tyrosine kinase receptor indistinguishable from the c-met protein. Nature, 339, 155–156.PubMedCrossRefGoogle Scholar
  6. 6.
    Stoker, M., Gherardi, E., Perryman, M., & Gray, J. (1987). Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature, 327, 239–242.PubMedCrossRefGoogle Scholar
  7. 7.
    Nakamura, T., Nishizawa, T., Hagiya, M., Seki, T., Shimonishi, M., Sugimura, A., et al. (1989). Molecular cloning and expression of human hepatocyte growth factor. Nature, 342, 440–443.PubMedCrossRefGoogle Scholar
  8. 8.
    Zarnegar, R., & Michalopoulos, G. (1989). Purification and biological characterization of human hepatopoietin A, a polypeptide growth factor for hepatocytes. Cancer Research, 49, 3314–3320.PubMedGoogle Scholar
  9. 9.
    Gherardi, E., & Stoker, M. (1990). Hepatocytes and scatter factor. Nature, 346, 228.PubMedCrossRefGoogle Scholar
  10. 10.
    Weidner, K. M., Arakaki, N., Hartmann, G., Vandekerckhove, J., Weingart, S., Rieder, H., et al. (1991). Evidence for the identity of human scatter factor and human hepatocyte growth factor. Proceedings of the National Academy of Sciences of the United States of America, 88, 7001–7005.PubMedCrossRefGoogle Scholar
  11. 11.
    Naldini, L., Vigna, E., Narsimhan, R. P., Gaudino, G., Zarnegar, R., Michalopoulos, G. K., et al. (1991). Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET. Oncogene, 6, 501–504.PubMedGoogle Scholar
  12. 12.
    Bottaro, D. P., Rubin, J. S., Faletto, D. L., Chan, A. M., Kmiecik, T. E., Vande Woude, G. F., et al. (1991). Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science, 251, 802–804.PubMedCrossRefGoogle Scholar
  13. 13.
    Comoglio, P. M. (2002). Trusolino L: Invasive growth: From development to metastasis. Journal of Clinical Investigation, 109, 857–862.PubMedCrossRefGoogle Scholar
  14. 14.
    Montesano, R., Matsumoto, K., Nakamura, T., & Orci, L. (1991). Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor. Cell, 67, 901–908.PubMedCrossRefGoogle Scholar
  15. 15.
    Trusolino, L., & Comoglio, P. M. (2002). Scatter-factor and semaphorin receptors: Cell signalling for invasive growth. Nature Reviews Cancer, 2, 289–300.PubMedCrossRefGoogle Scholar
  16. 16.
    Maina, F., Casagranda, F., Audero, E., Simeone, A., Comoglio, P. M., Klein, R., et al. (1996). Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development. Cell, 87, 531–542.PubMedCrossRefGoogle Scholar
  17. 17.
    Ponzetto, C., Bardelli, A., Zhen, Z., Maina, F., Dalla, Z. P., Giordano, S., et al. (1994). A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell, 77, 261–271.PubMedCrossRefGoogle Scholar
  18. 18.
    Zanetti, A., Stoppacciaro, A., Marzullo, A., Ciabatta, M., Fazioli, F., Prat, M., et al. (1998). Expression of Met protein and urokinase-type plasminogen activator receptor (uPA-R) in papillary carcinoma of the thyroid. Journal of Pathology, 186, 287–291.PubMedCrossRefGoogle Scholar
  19. 19.
    Gaudino, G., Follenzi, A., Naldini, L., Collesi, C., Santoro, M., Gallo, K. A., et al. (1994). RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. European Molecular Biology Organization Journal, 13, 3524–3532.Google Scholar
  20. 20.
    Huff, J. L., Jelinek, M. A., Borgman, C. A., Lansing, T. J., & Parsons, J. T. (1993). The protooncogene c-sea encodes a transmembrane protein-tyrosine kinase related to the Met/hepatocyte growth factor/scatter factor receptor. Proceedings of the National Academy of Sciences of the United States of America, 90, 6140–6144.PubMedCrossRefGoogle Scholar
  21. 21.
    Birchmeier, C., Birchmeier, W., Gherardi, E., & Vande Woude, G. F. (2003). Met, metastasis, motility and more. Nature Reviews. Molecular Cell Biology, 4, 915–925.PubMedCrossRefGoogle Scholar
  22. 22.
    Gandino, L., Longati, P., Medico, E., Prat, M., & Comoglio, P. M. (1994). Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase. Journal of Biological Chemistry, 269, 1815–1820.PubMedGoogle Scholar
  23. 23.
    Peschard, P., Fournier, T. M., Lamorte, L., Naujokas, M. A., Band, H., Langdon, W. Y., et al. (2001). Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Molecular Cell, 8, 995–1004.PubMedCrossRefGoogle Scholar
  24. 24.
    Furge, K. A., Zhang, Y. W., & Vande Woude, G. F. (2000). Met receptor tyrosine kinase: Enhanced signaling through adapter proteins. Oncogene, 19, 5582–5589.PubMedCrossRefGoogle Scholar
  25. 25.
    Pelicci, G., Giordano, S., Zhen, Z., Salcini, A. E., Lanfrancone, L., Bardelli, A., et al. (1995). The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein. Oncogene, 10, 1631–1638.PubMedGoogle Scholar
  26. 26.
    Weidner, K. M., Di, C. S., Sachs, M., Brinkmann, V., Behrens, J., & Birchmeier, W. (1996). Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature, 384, 173–176.PubMedCrossRefGoogle Scholar
  27. 27.
    Gual, P., Giordano, S., Anguissola, S., Parker, P. J., & Comoglio, P. M. (2001). Gab1 phosphorylation: A novel mechanism for negative regulation of HGF receptor signaling. Oncogene, 20, 156–166.PubMedCrossRefGoogle Scholar
  28. 28.
    Gual, P., Giordano, S., Williams, T. A., Rocchi, S., Van, O. E., & Comoglio, P. M. (2000). Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis. Oncogene, 19, 1509–1518.PubMedCrossRefGoogle Scholar
  29. 29.
    Maroun, C. R., Naujokas, M. A., Holgado-Madruga, M., Wong, A. J., & Park, M. (2000). The tyrosine phosphatase SHP-2 is required for sustained activation of extracellular signal-regulated kinase and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Molecular Cell Biology, 20, 8513–8525.CrossRefGoogle Scholar
  30. 30.
    Fournier, T. M., Kamikura, D., Teng, K., & Park, M. (1996). Branching tubulogenesis but not scatter of Madin–Darby canine kidney cells requires a functional Grb2 binding site in the Met receptor tyrosine kinase. Journal of Biological Chemistry, 271, 22211–22217.PubMedCrossRefGoogle Scholar
  31. 31.
    O’brien, L. E., Tang, K., Kats, E. S., Schutz-Geschwender, A., Lipschutz, J. H., & Mostov, K. E. (2004). ERK and MMPs sequentially regulate distinct stages of epithelial tubule development. Developments in Cell, 7, 21–32.CrossRefGoogle Scholar
  32. 32.
    Marshall, C. J. (1995). Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation. Cell, 80, 179–185.PubMedCrossRefGoogle Scholar
  33. 33.
    Graziani, A., Gramaglia, D., Cantley, L. C., & Comoglio, P. M. (1991). The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase. Journal of Biological Chemistry, 266, 22087–22090.PubMedGoogle Scholar
  34. 34.
    Ponzetto, C., Bardelli, A., Maina, F., Longati, P., Panayotou, G., Dhand, R., et al. (1993). A novel recognition motif for phosphatidylinositol 3-kinase binding mediates its association with the hepatocyte growth factor/scatter factor receptor. Molecular Cell Biology, 13, 4600–4608.Google Scholar
  35. 35.
    Royal, I., & Park, M. (1995). Hepatocyte growth factor-induced scatter of Madin–Darby canine kidney cells requires phosphatidylinositol 3-kinase. Journal of Biological Chemistry, 270, 27780–27787.PubMedCrossRefGoogle Scholar
  36. 36.
    Trusolino, L., Cavassa, S., Angelini, P., Ando, M., Bertotti, A., Comoglio, P. M., et al. (2000). HGF/scatter factor selectively promotes cell invasion by increasing integrin avidity. FASEB Jounal, 14, 1629–1640.CrossRefGoogle Scholar
  37. 37.
    Xiao, G. H., Jeffers, M., Bellacosa, A., Mitsuuchi, Y., Vande Woude, G. F., & Testa, J. R. (2001). Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proceedings of the National Academy of Sciences of the United States of America, 98, 247–252.PubMedCrossRefGoogle Scholar
  38. 38.
    Wells, C. M., Abo, A., & Ridley, A. J. (2002). PAK4 is activated via PI3K in HGF-stimulated epithelial cells. Journal of Cell Science, 115, 3947–3956.PubMedCrossRefGoogle Scholar
  39. 39.
    Boccaccio, C., Ando, M., Tamagnone, L., Bardelli, A., Michieli, P., Battistini, C., et al. (1998). Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature, 391, 285–288.PubMedCrossRefGoogle Scholar
  40. 40.
    Corso, S., Comoglio, P. M., & Giordano, S. (2005). Cancer therapy: Can the challenge be MET. Trends in Molecular Medicine, 11, 284–292.PubMedCrossRefGoogle Scholar
  41. 41.
    Palka, H. L., Park, M., & Tonks, N. K. (2003). Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase DEP-1. Journal of Biological Chemistry, 278, 5728–5735.PubMedCrossRefGoogle Scholar
  42. 42.
    Sangwan, V., Paliouras, G. N., Cheng, A., Dube, N., Tremblay, M. L., & Park, M. (2006). Protein-tyrosine phosphatase 1B deficiency protects against Fas-induced hepatic failure. Journal of Biological Chemistry, 281, 221–228.PubMedCrossRefGoogle Scholar
  43. 43.
    Machide, M., Hashigasako, A., Matsumoto, K., & Nakamura, T. (2006). Contact inhibition of hepatocyte growth regulated by functional association of the c-Met/hepatocyte growth factor receptor and LAR protein-tyrosine phosphatase. Journal of Biological Chemistry, 281, 8765–8772.PubMedCrossRefGoogle Scholar
  44. 44.
    Birchmeier, C., & Gherardi, E. (1998). Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends in Cell Biology, 8, 404–410.PubMedCrossRefGoogle Scholar
  45. 45.
    Uehara, Y., Minowa, O., Mori, C., Shiota, K., Kuno, J., Noda, T., et al. (1995). Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature, 373, 702–705.PubMedCrossRefGoogle Scholar
  46. 46.
    Bladt, F., Riethmacher, D., Isenmann, S., Aguzzi, A., & Birchmeier, C. (1995). Essential role for the c-Met receptor in the migration of myogenic precursor cells into the limb bud. Nature, 376, 768–771.PubMedCrossRefGoogle Scholar
  47. 47.
    Schmidt, C., Bladt, F., Goedecke, S., Brinkmann, V., Zschiesche, W., Sharpe, M., et al. (1995). Scatter factor/hepatocyte growth factor is essential for liver development. Nature, 373, 699–702.PubMedCrossRefGoogle Scholar
  48. 48.
    Maina, F., Pante, G., Helmbacher, F., Andres, R., Porthin, A., Davies, A. M., et al. (2001). Coupling Met to specific pathways results in distinct developmental outcomes. Molecular Cell, 7, 1293–1306.PubMedCrossRefGoogle Scholar
  49. 49.
    Huh, C. G., Factor, V. M., Sanchez, A., Uchida, K., Conner, E. A., & Thorgeirsson, S. S. (2004). Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proceedings of the National Academy of Sciences of the United States of America, 101, 4477–4482.PubMedCrossRefGoogle Scholar
  50. 50.
    Chmielowiec, J., Borowiak, M., Morkel, M., Stradal, T., Munz, B., Werner, S., et al. (2007). c-Met is essential for wound healing in the skin. Journal of Cell Biology, 177, 151–162.PubMedCrossRefGoogle Scholar
  51. 51.
    Bussolino, F., Di Renzo, M. F., Ziche, M., Bocchietto, E., Olivero, M., Naldini, L., et al. (1992). Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. Journal of Cell Biology, 119, 629–641.PubMedCrossRefGoogle Scholar
  52. 52.
    Boccaccio, C., Sabatino, G., Medico, E., Girolami, F., Follenzi, A., Reato, G., et al. (2005). The MET oncogene drives a genetic programme linking cancer to haemostasis. Nature, 434, 396–400.PubMedCrossRefGoogle Scholar
  53. 53.
    Boccaccio, C., & Medico, E. (2006). Cancer and blood coagulation. Cellular and Molecular Life Sciences, 63, 1024–1027.PubMedCrossRefGoogle Scholar
  54. 54.
    Rickles, F. R., & Levine, M. N. (2001). Epidemiology of thrombosis in cancer. Acta Haematologica, 106, 6–12.PubMedCrossRefGoogle Scholar
  55. 55.
    Rong, S., Segal, S., Anver, M., Resau, J. H., & Vande Woude, G. F. (1994). Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proceedings of the National Academy of Sciences of the United States of America, 91, 4731–4735.PubMedCrossRefGoogle Scholar
  56. 56.
    Taulli, R., Scuoppo, C., Bersani, F., Accornero, P., Forni, P. E., Miretti, S., et al. (2006). Validation of Met as a therapeutic target in alveolar and embryonal rhabdomyosarcoma. Cancer Research, 66, 4742–4749.PubMedCrossRefGoogle Scholar
  57. 57.
    Lutterbach, B., Zeng, Q., Davis, L. J., Hatch, H., Hang, G., Kohl, N. E., et al. (2007). Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Research, 67, 2081–2088.PubMedCrossRefGoogle Scholar
  58. 58.
    Takayama, H., LaRochelle, W. J., Sharp, R., Otsuka, T., Kriebel, P., Anver, M., et al. (1997). Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proceedings of the National Academy of Sciences of the United States of America, 94, 701–706.PubMedCrossRefGoogle Scholar
  59. 59.
    Wang, R., Ferrell, L. D., Faouzi, S., Maher, J. J., & Bishop, J. M. (2001). Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. Journal of Cell Biology, 153, 1023–1034.PubMedCrossRefGoogle Scholar
  60. 60.
    Schmidt, L., Junker, K., Nakaigawa, N., Kinjerski, T., Weirich, G., Miller, M., et al. (1999). Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene, 18, 2343–2350.PubMedCrossRefGoogle Scholar
  61. 61.
    Ferracini, R., Di Renzo, M. F., Scotlandi, K., Baldini, N., Olivero, M., Lollini, P., et al. (1995). The Met/HGF receptor is over-expressed in human osteosarcomas and is activated by either a paracrine or an autocrine circuit. Oncogene, 10, 739–749.PubMedGoogle Scholar
  62. 62.
    Ferracini, R., Olivero, M., Di Renzo, M. F., Martano, M., De, G. C., Nanni, P., et al. (1996). Retrogenic expression of the MET proto-oncogene correlates with the invasive phenotype of human rhabdomyosarcomas. Oncogene, 12, 1697–1705.PubMedGoogle Scholar
  63. 63.
    Tuck, A. B., Park, M., Sterns, E. E., Boag, A., & Elliott, B. E. (1996). Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. American Journal of Pathology, 148, 225–232.PubMedGoogle Scholar
  64. 64.
    Koochekpour, S., Jeffers, M., Rulong, S., Taylor, G., Klineberg, E., Hudson, E. A., et al. (1997). Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Research, 57, 5391–5398.PubMedGoogle Scholar
  65. 65.
    Kijima, Y., Hokita, S., Yoshinaka, H., Itoh, T., Koriyama, C., Eizuru, Y., et al. (2002). Amplification and overexpression of c-met gene in Epstein–Barr virus-associated gastric carcinomas. Oncology, 62, 60–65.PubMedCrossRefGoogle Scholar
  66. 66.
    Nakazawa, K., Dobashi, Y., Suzuki, S., Fujii, H., Takeda, Y., & Ooi, A. (2005). Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-Met in biliary tract cancers. Journal of Pathology, 206, 356–365.PubMedCrossRefGoogle Scholar
  67. 67.
    Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., et al. (2007). MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science, 316, 1039–1043.PubMedCrossRefGoogle Scholar
  68. 68.
    Christensen, J. G., Burrows, J., & Salgia, R. (2005). c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Letters, 225, 1–26.PubMedCrossRefGoogle Scholar
  69. 69.
    Di Renzo, M. F., Olivero, M., Martone, T., Maffe, A., Maggiora, P., Stefani, A. D., et al. (2000). Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene, 19, 1547–1555.PubMedCrossRefGoogle Scholar
  70. 70.
    Ivan, M., Bond, J. A., Prat, M., Comoglio, P. M., & Wynford-Thomas, D. (1997). Activated Ras and Ret oncogenes induce over-expression of c-Met (hepatocyte growth factor receptor) in human thyroid epithelial cells. Oncogene, 14, 2417–2423.PubMedCrossRefGoogle Scholar
  71. 71.
    Shirasaki, F., Makhluf, H. A., LeRoy, C., Watson, D. K., & Trojanowska, M. (1999). Ets transcription factors cooperate with Sp1 to activate the human tenascin-C promoter. Oncogene, 18, 7755–7764.PubMedCrossRefGoogle Scholar
  72. 72.
    Gambarotta, G., Boccaccio, C., Giordano, S., Ando, M., Stella, M. C., & Comoglio, P. M. (1996). Ets up-regulates MET transcription. Oncogene, 13, 1911–1917.PubMedGoogle Scholar
  73. 73.
    Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, M., Giordano, S., & Comoglio, P. M. (2003). Hypoxia promotes invasive growth by transcriptional activation of the Met protooncogene. Cancer Cell, 3, 347–361.PubMedCrossRefGoogle Scholar
  74. 74.
    Morotti, A., Mila, S., Accornero, P., Tagliabue, E., & Ponzetto, C. (2002). K252a inhibits the oncogenic properties of Met, the HGF receptor. Oncogene, 21, 4885–4893.PubMedCrossRefGoogle Scholar
  75. 75.
    Berthou, S., Aebersold, D. M., Schmidt, L. S., Stroka, D., Heigl, C., Streit, B., et al. (2004). The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants. Oncogene, 23, 5387–5393.PubMedCrossRefGoogle Scholar
  76. 76.
    Christensen, J. G., Schreck, R., Burrows, J., Kuruganti, P., Chan, E., Le, P., et al. (2003). A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Research, 63, 7345–7355.PubMedGoogle Scholar
  77. 77.
    Smolen, G. A., Sordella, R., Muir, B., Mohapatra, G., Barmettler, A., Archibald, H., et al. (2006). Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proceedings of the National Academy of Sciences of the United States of America, 103, 2316–2321.PubMedCrossRefGoogle Scholar
  78. 78.
    Date, K., Matsumoto, K., Kuba, K., Shimura, H., Tanaka, M., & Nakamura, T. (1998). Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor. Oncogene, 17, 3045–3054.PubMedCrossRefGoogle Scholar
  79. 79.
    Matsumoto, K., & Nakamura, T. (2003). NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics. Cancer Science, 94, 321–327.PubMedCrossRefGoogle Scholar
  80. 80.
    Cao, B., Su, Y., Oskarsson, M., Zhao, P., Kort, E. J., Fisher, R. J., et al. (2001). Neutralizing monoclonal antibodies to hepatocyte growth factor/scatter factor (HGF/SF) display antitumor activity in animal models. Proceedings of the National Academy of Sciences of the United States of America, 98, 7443–7448.PubMedCrossRefGoogle Scholar
  81. 81.
    Burgess, T., Coxon, A., Meyer, S., Sun, J., Rex, K., Tsuruda, T., et al. (2006). Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors. Cancer Research, 66, 1721–1729.PubMedCrossRefGoogle Scholar
  82. 82.
    Mazzone, M., Basilico, C., Cavassa, S., Pennacchietti, S., Risio, M., Naldini, L., et al. (2004). An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice. Journal of Clinical Investigation, 114, 1418–1432.PubMedCrossRefGoogle Scholar
  83. 83.
    Michieli, P., Mazzone, M., Basilico, C., Cavassa, S., Sottile, A., Naldini, L., et al. (2004). Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell, 6, 61–73.PubMedCrossRefGoogle Scholar
  84. 84.
    Kong-Beltran, M., Stamos, J., & Wickramasinghe, D. (2004). The Sema domain of Met is necessary for receptor dimerization and activation. Cancer Cell, 6, 75–84.PubMedCrossRefGoogle Scholar
  85. 85.
    Petrelli, A., Circosta, P., Granziero, L., Mazzone, M., Pisacane, A., Fenoglio, S., et al. (2006). Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity. Proceedings of the National Academy of Sciences of the United States of America, 103, 5090–5095.PubMedCrossRefGoogle Scholar
  86. 86.
    Corso, S., Migliore, C., Ghiso, E., De Rosa, G., Comoglio, P. M., & Giordano, S. (2007). Silencing the MET oncogene leads to regression of experimental tumors and metastases. Oncogene (in press). DOI  10.1038/sj.onc.1210697.

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Alessandra Gentile
    • 1
  • Livio Trusolino
    • 1
  • Paolo M. Comoglio
    • 1
    Email author
  1. 1.Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC)University of Turin Medical SchoolCandiolo (Torino)Italy

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