HGF/c-MET Signaling in Advanced Cancers

Part of the Cancer Genetics book series (CANGENETICS)


Papillary renal carcinoma (RCCP) is histologically and genetically distinct from other forms of inherited renal carcinoma (e.g., von Hippel–Lindau disease, which is caused by inactivation of the VHL gene –( see Chapter 6). RCCP genes map to several loci; one of each on 7q31.1-q34 encodes the c-Met oncoprotein (Schmidt et al. 1997). In the original publication, missense mutations in the tyrosine kinase domain of the MET gene were found both in the germlines of affected patients and in a subset of sporadic papillary renal carcinomas. Additionally, tumors from RCCP patients commonly show trisomy of chromosome 7 harboring non-random duplication of the mutant MET allele (Zhuang et al. 1998).


Vascular Endothelial Growth Factor Hepatocyte Growth Factor Small Cell Lung Cancer Focal Adhesion Kinase Tyrosine Kinase Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Adebonojo SA, Bowser AN, Moritz DM, Corcoran PC (1999) Impact of revised stage classification of lung cancer on survival: a military experience. Chest 115:1507–1513.PubMedCrossRefGoogle Scholar
  2. Aebersold DM, Kollar A, Beer KT, Laissue J, Greiner RH, Djonov V (2001) Involvement of the hepatocyte growth factor/scatter factor receptor c-met and of Bcl-xL in the resistance of oropharyngeal cancer to ionizing radiation. Int J Cancer 96:41–54.PubMedCrossRefGoogle Scholar
  3. Aebersold DM, Landt O, Berthou S, Gruber G, Beer KT, Greiner RH, Zimmer Y (2003) Prevalence and clinical impact of Met Y1253D-activating point mutation in radiotherapy-treated squamous cell cancer of the oropharynx. Oncogene 22:8519–8523.PubMedCrossRefGoogle Scholar
  4. Atabey N, Gao Y, Yao ZJ, Breckenridge D, Soon L, Soriano JV, Burke TR Jr, Bottaro DP (2001) Potent blockade of hepatocyte growth factor-stimulated cell motility, matrix invasion and branching morphogenesis by antagonists of Grb2 Src homology 2 domain interactions. J Biol Chem 276:14308–14314.PubMedGoogle Scholar
  5. Bardelli A, Longati P, Williams TA, Benvenuti S, Comoglio PM (1999) A peptide representing the carboxyl-terminal tail of the met receptor inhibits kinase activity and invasive growth. J Biol Chem 274:29274–29281.PubMedCrossRefGoogle Scholar
  6. Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, Balak M, Chang WC, Yu CJ, Gazdar A, Pass H, Rusch V, Gerald W, Huang SF, Yang PC, Miller V, Ladanyi M, Yang CH, Pao W (2007) MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 104:20932–20937.PubMedCrossRefGoogle Scholar
  7. Bergot E, Richard N, Zalcman G (2007) [Mechanisms of action of targeted therapies ... and mechanisms of resistance]. Rev Mal Respir 24:6S180–187.PubMedGoogle Scholar
  8. Beviglia L, Matsumoto K, Lin CS, Ziober BL, Kramer RH (1997) Expression of the c-Met/HGF receptor in human breast carcinoma: correlation with tumor progression. Int J Cancer 74:301–309.PubMedCrossRefGoogle Scholar
  9. Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA (1991) Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251:802–804.PubMedCrossRefGoogle Scholar
  10. Bowers DC, Fan S, Walter KA, Abounader R, Williams JA, Rosen EM, Laterra J (2000) Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways. Cancer Res 60:4277–4283.PubMedGoogle Scholar
  11. Cantrell DA (2001) Phosphoinositide 3-kinase signalling pathways. J Cell Sci 114:1439–1445PubMedGoogle Scholar
  12. Cattley RC and Radinsky RR (2004) Cancer therapeutics: understanding the mechanism of action. Toxicol Pathol 32 Suppl 1:116–121.Google Scholar
  13. Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R, Lipson KE, Ramphal J, Do S, Cui JJ, Cherrington JM, Mendel DB (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 Res 63:7345–7355.PubMedGoogle Scholar
  14. Christensen JG, Burrows J, Salgia R (2005) c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett 225:1–26.PubMedCrossRefGoogle Scholar
  15. Chute JP, Chen T, Feigal E, Simon R, Johnson BE (1999) Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol 17:1794–1801.PubMedGoogle Scholar
  16. Comoglio PM (1993) Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells. Exs 65:131–165.PubMedGoogle Scholar
  17. Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM, Vande Woude GF (1984) Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311:29–33.PubMedCrossRefGoogle Scholar
  18. Davies G, Jiang WG, Mason MD (2001) HGF/SF modifies the interaction between its receptor c-Met, and the E-cadherin/catenin complex in prostate cancer cells. Int J Mol Med 7:385–388.PubMedGoogle Scholar
  19. Derman MP, Cunha MJ, Barros EJ, Nigam SK, Cantley LG (1995) HGF-mediated chemotaxis and tubulogenesis require activation of the phosphatidylinositol 3-kinase. Am J Physiol 268:F1211–1217.PubMedGoogle Scholar
  20. Di Renzo MF, Olivero M, Martone T, Maffe A, Maggiora P, Stefani AD, Valente G, Giordano S, Cortesina G, Comoglio PM (2000) Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene 19:1547–1555.PubMedCrossRefGoogle Scholar
  21. Eliceiri BP, Klemke R, Stromblad S, Cheresh DA (1998) Integrin alphavbeta3 requirement for sustained mitogen-activated protein kinase activity during angiogenesis. J Cell Biol 140:1255–1263.PubMedCrossRefGoogle Scholar
  22. Ellison DH and Berl T (2007) Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 356:2064–2072.PubMedCrossRefGoogle Scholar
  23. Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD (2002) The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 3:53–57.PubMedCrossRefGoogle Scholar
  24. Furge KA, Zhang YW, Vande Woude GF (2000) Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene 19:5582–5589.PubMedCrossRefGoogle Scholar
  25. Furge KA, Kiewlich D, Le P, Vo MN, Faure M, Howlett AR, Lipson KE, Woude GF, Webb CP (2001) Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor tyrosine kinase. Proc Natl Acad Sci U S A 98:10722–10727.PubMedCrossRefGoogle Scholar
  26. Gherardi E, Sandin S, Petoukhov MV, Finch J, Youles ME, Ofverstedt LG, Miguel RN, Blundell TL, Vande Woude GF, Skoglund U, Svergun DI (2006) Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci U S A 103:4046–4051.PubMedCrossRefGoogle Scholar
  27. Gohda E, Matsunaga T, Kataoka H, Takebe T, Yamamoto I (1994) Induction of hepatocyte growth factor in human skin fibroblasts by epidermal growth factor, platelet-derived growth factor and fibroblast growth factor. Cytokine 6:633–640.PubMedCrossRefGoogle Scholar
  28. Graziani A, Gramaglia D, dalla Zonca P, Comoglio PM (1993) Hepatocyte growth factor/scatter factor stimulates the Ras-guanine nucleotide exchanger. J Biol Chem 268:9165–9168.PubMedGoogle Scholar
  29. Griffioen AW and Molema G (2000) Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 52:237–268.PubMedGoogle Scholar
  30. Gu H and Neel BG (2003) The “Gab” in signal transduction. Trends Cell Biol 13:122–130.PubMedCrossRefGoogle Scholar
  31. Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM (2000) Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis. Oncogene 19:1509–1518.PubMedCrossRefGoogle Scholar
  32. Gual P, Giordano S, Anguissola S, Parker PJ, Comoglio PM (2001) Gab1 phosphorylation: a novel mechanism for negative regulation of HGF receptor signaling. Oncogene 20:156–166.PubMedCrossRefGoogle Scholar
  33. Hagel M, George EL, Kim A, Tamimi R, Opitz SL, Turner CE, Imamoto A, Thomas SM (2002) The adaptor protein paxillin is essential for normal development in the mouse and is a critical transducer of fibronectin signaling. Mol Cell Biol 22:901–915.PubMedCrossRefGoogle Scholar
  34. Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25.PubMedCrossRefGoogle Scholar
  35. Ichimura E, Maeshima A, Nakajima T, Nakamura T (1996) Expression of c-met/HGF receptor in human non-small cell lung carcinomas in vitro and in vivo and its prognostic significance. Jpn J Cancer Res 87:1063–1069.PubMedGoogle Scholar
  36. Jafri NF, Ma PC, Maulik G, Salgia R (2003) Mechanisms of metastasis as related to receptor tyrosine kinases in small-cell lung cancer. J Environ Pathol Toxicol Oncol 22:147–165.PubMedCrossRefGoogle Scholar
  37. Jagadeeswaran R, Surawska H, Krishnaswamy S, Janamanchi V, Mackinnon AC, Seiwert TY, Loganathan S, Kanteti R, Reichman T, Nallasura V, Schwartz S, Faoro L, Wang YC, Girard L, Tretiakova MS, Ahmed S, Zumba O, Soulii L, Bindokas VP, Szeto LL, Gordon GJ, Bueno R, Sugarbaker D, Lingen MW, Sattler M, Krausz T, Vigneswaran W, Natarajan V, Minna J, Vokes EE, Ferguson MK, Husain AN, Salgia R (2008) Paxillin is a target for somatic mutations in lung cancer: implications for cell growth and invasion. Cancer Res 68:132–142.PubMedCrossRefGoogle Scholar
  38. Jeffers M, Rong S, Vande Woude GF (1996) Enhanced tumorigenicity and invasion-metastasis by hepatocyte growth factor/scatter factor-met signalling in human cells concomitant with induction of the urokinase proteolysis network. Mol Cell Biol 16:1115–1125.PubMedGoogle Scholar
  39. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66.PubMedCrossRefGoogle Scholar
  40. Jiang WG, Hiscox SE, Parr C, Martin TA, Matsumoto K, Nakamura T, Mansel RE (1999) Antagonistic effect of NK4, a novel hepatocyte growth factor variant, on in vitro angiogenesis of human vascular endothelial cells. Clin Cancer Res 5:3695–3703.PubMedGoogle Scholar
  41. Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker B, Demetri GD (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056.PubMedCrossRefGoogle Scholar
  42. Jun HT, Sun J, Rex K, Radinsky R, Kendall R, Coxon A, Burgess TL (2007) AMG 102, a fully human anti-hepatocyte growth factor/scatter factor neutralizing antibody, enhances the efficacy of temozolomide or docetaxel in U-87 MG cells and xenografts. Clin Cancer Res 13:6735–6742.PubMedCrossRefGoogle Scholar
  43. Kaji M, Yonemura Y, Harada S, Liu X, Terada I, Yamamoto H (1996) Participation of c-met in the progression of human gastric cancers: anti-c-met oligonucleotides inhibit proliferation or invasiveness of gastric cancer cells. Cancer Gene Ther 3:393–404.PubMedGoogle Scholar
  44. Koochekpour S, Jeffers M, Wang PH, Gong C, Taylor GA, Roessler LM, Stearman R, Vasselli JR, Stetler-Stevenson WG, Kaelin WG Jr, Linehan WM, Klausner RD, Gnarra JR, Vande Woude GF (1999) The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol 19:5902–5912.PubMedGoogle Scholar
  45. Kuniyasu H, Yasui W, Kitadai Y, Yokozaki H, Ito H, Tahara E (1992) Frequent amplification of the c-met gene in scirrhous type stomach cancer. Biochem Biophys Res Commun 189:227–232.PubMedCrossRefGoogle Scholar
  46. Kuniyasu H, Yasui W, Yokozaki H, Kitadai Y, Tahara E (1993) Aberrant expression of c-met mRNA in human gastric carcinomas. Int J Cancer 55:72–75.PubMedCrossRefGoogle Scholar
  47. Kurayoshi M, Oue N, Yamamoto H, Kishida M, Inoue A, Asahara T, Yasui W, Kikuchi A (2006) Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. Cancer Res 66:10439–10448.PubMedCrossRefGoogle Scholar
  48. Lai JF, Kao SC, Jiang ST, Tang MJ, Chan PC, Chen HC (2000) Involvement of focal adhesion kinase in hepatocyte growth factor-induced scatter of Madin-Darby canine kidney cells. J Biol Chem 275:7474–7480.PubMedCrossRefGoogle Scholar
  49. Lee JH, Han SU, Cho H, Jennings B, Gerrard B, Dean M, Schmidt L, Zbar B, Vande Woude GF (2000) A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene 19:4947–4953.PubMedCrossRefGoogle Scholar
  50. Legros L, Bourcier C, Jacquel A, Mahon FX, Cassuto JP, Auberger P, Pagès G (2004) Imatinib mesylate (STI571) decreases the vascular endothelial growth factor plasma concentration in patients with chronic myeloid leukemia. Blood 104:495–501.PubMedCrossRefGoogle Scholar
  51. Liu Y (1998) The human hepatocyte growth factor receptor gene: complete structural organization and promoter characterization. Gene 215:159–169.PubMedCrossRefGoogle Scholar
  52. Liu C and Tsao MS (1993) In vitro and in vivo expressions of transforming growth factor-alpha and tyrosine kinase receptors in human non-small-cell lung carcinomas. Am J Pathol 142:1155–1162.PubMedGoogle Scholar
  53. Liu Z, Greco AJ, Hellman NE, Spector J, Robinson J, Tang OT, Lipschutz JH (2007) Intracellular signaling via ERK/MAPK completes the pathway for tubulogenic fibronectin in MDCK cells. Biochem Biophys Res Commun 353:793–798.PubMedCrossRefGoogle Scholar
  54. Lorenzato A, Olivero M, Patanè S, Rosso E, Oliaro A, Comoglio PM, Di Renzo MF (2002) Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion. Cancer Res 62:7025–7030.PubMedGoogle Scholar
  55. Luo J, Manning BD, Cantley LC (2003) Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4:257–262.PubMedCrossRefGoogle Scholar
  56. Ma PC, Kijima T, Maulik G, Fox EA, Sattler M, Griffin JD, Johnson BE, Salgia R (2003) c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res 63:6272–6281.PubMedGoogle Scholar
  57. Ma PC, Jagadeeswaran R, Jagadeesh S, Tretiakova MS, Nallasura V, Fox EA, Hansen M, Schaefer E, Naoki K, Lader A, Richards W, Sugarbaker D, Husain AN, Christensen JG, Salgia R (2005a) Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res 65:1479–1488.PubMedCrossRefGoogle Scholar
  58. Ma PC, Schaefer E, Christensen JG, Salgia R (2005b) A selective small molecule c-MET Inhibitor, PHA665752, cooperates with rapamycin. Clin Cancer Res 11:2312–2319.PubMedCrossRefGoogle Scholar
  59. Matsumoto K, Matsumoto K, Nakamura T, Kramer RH (1994) Hepatocyte growth factor/scatter factor induces tyrosine phosphorylation of focal adhesion kinase (p125FAK) and promotes migration and invasion by oral squamous cell carcinoma cells. J Biol Chem 269:31807–31813.PubMedGoogle Scholar
  60. Matsumoto K, Ziober BL, Yao CC, Kramer RH (1995) Growth factor regulation of integrin-mediated cell motility. Cancer Metastasis Rev 14:205–217.PubMedCrossRefGoogle Scholar
  61. Maulik G, Kijima T, Ma PC, Ghosh SK, Lin J, Shapiro GI, Schaefer E, Tibaldi E, Johnson BE, Salgia R (2002a) Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res 8:620–627.PubMedGoogle Scholar
  62. Maulik G, Shrikhande A, Kijima T, Ma PC, Morrison PT, Salgia R (2002b) Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev 13:41–59.PubMedCrossRefGoogle Scholar
  63. McAuliffe JC, Lazar AJ, Yang D, Steinert DM, Qiao W, Thall PF, Raymond AK, Benjamin RS, Trent JC (2007) Association of intratumoral vascular endothelial growth factor expression and clinical outcome for patients with gastrointestinal stromal tumors treated with imatinib mesylate. Clin Cancer Res 13:6727–6734.PubMedCrossRefGoogle Scholar
  64. Michieli P, Basilico C, Pennacchietti S, Maffè A, Tamagnone L, Giordano S, Bardelli A, Comoglio PM (1999) Mutant Met-mediated transformation is ligand-dependent and can be inhibited by HGF antagonists. Oncogene 18:5221–5231.PubMedCrossRefGoogle Scholar
  65. Murray N, Salgia R, Fossella FV (2004) Targeted molecules in small cell lung cancer. Semin Oncol 31:106–111.PubMedCrossRefGoogle Scholar
  66. Nabeshima K, Shimao Y, Inoue T, Itoh H, Kataoka H, Koono M (1998) Hepatocyte growth factor/scatter factor induces not only scattering but also cohort migration of human colorectal-adenocarcinoma cells. Int J Cancer 78:750–759.PubMedCrossRefGoogle Scholar
  67. Neckers L, Schulte TW, Mimnaugh E (1999) Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest New Drugs 17:361–373.PubMedCrossRefGoogle Scholar
  68. Nobes CD and Hall A (1999) Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol 144:1235–1244.PubMedCrossRefGoogle Scholar
  69. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ; IRIS Investigators (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004.PubMedCrossRefGoogle Scholar
  70. Olivero M, Rizzo M, Madeddu R, Casadio C, Pennacchietti S, Nicotra MR, Prat M, Maggi G, Arena N, Natali PG, Comoglio PM, Di Renzo MF (1996) Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas. Br J Cancer 74:1862–1868.PubMedCrossRefGoogle Scholar
  71. Otsuka T, Jakubczak J, Vieira W, Bottaro DP, Breckenridge D, Larochelle WJ, Merlino G (2000) Disassociation of met-mediated biological responses in vivo: the natural hepatocyte growth factor/scatter factor splice variant NK2 antagonizes growth but facilitates metastasis. Mol Cell Biol 20:2055–2065.PubMedCrossRefGoogle Scholar
  72. Park WS, Oh RR, Kim YS, Park JY, Shin MS, Lee HK, Lee SH, Yoo NJ, Lee JY (2000) Absence of mutations in the kinase domain of the Met gene and frequent expression of Met and HGF/SF protein in primary gastric carcinomas. Apmis 108:195–200.PubMedCrossRefGoogle Scholar
  73. Parr C, Hiscox S, Nakamura T, Matsumoto K, Jiang WG (2000) Nk4, a new HGF/SF variant, is an antagonist to the influence of HGF/SF on the motility and invasion of colon cancer cells. Int J Cancer 85:563–570.PubMedCrossRefGoogle Scholar
  74. Parr C, Davies G, Nakamura T, Matsumoto K, Mason MD, Jiang WG (2001) The HGF/SF-induced phosphorylation of paxillin, matrix adhesion, and invasion of prostate cancer cells were suppressed by NK4, an HGF/SF variant. Biochem Biophys Res Commun 285:1330–1337.PubMedCrossRefGoogle Scholar
  75. Puri N, Khramtsov A, Ahmed S, Nallasura V, Hetzel JT, Jagadeeswaran R, Karczmar G, Salgia R (2007) A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts. Cancer Res 67:3529–3534.PubMedCrossRefGoogle Scholar
  76. Rahimi N, Hung W, Tremblay E, Saulnier R, Elliott B (1998) c-Src kinase activity is required for hepatocyte growth factor-induced motility and anchorage-independent growth of mammary carcinoma cells. J Biol Chem 273:33714–33721.PubMedCrossRefGoogle Scholar
  77. Rosen EM, Meromsky L, Setter E, Vinter DW, Goldberg ID (1990) Purified scatter factor stimulates epithelial and vascular endothelial cell migration. Proc Soc Exp Biol Med 195:34–43.PubMedGoogle Scholar
  78. Rosen EM, Lamszus K, Laterra J, Polverini PJ, Rubin JS, Goldberg ID (1997) HGF/SF in angiogenesis. Ciba Found Symp 212:215–226; discussion 227–219.PubMedGoogle Scholar
  79. Sachs M, Brohmann H, Zechner D, Müller T, Hülsken J, Walther I, Schaeper U, Birchmeier C, Birchmeier W (2000) Essential role of Gab1 for signaling by the c-Met receptor in vivo. J Cell Biol 150:1375–1384.PubMedCrossRefGoogle Scholar
  80. Sakkab D, Lewitzky M, Posern G, Schaeper U, Sachs M, Birchmeier W, Feller SM (2000) Signaling of hepatocyte growth factor/scatter factor (HGF) to the small GTPase Rap1 via the large docking protein Gab1 and the adapter protein CRKL. J Biol Chem 275:10772–10778.PubMedCrossRefGoogle Scholar
  81. Salgia R, Li JL, Ewaniuk DS, Wang YB, Sattler M, Chen WC, Richards W, Pisick E, Shapiro GI, Rollins BJ, Chen LB, Griffin JD, Sugarbaker DJ (1999) Expression of the focal adhesion protein paxillin in lung cancer and its relation to cell motility. Oncogene 18:67–77.PubMedCrossRefGoogle Scholar
  82. Salgia RS, S. Hong, D.S. Ng, C.S. Frye, J. Janisch, L. Ratain, M.J. Kurzrock, R (2008) A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC). J Clin Oncol 26:2008 (May 20 suppl; abstr 3522).Google Scholar
  83. Sattler M and Salgia R (2007) c-Met and hepatocyte growth factor: potential as novel targets in cancer therapy. Curr Oncol Rep 9:102–108.PubMedCrossRefGoogle Scholar
  84. Sattler M, Pride YB, Ma P, Gramlich JL, Chu SC, Quinnan LA, Shirazian S, Liang C, Podar K, Christensen JG, Salgia R (2003) A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase. Cancer Res 63: 5462–5469.PubMedGoogle Scholar
  85. Schaller MD and Sasaki T (1997) Differential signaling by the focal adhesion kinase and cell adhesion kinase beta. J Biol Chem 272:25319–25325.PubMedCrossRefGoogle Scholar
  86. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B (1997) Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16:68–73.PubMedCrossRefGoogle Scholar
  87. Schmidt L, Junker K, Weirich G, Glenn G, Choyke P, Lubensky I, Zhuang Z, Jeffers M, Vande Woude G, Neumann H, Walther M, Linehan WM, Zbar B (1998) Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res 58:1719–1722.PubMedGoogle Scholar
  88. Seki T, Hagiya M, Shimonishi M, Nakamura T, Shimizu S (1991) Organization of the human hepatocyte growth factor-encoding gene. Gene 102:213–219.PubMedCrossRefGoogle Scholar
  89. Sengupta S, Gherardi E, Sellers LA, Wood JM, Sasisekharan R, Fan TP (2003) Hepatocyte growth factor/scatter factor can induce angiogenesis independently of vascular endothelial growth factor. Arterioscler Thromb Vasc Biol 23:69–75.PubMedCrossRefGoogle Scholar
  90. Siddiqui SS, Loganathan S, Krishnaswamy S, Faoro L, Jagadeeswaran R, Salgia R (2008) C. elegans as a model organism for in vivo screening in cancer: effects of human c-Met in lung cancer affect C. elegans vulva phenotypes. Cancer Biol Ther 7.Google Scholar
  91. Siegfried JM, Weissfeld LA, Singh-Kaw P, Weyant RJ, Testa JR, Landreneau RJ (1997) Association of immunoreactive hepatocyte growth factor with poor survival in resectable non-small cell lung cancer. Cancer Res 57:433–439.PubMedGoogle Scholar
  92. Siegfried JM, Weissfeld LA, Luketich JD, Weyant RJ, Gubish CT, Landreneau RJ (1998) The clinical significance of hepatocyte growth factor for non-small cell lung cancer. Ann Thorac Surg 66:1915–1918.PubMedCrossRefGoogle Scholar
  93. Sugimura H, Nichols FC, Yang P, Allen MS, Cassivi SD, Deschamps C, Williams BA, Pairolero PC (2007) Survival after recurrent nonsmall-cell lung cancer after complete pulmonary resection. Ann Thorac Surg 83:409–417; discussion 417–408.PubMedCrossRefGoogle Scholar
  94. Takaishi K, Sasaki T, Kato M, Yamochi W, Kuroda S, Nakamura T, Takeichi M, Takai Y (1994) Involvement of Rho p21 small GTP-binding protein and its regulator in the HGF-induced cell motility. Oncogene 9:273–279.PubMedGoogle Scholar
  95. Takanami I, Tanana F, Hashizume T, Kikuchi K, Yamamoto Y, Yamamoto T, Kodaira S (1996) Hepatocyte growth factor and c-Met/hepatocyte growth factor receptor in pulmonary adenocarcinomas: an evaluation of their expression as prognostic markers. Oncology 53:392–397.PubMedCrossRefGoogle Scholar
  96. Tamagnone L and Comoglio PM (2000) Signalling by semaphorin receptors: cell guidance and beyond. Trends Cell Biol 10:377–383.PubMedCrossRefGoogle Scholar
  97. Tokunou M, Niki T, Eguchi K, Iba S, Tsuda H, Yamada T, Matsuno Y, Kondo H, Saitoh Y, Imamura H, Hirohashi S (2001) c-MET expression in myofibroblasts: role in autocrine activation and prognostic significance in lung adenocarcinoma. Am J Pathol 158:1451–1463.PubMedCrossRefGoogle Scholar
  98. Trusolino L, Serini G, Cecchini G, Besati C, Ambesi-Impiombato FS, Marchisio PC, De Filippi R (1998) Growth factor-dependent activation of alphavbeta3 integrin in normal epithelial cells: implications for tumor invasion. J Cell Biol 142:1145–1156.PubMedCrossRefGoogle Scholar
  99. Uemura N, Salgia R, Li JL, Pisick E, Sattler M, Griffin JD (1997) The BCR/ABL oncogene alters interaction of the adapter proteins CRKL and CRK with cellular proteins. Leukemia 11:376–385.PubMedCrossRefGoogle Scholar
  100. Van Belle E, Witzenbichler B, Chen D, Silver M, Chang L, Schwall R, Isner JM (1998) Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis. Circulation 97:381–390.PubMedGoogle Scholar
  101. Webb CP, Hose CD, Koochekpour S, Jeffers M, Oskarsson M, Sausville E, Monks A, Vande Woude GF (2000) The geldanamycins are potent inhibitors of the hepatocyte growth factor/scatter factor-met-urokinase plasminogen activator-plasmin proteolytic network. Cancer Res 60:342–349.PubMedGoogle Scholar
  102. Wojta J, Kaun C, Breuss JM, Koshelnick Y, Beckmann R, Hattey E, Mildner M, Weninger W, Nakamura T, Tschachler E, Binder BR (1999) Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells. Lab Invest 79:427–438.PubMedGoogle Scholar
  103. Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF, Testa JR (2001) Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc Natl Acad Sci U S A 98:247–252.PubMedCrossRefGoogle Scholar
  104. Zeng ZJ, Yang LY, Ding X, Wang W (2004) Expressions of cysteine-rich61, connective tissue growth factor and Nov genes in hepatocellular carcinoma and their clinical significance. World J Gastroenterol 10:3414–3418.PubMedGoogle Scholar
  105. Zhang YW, Su Y, Volpert OV, Vande Woude GF (2003) Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation. Proc Natl Acad Sci U S A 100:12718–12723.PubMedCrossRefGoogle Scholar
  106. Zhuang Z, Park WS, Pack S, Schmidt L, Vortmeyer AO, Pak E, Pham T, Weil RJ, Candidus S, Lubensky IA, Linehan WM, Zbar B, Weirich G (1998) Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet 20:66–69.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of MedicineUniversity of ChicagoChicagoUSA
  2. 2.Department of MedicineUniversity of ChicagoChicagoUSA

Personalised recommendations