Cancer Letters
Volume 225, Issue 1 , Pages 1-26 , 8 July 2005

c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention

  • James G. Christensen

      Affiliations

    • Research Pharmacology, Pfizer Inc., La Jolla, CA 92121, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 858 638 6336; fax: +1 858 526 4275.
    • ,
  • Jon Burrows

      Affiliations

    • Rigel Inc. Pharmacology Department, South San Francisco, CA 94080, USA
    • ,
  • Ravi Salgia

      Affiliations

    • Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medical Center, Pritzker School of Medicine, Chicago, IL 60637, USA

Received 20 September 2004 ,Accepted 29 September 2004.

References 

  1. Laird AD, Cherrington JM. Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents. Expert. Opin. Investig. Drugs. 2003;12:51–64
  2. Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, et al Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. Eur. Mol. Biol. Org. J. 1991;10:2867–2878
  3. Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991;251:802–804
  4. Di Renzo MF, Narsimhan RP, Olivero M, Bretti S, Giordano S, Medico E, et al. Expression of the Met/HGF receptor in normal and neoplastic human tissues. Oncogene. 1991;6:1997–2003
  5. Sonnenberg E, Meyer D, Weidner KM, Birchmeier C. Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J. Cell Biol. 1993;123:223–235
  6. Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud [see comment]. Nature. 1995;376:768–771
  7. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995;373:699–702
  8. Tsarfaty I, Rong S, Resau JH, Rulong S, da Silva PP, Vande Woude GF. The Met proto-oncogene mesenchymal to epithelial cell conversion. Science. 1994;263:98–101
  9. Comoglio PM, Boccaccio C. Scatter factors and invasive growth. Semin. Cancer Biol. 2001;11:153–165
  10. Jiang W, Hiscox S, Matsumoto K, Nakamura T. Hepatocyte growth factor/scatter factor, its molecular, cellular and clinical implications in cancer. Crit. Rev. Oncol.–Hematol. 1999;29:209–248
  11. Naldini L, Vigna E, Ferracini R, Longati P, Gandino L, Prat M, et al. The tyrosine kinase encoded by the MET proto-oncogene is activated by autophosphorylation. Mol. Cell. Biol. 1991;11:1793–1803
  12. Rodrigues GA, Park M. Autophosphorylation modulates the kinase activity and oncogenic potential of the Met receptor tyrosine kinase. Oncogene. 1994;9:2019–2027
  13. Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell. 1994;77:261–271
  14. Fournier TM, Lamorte L, Maroun CR, Lupher M, Band H, Langdon W, et al. Cbl-transforming variants trigger a cascade of molecular alterations that lead to epithelial mesenchymal conversion. Mol. Biol. Cell. 2000;11:3397–3410
  15. Furge KA, Zhang YW, Vande Woude GF. Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene. 2000;19:5582–5589
  16. Sachs M, Brohmann H, Zechner D, Muller T, Hulsken J, Walther I, et al. Essential role of Gab1 for signaling by the c-Met receptor in vivo. J. Cell Biol. 2000;150:1375–1384
  17. Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W. Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature. 1996;384:173–176
  18. Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, et al. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat. Cell Biol. 2002;4:720–724
  19. Trusolino L, Bertotti A, Comoglio PM. A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Cell. 2001;107:643–654
  20. van der Voort R, Taher TE, Wielenga VJ, Spaargaren M, Prevo R, Smit L, et al. Heparan sulfate-modified CD44 promotes hepatocyte growth factor/scatter factor-induced signal transduction through the receptor tyrosine kinase c-Met. J. Biol. Chem. 1999;274:6499–6506
  21. Gu H, Neel BG. The ‘Gab’ in signal transduction. Trends Cell Biol. 2003;13:122–130
  22. Maroun CR, Holgado-Madruga M, Royal I, Naujokas MA, Fournier TM, Wong AJ, et al. The Gab1 PH domain is required for localization of Gab1 at sites of cell–cell contact and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol. Cell. Biol. 1999;19:1784–1799
  23. Day RM, Cioce V, Breckenridge D, Castagnino P, Bottaro DP. Differential signaling by alternative HGF isoforms through c-Met: activation of both MAP kinase and PI 3-kinase pathways is insufficient for mitogenesis. Oncogene. 1999;18:3399–3406
  24. Nakanishi K, Fujimoto J, Ueki T, Kishimoto K, Hashimoto-Tamaoki T, Furuyama J, et al. Hepatocyte growth factor promotes migration of human hepatocellular carcinoma via phosphatidylinositol 3-kinase. Clin. Exp. Metastatis. 1999;17:507–514
  25. Potempa S, Ridley AJ. Activation of both MAP kinase and phosphatidylinositide 3-kinase by Ras is required for hepatocyte growth factor/scatter factor-induced adherens junction disassembly. Mol. Biol. Cell. 1998;9:2185–2200
  26. Fan S, Ma YX, Wang JA, Yuan RQ, Meng Q, Cao Y, et al. The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′ kinase. Oncogene. 2000;19:2212–2223
  27. Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF, Testa JR. Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc. Natl Acad. Sci. USA. 2001;98:247–252
  28. Royal I, Lamarche-Vane N, Lamorte L, Kaibuchi K, Park M. Activation of cdc42, rac, PAK, and rho-kinase in response to hepatocyte growth factor differentially regulates epithelial cell colony spreading and dissociation. Mol. Biol. Cell. 2000;11:1709–1725
  29. Kodama A, Takaishi K, Nakano K, Nishioka H, Takai Y. Involvement of Cdc42 small G protein in cell–cell adhesion, migration and morphology of MDCK cells. Oncogene. 1999;18:3996–4006
  30. Ridley AJ, Comoglio PM, Hall A. Regulation of scatter factor/hepatocyte growth factor responses by Ras, Rac, and Rho in MDCK cells. Mol. Cell. Biol. 1995;15:1110–1122
  31. Lamorte L, Rodrigues S, Sangwan V, Turner CE, Park M. Crk associates with a multimolecular Paxillin/GIT2/beta-PIX complex and promotes Rac-dependent relocalization of Paxillin to focal contacts. Mol. Biol. Cell. 2003;14:2818–2831
  32. Lamorte L, Royal I, Naujokas M, Park M. Crk adapter proteins promote an epithelial–mesenchymal-like transition and are required for HGF-mediated cell spreading and breakdown of epithelial adherens junctions. Mol. Biol. Cell. 2002;13:1449–1461
  33. Lamorte L, Kamikura DM, Park M. A switch from p130Cas/Crk to Gab1/Crk signaling correlates with anchorage independent growth and JNK activation in cells transformed by the Met receptor oncoprotein. Oncogene. 2000;19:5973–5981
  34. Sakkab D, Lewitzky M, Posern G, Schaeper U, Sachs M, Birchmeier W, et al. 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. 2000;275:10772–10778
  35. Lai JF, Kao SC, Jiang ST, Tang MJ, Chan PC, Chen HC. Involvement of focal adhesion kinase in hepatocyte growth factor-induced scatter of Madin-Darby canine kidney cells. J. Biol. Chem. 2000;275:7474–7480
  36. Chen HC, Chan PC, Tang MJ, Cheng CH, Chang TJ. Tyrosine phosphorylation of focal adhesion kinase stimulated by hepatocyte growth factor leads to mitogen-activated protein kinase activation. J. Biol. Chem. 1998;273:25777–25782
  37. Boccaccio C, Ando M, Tamagnone L, Bardelli A, Michieli P, Battistini C, et al. Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature. 1998;391:285–288
  38. Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM. Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis. Oncogene. 2000;19:1509–1518
  39. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol. 2003;4:915–925
  40. Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastatis Rev. 2003;22:309–325
  41. Trusolino L, Comoglio PM. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat. Rev. Cancer. 2002;2:289–300
  42. Maulik G, Shrikhande A, Kijima T, Ma PC, Morrison PT, Salgia R. Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev. 2002;13:41–59
  43. Moghul A, Lin L, Beedle A, Kanbour-Shakir A, DeFrances MC, Liu Y, et al. Modulation of c-MET proto-oncogene (HGF receptor) mRNA abundance by cytokines and hormones: evidence for rapid decay of the 8kb c-MET transcript. Oncogene. 1994;9:2045–2052
  44. Furge KA, Kiewlich D, Le P, Vo MN, Faure M, Howlett AR, et al. Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor tyrosine kinase. Proc. Natl Acad. Sci. USA. 2001;98:10722–10727
  45. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3:347–361
  46. Kuniyasu H, Yasui W, Kitadai Y, Yokozaki H, Ito H, Tahara E. Frequent amplification of the c-met gene in scirrhous type stomach cancer. Biochem. Biophys. Res. Commun. 1992;189:227–232
  47. Di Renzo MF, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L, et al. Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin. Cancer Res. 1995;1:147–154
  48. Hara T, Ooi A, Kobayashi M, Mai M, Yanagihara K, Nakanishi I. Amplification of c-myc, K-sam, and c-met in gastric cancers: detection by fluorescence in situ hybridization. Lab. Invest. 1998;78:1143–1153
  49. Wullich B, Sattler HP, Fischer U, Meese E. Two independent amplification events on chromosome 7 in glioma: amplification of the epidermal growth factor receptor gene and amplification of the oncogene MET. Anticancer Res. 1994;14:577–579
  50. Matsumoto K, Date K, Shimura H, Nakamura T. Acquisition of invasive phenotype in gallbladder cancer cells via mutual interaction of stromal fibroblasts and cancer cells as mediated by hepatocyte growth factor. Jpn. J. Cancer Res. 1996;87:702–710
  51. Matsumoto K, Date K, Ohmichi H, Nakamura T. Hepatocyte growth factor in lung morphogenesis and tumor invasion: role as a mediator in epithelium–mesenchyme and tumor–stroma interactions. Cancer Chemother. Pharmacol. 1996;38:S42–S47
  52. Matsumoto K, Nakamura T. Emerging multipotent aspects of hepatocyte growth factor. J. Biochem. 1996;119:591–600
  53. Nakamura T, Matsumoto K, Kiritoshi A, Tano Y. Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: in vitro analysis of tumor–stromal interactions. Cancer Res. 1997;57:3305–3313
  54. Gohda E, Matsunaga T, Kataoka H, Takebe T, Yamamoto I. Induction of hepatocyte growth factor in human skin fibroblasts by epidermal growth factor, platelet-derived growth factor and fibroblast growth factor. Cytokine. 1994;6:633–640
  55. Tamura M, Arakaki N, Tsubouchi H, Takada H, Daikuhara Y. Enhancement of human hepatocyte growth factor production by interleukin-1 alpha and -1 beta and tumor necrosis factor-alpha by fibroblasts in culture. J. Biol. Chem. 1993;268:8140–8145
  56. Tuck AB, Park M, Sterns EE, Boag A, Elliott BE. Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. Am. J. Pathol. 1996;148:225–232
  57. Yamashita J, Ogawa M, Yamashita S, Nomura K, Kuramoto M, Saishoji T, et al. Immunoreactive hepatocyte growth factor is a strong and independent predictor of recurrence and survival in human breast cancer. Cancer Res. 1994;54:1630–1633
  58. Taniguchi Y, Yorioka N, Yamashita K, Xue-Feng Y, Nishiki T, Ogawa T, et al. Localization of hepatocyte growth factor and tubulointerstitial lesions in IgA nephropathy. Am. J. Nephrol. 1997;17:413–416
  59. Moriyama T, Kataoka H, Tsubouchi H, Koono M. Concomitant expression of hepatocyte growth factor (HGF), HGF activator and c-met genes in human glioma cells in vitro. Fed. Eur. Biochem. Soc. Lett. 1995;372:78–82
  60. Ljubimova JY, Petrovic LM, Wilson SE, Geller SA, Demetriou AA. Expression of HGF, its receptor c-met, c-myc, and albumin in cirrhotic and neoplastic human liver tissue. J. Histochem. Cytochem. 1997;45:79–87
  61. Siegfried JM, Weissfeld LA, Singh-Kaw P, Weyant RJ, Testa JR, Landreneau RJ. Association of immunoreactive hepatocyte growth factor with poor survival in resectable non-small cell lung cancer. Cancer Res. 1997;57:433–439
  62. Furukawa T, Duguid WP, Kobari M, Matsuno S, Tsao MS. Hepatocyte growth factor and Met receptor expression in human pancreatic carcinogenesis. Am. J. Pathol. 1995;147:889–895
  63. Ferracini R, Di Renzo MF, Scotlandi K, Baldini N, Olivero M, Lollini P, et al. The Met/HGF receptor is over-expressed in human osteosarcomas and is activated by either a paracrine or an autocrine circuit. Oncogene. 1995;10:739–749
  64. Borset M, Lien E, Espevik T, Helseth E, Waage A, Sundan A. Concomitant expression of hepatocyte growth factor/scatter factor and the receptor c-MET in human myeloma cell lines. J. Biol. Chem. 1996;271:24655–24661
  65. Wang R, Ferrell LD, Faouzi S, Maher JJ, Bishop JM. Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J. Cell Biol. 2001;153:1023–1034
  66. Wallenius V, Hisaoka M, Helou K, Levan G, Mandahl N, Meis-Kindblom JM, et al. Overexpression of the hepatocyte growth factor (HGF) receptor (Met) and presence of a truncated and activated intracellular HGF receptor fragment in locally aggressive/malignant human musculoskeletal tumors. Am. J. Pathol. 2000;156:821–829
  67. Prat M, Crepaldi T, Gandino L, Giordano S, Longati P, Comoglio P. C-terminal truncated forms of Met, the hepatocyte growth factor receptor. Mol. Cell. Biol. 1991;11:5954–5962
  68. Park M, Dean M, Cooper CS, Schmidt M, O'Brien SJ, Blair DG, et al. Mechanism of met oncogene activation. Cell. 1986;45:895–904
  69. Follenzi A, Bakovic S, Gual P, Stella MC, Longati P, Comoglio PM. Cross-talk between the proto-oncogenes Met and Ron. Oncogene. 2000;19:3041–3049
  70. Jo M, Stolz DB, Esplen JE, Dorko K, Michalopoulos GK, Strom SC. Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J. Biol. Chem. 2000;275:8806–8811
  71. Oh RR, Park JY, Lee JH, Shin MS, Kim HS, Lee SK, et al. Expression of HGF/SF and Met protein is associated with genetic alterations of VHL gene in primary renal cell carcinomas. Acta Pathol. Microbiol. Immunol. Scand. 2002;110:229–238
  72. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat. Genet. 1997;16:68–73
  73. Schmidt L, Junker K, Weirich G, Glenn G, Choyke P, Lubensky I, et al. Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res. 1998;58:1719–1722
  74. Lee JH, Han SU, Cho H, Jennings B, Gerrard B, Dean M, et al. A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene. 2000;19:4947–4953
  75. Park WS, Dong SM, Kim SY, Na EY, Shin MS, Pi JH, et al. Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res. 1999;59:307–310
  76. Tanyi J, Tory K, Rigo J, Nagy B, Papp Z. Evaluation of the tyrosine kinase domain of the Met proto-oncogene in sporadic ovarian carcinomas*. Pathol. Oncol. Res. 1999;5:187–191
  77. Ma PC, Kijima T, Maulik G, Fox EA, Sattler M, Griffin JD, et al. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res. 2003;63:6272–6281
  78. Ma PC, Jagdeesh S, Jagadeeswaran R, Fox EA, Christensen JG, Maulik G, et al. c-MET expression/activation, functions, and mutations in non-small cell lung cancer. Proc. Am. Assoc. Cancer Res. 2004;44:1875
  79. Kong-Beltran M, Stamos J, Wickramasinghe D. The Sema domain of Met is necessary for receptor dimerization and activation. Cancer Cell. 2004;6:75–84
  80. Stamos J, Lazarus RA, Yao X, Kirchhofer D, Wiesmann C. Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor. Eur. Mol. Biol. Org. J. 2004;23:2325–2335
  81. Di Renzo MF, Olivero M, Martone T, Maffe A, Maggiora P, Stefani AD, et al. Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene. 2000;19:1547–1555
  82. Aebersold DM, Landt O, Berthou S, Gruber G, Beer KT, Greiner RH, et al. Prevalence and clinical impact of Met Y1253D-activating point mutation in radiotherapy-treated squamous cell cancer of the oropharynx. Oncogene. 2003;22:8519–8523
  83. Lorenzato A, Olivero M, Patane S, Rosso E, Oliaro A, Comoglio PM, et al. Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion. Cancer Res. 2002;62:7025–7030
  84. Zeng Z-S, Nash GM, Gimbel M, Nathanson DR, Culliford AT, D'Alessio, M, et al. Comparative analysis of c-Met gene amplification in primary colorectal cancer and liver metastasis using PCR/LDR assay. Proc. Am. Assoc. Cancer Res. 2004;44:5075
  85. Jin L, Fuchs A, Schnitt SJ, Yao Y, Joseph A, Lamszus K, et al. Expression of scatter factor and c-met receptor in benign and malignant breast tissue. Cancer. 1997;79:749–760
  86. Beviglia L, Matsumoto K, Lin CS, Ziober BL, Kramer RH. Expression of the c-Met/HGF receptor in human breast carcinoma: correlation with tumor progression. Int. J. Cancer. 1997;74:301–309
  87. Edakuni G, Sasatomi E, Satoh T, Tokunaga O, Miyazaki K. Expression of the hepatocyte growth factor/c-Met pathway is increased at the cancer front in breast carcinoma. Pathol. Int. 2001;51:172–178
  88. Tsarfaty I, Alvord WG, Resau JH, Altstock RT, Lidereau R, Bieche I, et al. Alteration of Met protooncogene product expression and prognosis in breast carcinomas. Anal. Quant. Cytol. Histol. 1999;21:397–408
  89. Ichimura E, Maeshima A, Nakajima T, Nakamura T. 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. 1996;87:1063–1069
  90. Yonemura Y, Kaji M, Hirono Y. Correlation between overexpression of c-met and the progression of gastric cancer. Int. J. Oncol. 1996;8:555–560
  91. Wu CW, Chi CW, Su TL, Liu TY, Lui WY, P'eng FK. Serum hepatocyte growth factor level associate with gastric cancer progression. Anticancer Res. 1998;18:3657–3659
  92. Aebersold DM, Kollar A, Beer KT, Laissue J, Greiner RH, Djonov V. 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. 2001;96:41–54
  93. Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E. Expression of hepatocyte growth factor and its receptor c-met proto-oncogene in hepatocellular carcinoma. Hepatology. 1997;25:862–866
  94. Iwasaki T, Hamano T, Ogata A, Hashimoto N, Kitano M, Kakishita E. Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma [see comment]. Br. J. Haematol. 2002;116:796–802
  95. Seidel C, Borset M, Turesson I, Abildgaard N, Sundan A, Waage A. Elevated serum concentrations of hepatocyte growth factor in patients with multiple myeloma. The Nordic Myeloma Study Group. Blood. 1998;91:806–812
  96. Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E. Expression of hepatocyte growth factor and its receptor, the c-met proto-oncogene, in hepatocellular carcinoma. Hepatology. 1997;25:619–623
  97. Ng EH, Pey HB, Law HY, Ng I, Ji CY, Lin V, et al. Loss of c-met protooncogene in primary and metastatic sites of breast cancer. Ann. Surg. Oncol. 1997;4:499–502
  98. Natali PG, Nicotra MR, Di Renzo MF, Prat M, Bigotti A, Cavaliere R, et al. Expression of the c-Met/HGF receptor in human melanocytic neoplasms: demonstration of the relationship to malignant melanoma tumour progression. Br. J. Cancer. 1993;68:746–750
  99. Koochekpour S, Jeffers M, Rulong S, Taylor G, Klineberg E, Hudson EA, et al. Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res. 1997;57:5391–5398
  100. Siegfried JM, Weissfeld LA, Luketich JD, Weyant RJ, Gubish CT, Landreneau RJ. The clinical significance of hepatocyte growth factor for non-small cell lung cancer. Ann. Thorac. Surg. 1998;66:1915–1918
  101. Uchida D, Kawamata H, Omotehara F, Nakashiro K, Kimura-Yanagawa T, Hino S, et al. Role of HGF/c-met system in invasion and metastasis of oral squamous cell carcinoma cells in vitro and its clinical significance. Int. J. Cancer. 2001;93:489–496
  102. Rong S, Segal S, Anver M, Resau JH, Vande Woude GF. Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proc. Natl Acad. Sci. USA. 1994;91:4731–4735
  103. Rong S, Bodescot M, Blair D, Dunn J, Nakamura T, Mizuno K, et al. Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor. Mol. Cell. Biol. 1992;12:5152–5158
  104. Rosen EM, Joseph A, Jin L, Rockwell S, Elias JA, Knesel J, et al. Regulation of scatter factor production via a soluble inducing factor. J. Cell Biol. 1994;127:225–234
  105. Jeffers M, Rao MS, Rulong S, Reddy JK, Subbarao V, Hudson E, et al. Hepatocyte growth factor/scatter factor-Met signaling induces proliferation, migration, and morphogenesis of pancreatic oval cells. Cell Growth Differ. 1996;7:1805–1813
  106. Jeffers M, Rong S, Woude GF. Hepatocyte growth factor/scatter factor-Met signaling in tumorigenicity and invasion/metastasis. J. Mol. Med. 1996;74:505–513
  107. Lamszus K, Jin L, Fuchs A, Shi E, Chowdhury S, Yao Y, et al. Scatter factor stimulates tumor growth and tumor angiogenesis in human breast cancers in the mammary fat pads of nude mice. Lab. Invest. 1997;76:339–353
  108. Jeffers M, Schmidt L, Nakaigawa N, Webb CP, Weirich G, Kishida T, et al. Activating mutations for the met tyrosine kinase receptor in human cancer. Proc. Natl Acad. Sci. USA. 1997;94:11445–11450
  109. Jeffers M, Fiscella M, Webb CP, Anver M, Koochekpour S, Vande Woude GF. The mutationally activated Met receptor mediates motility and metastasis. Proc. Natl Acad. Sci. USA. 1998;95:14417–14422
  110. Sattler M, Pride YB, Ma P, Gramlich JL, Chu SC, Quinnan LA, et al. A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase. Cancer Res. 2003;63:5462–5469
  111. Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P, Anver M, et al. Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proc. Natl Acad. Sci. USA. 1997;94:701–706
  112. Otsuka T, Takayama H, Sharp R, Celli G, LaRochelle WJ, Bottaro DP, et al. c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype. Cancer Res. 1998;58:5157–5167
  113. Gallego MI, Bierie B, Hennighausen L. Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways. Oncogene. 2003;22:8498–8508
  114. Horiguchi N, Takayama H, Toyoda M, Otsuka T, Fukusato T, Merlino G, et al. Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine. Oncogene. 2002;21:1791–1799
  115. Noonan FP, Otsuka T, Bang S, Anver MR, Merlino G. Accelerated ultraviolet radiation-induced carcinogenesis in hepatocyte growth factor/scatter factor transgenic mice. Cancer Res. 2000;60:3738–3743
  116. Recio JA, Noonan FP, Takayama H, Anver MR, Duray P, Rush WL, et al. Ink4a/arf deficiency promotes ultraviolet radiation-induced melanomagenesis. Cancer Res. 2002;62:6724–6730
  117. Sharp R, Recio JA, Jhappan C, Otsuka T, Liu S, Yu Y, et al. Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis [see comment] [erratum appears in Nat. Med. 2003 Jan;9(1):146]. Nat. Med. 2002;8:1276–1280
  118. Graveel CR, Su Y, Wang LM, Fiscella M, Lino T, Birchmeier C, et al. Tumorigenic effects of activating Met mutations in a knock-in mouse model. Proc. Am. Assoc. Cancer Res. 2004;44:5102
  119. Liang TJ, Reid AE, Xavier R, Cardiff RD, Wang TC. Transgenic expression of tpr-met oncogene leads to development of mammary hyperplasia and tumors. J. Clin. Invest. 1996;97:2872–2877
  120. Nakamura Y, Morishita R, Higaki J, Kida I, Aoki M, Moriguchi A, et al. Expression of local hepatocyte growth factor system in vascular tissues. Biochem. Biophys. Res. Commun. 1995;215:483–488
  121. Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, et al. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J. Cell Biol. 1992;119:629–641
  122. Rosen EM, Carley W, Goldberg ID. Scatter factor regulates vascular endothelial cell motility. Cancer Invest. 1990;8:647–650
  123. Rosen EM, Grant D, Kleinman H, Jaken S, Donovan MA, Setter E, et al. Scatter factor stimulates migration of vascular endothelium and capillary-like tube formation. Supplementum to Experientia. 1991;59:76–88
  124. Rosen EM, Meromsky L, Setter E, Vinter DW, Goldberg ID. Purified scatter factor stimulates epithelial and vascular endothelial cell migration. Proc. Soc. Exp. Biol. Med. 1990;195:34–43
  125. Grant DS, Kleinman HK, Goldberg ID, Bhargava MM, Nickoloff BJ, Kinsella JL, et al. Scatter factor induces blood vessel formation in vivo. Proc. Natl Acad. Sci. USA. 1993;90:1937–1941
  126. Dong G, Chen Z, Li ZY, Yeh NT, Bancroft CC, Van Waes C. Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Cancer Res. 2001;61:5911–5918
  127. Gille J, Khalik M, Konig V, Kaufmann R. Hepatocyte growth factor/scatter factor (HGF/SF) induces vascular permeability factor (VPF/VEGF) expression by cultured keratinocytes. J. Invest. Dermatol. 1998;111:1160–1165
  128. Van Belle E, Witzenbichler B, Chen D, Silver M, Chang L, Schwall R, et al. Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis. Circulation. 1998;97:381–390
  129. Zhang YW, Su Y, Volpert OV, Vande Woude GF. Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation. Proc. Natl Acad. Sci. USA. 2003;100:12718–12723
  130. Wojta J, Kaun C, Breuss JM, Koshelnick Y, Beckmann R, Hattey E, et al. 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. 1999;79:427–438
  131. Xin X, Yang S, Ingle G, Zlot C, Rangell L, Kowalski J, et al. Hepatocyte growth factor enhances vascular endothelial growth factor-induced angiogenesis in vitro and in vivo. Am. J. Pathol. 2001;158:1111–1120
  132. Morimoto A, Tada K, Nakayama Y, Kohno K, Naito S, Ono M, et al. Cooperative roles of hepatocyte growth factor and plasminogen activator in tubular morphogenesis by human microvascular endothelial cells. Jpn. J. Cancer Res. 1994;85:53–62
  133. Laterra J, Rosen E, Nam M, Ranganathan S, Fielding K, Johnston P. Scatter factor/hepatocyte growth factor expression enhances human glioblastoma tumorigenicity and growth. Biochem. Biophys. Res. Commun. 1997;235:743–747
  134. Tolnay E, Kuhnen C, Wiethege T, Konig JE, Voss B, Muller KM. Hepatocyte growth factor/scatter factor and its receptor c-Met are overexpressed and associated with an increased microvessel density in malignant pleural mesothelioma. J. Cancer Res. Clin. Oncol. 1998;124:291–296
  135. Abounader R, Ranganathan S, Lal B, Fielding K, Book A, Dietz H, et al. Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expression. J. Natl Cancer Inst. 1999;91:1548–1556
  136. Herynk MH, Stoeltzing O, Reinmuth N, Parikh NU, Abounader R, Laterra J, et al. Down-regulation of c-Met inhibits growth in the liver of human colorectal carcinoma cells. Cancer Res. 2003;63:2990–2996
  137. Kaplan O, Firon M, Vivi A, Navon G, Tsarfaty I. HGF/SF activates glycolysis and oxidative phosphorylation in DA3 murine mammary cancer cells. Neoplasia (New York). 2000;2:365–377
  138. Webb CP, Taylor GA, Jeffers M, Fiscella M, Oskarsson M, Resau JH, et al. Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/metastasis. Oncogene. 1998;17:2019–2025
  139. Bardelli A, Longati P, Gramaglia D, Basilico C, Tamagnone L, Giordano S, et al. Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth. Proc. Natl Acad. Sci. USA. 1998;95:14379–14383
  140. Atabey N, Gao Y, Yao ZJ, Breckenridge D, Soon L, Soriano JV, et al. 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. 2001;276:14308–14314
  141. Michieli P, Mazzone M, Basilico C, Cavassa S, Sottile A, Naldini L, et al. Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell. 2004;6:61–73
  142. Date K, Matsumoto K, Shimura H, Tanaka M, Nakamura T. HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor. Fed. Eur. Biochem. Soc. Lett. 1997;420:1–6
  143. Matsumoto K, Nakamura T. NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics. Cancer Sci. 2003;94:321–327
  144. Kuba K, Matsumoto K, Date K, Shimura H, Tanaka M, Nakamura T. HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Cancer Res. 2000;60:6737–6743
  145. Date K, Matsumoto K, Kuba K, Shimura H, Tanaka M, Nakamura T. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor. Oncogene. 1998;17:3045–3054
  146. Tomioka D, Maehara N, Kuba K, Mizumoto K, Tanaka M, Matsumoto K, et al. Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer Res. 2001;61:7518–7524
  147. Davies G, Mason MD, Martin TA, Parr C, Watkins G, Lane J, et al. The HGF/SF antagonist NK4 reverses fibroblast- and HGF-induced prostate tumor growth and angiogenesis in vivo. Int. J. Cancer. 2003;106:348–354
  148. Martin TA, Parr C, Davies G, Watkins G, Lane J, Matsumoto K, et al. Growth and angiogenesis of human breast cancer in a nude mouse tumour model is reduced by NK4, a HGF/SF antagonist. Carcinogenesis. 2003;24:1317–1323
  149. Saga Y, Mizukami H, Suzuki M, Urabe M, Kume A, Nakamura T, et al. Expression of HGF/NK4 in ovarian cancer cells suppresses intraperitoneal dissemination and extends host survival. Gene Ther. 2001;8:1450–1455
  150. Saimura M, Nagai E, Mizumoto K, Maehara N, Okino H, Katano M, et al. Intraperitoneal injection of adenovirus-mediated NK4 gene suppresses peritoneal dissemination of pancreatic cancer cell line AsPC-1 in nude mice. Cancer Gene Ther. 2002;9:799–806
  151. Maemondo M, Narumi K, Saijo Y, Usui K, Tahara M, Tazawa R, et al. Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy. Mol. Ther. 2002;5:177–185
  152. Hirao S, Yamada Y, Koyama F, Fujimoto H, Takahama Y, Ueno M, et al. Tumor suppression effect using NK4, a molecule acting as an antagonist of HGF, on human gastric carcinomas. Cancer Gene Ther. 2002;9:700–707
  153. Nakabayashi M, Morishita R, Nakagami H, Kuba K, Matsumoto K, Nakamura T, et al. HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model. Diabetologia. 2003;46:115–123
  154. Kuba K, Matsumoto K, Ohnishi K, Shiratsuchi T, Tanaka M, Nakamura T. Kringle 1-4 of hepatocyte growth factor inhibits proliferation and migration of human microvascular endothelial cells. Biochem. Biophys. Res. Commun. 2000;279:846–852
  155. Cao B, Su Y, Oskarsson M, Zhao P, Kort EJ, Fisher RJ, et al. Neutralizing monoclonal antibodies to hepatocyte growth factor/scatter factor (HGF/SF) display antitumor activity in animal models. Proc. Natl Acad. Sci. USA. 2001;98:7443–7448
  156. Zheng Z, Adams C, Moffat B, Schwall R. A chimeric Fab antibody serves as an antagonist to the HGF/SF receptor c-Met. Proc. Am. Assoc. Cancer Res. 2003;43:5717
  157. Morton PA, Joy WD, Bono CP, Arbuckle A, Evans ML, Huynh MS, et al. In vitro and in vivo activity of fully-human monoclonal antibody antagonists to c-Met protein tyrosine kinase. Proc. Am. Assoc. Cancer Res. 2003;43:5604
  158. Schwall R, Adams CW, Zheng Z, Romero M, Mai E, Moffat B, et al. Inhibition of cmet activation by a one-armed antibody. Proc. Am. Assoc. Cancer Res. 2004;44:1424
  159. Neckers L, Schulte T, Mimnaugh E. Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest. New Drugs. 1999;17:361–373
  160. Webb CP, Hose CD, Koochekpour S, Jeffers M, Oskarsson M, Sausville E, et al. The geldanamycins are potent inhibitors of the hepatocyte growth factor/scatter factor-met-urokinase plasminogen activator–plasmin proteolytic network. Cancer Res. 2000;60:342–349
  161. Morotti A, Mila S, Accornero P, Tagliabue E, Ponzetto C. K252a inhibits the oncogenic properties of Met, the HGF receptor. Oncogene. 2002;21:4885–4893
  162. Schiering N, Knapp S, Marconi M, Flocco MM, Cui J, Perego R, et al. Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a. Proc. Natl Acad. Sci. USA. 2003;100:12654–12659
  163. Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, et al. 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. 2003;63:7345–7355
  164. Wang X, Le P, Liang C, Chan J, Kiewlich D, Miller T, et al. Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion. Mol. Cancer Ther. 2003;2:1085–1092
  165. F. Yasunari, N. Terufumi, T. Osawa, A. Miwa, K, Nakamura. Preparation of quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of hepatocyte growth factor receptor as antitumor agents, WO 2003000660 A1, Kirin Beer Kabushiki, Japan, 2003.
  166. Berthou S, Aebersold DM, Schmidt LS, Stroka D, Heigl C, Streit B, et al. The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants. Oncogene. 2004;1–7
  167. Maulik G, Ma PC, Rajgor M, Jagadeesh S, Schaefer E, Shirazian S, et al. c-Met pathway inhibition through a novel tyrosine kinase inhibitor in small cell lung cancer. Proc. Am. Assoc. Cancer Res. 2003;43:6200
  168. Khwaja A, Lehmann K, Marte BM, Downward J. Phosphoinositide 3-kinase induces scattering and tubulogenesis in epithelial cells through a novel pathway. J. Biol. Chem. 1998;273:18793–18801
  169. Karihaloo A, O'Rourke DA, Nickel C, Spokes K, Cantley LG. Differential MAPK pathways utilized for HGF- and EGF-dependent renal epithelial morphogenesis. J. Biol. Chem. 2001;276:9166–9173
  170. Nakaigawa N, Weirich G, Schmidt L, Zbar B. Tumorigenesis mediated by MET mutant M1268T is inhibited by dominant-negative Src. Oncogene. 2000;19:2996–3002
  171. Liu ZX, Yu CF, Nickel C, Thomas S, Cantley LG. Hepatocyte growth factor induces ERK-dependent paxillin phosphorylation and regulates paxillin-focal adhesion kinase association. J. Biol. Chem. 2002;277:10452–10458
  172. Koon EC, Ma PC, Salgia R, Christensen JG, Muto MG, Berkowitz RS, et al. Effect of a c-met specific ATP-competitive small-molecule (SU-MI-2) on human ovarian carcinoma cell growth, motility and invasion. Proc. Am. Assoc. Cancer Res. 2004;44:5363
  173. Hov H, Holt RU, Ro TB, Fagerli U-M, Hjorth-Hansen H, Baykov V, et al. A selective c-Met inhibitor blocks an autocrine HGF growth loop in ANBL-6 cells and prevents migration and adhesion of myeloma cells. Clin. Cancer Res. 2004;10:6686–6694
  174. Hay RV, Cao B, Skinner RS, Wang LM, Su Y, Resau JH, et al. Radioimmunoscintigraphy of tumors autocrine for human met and hepatocyte growth factor/scatter factor. Mol. Imaging. 2002;1:56–62
  175. Shaharabany M, Abramovitch R, Kushnir T, Tsarfaty G, Ravid-Megido M, Horev J, et al. In vivo molecular imaging of met tyrosine kinase growth factor receptor activity in normal organs and breast tumors. Cancer Res. 2001;61:4873–4878
  176. Takanami I, Tanana F, Hashizume T, Kikuchi K, Yamamoto Y, Yamamoto T, et al. Hepatocyte growth factor and c-Met/hepatocyte growth factor receptor in pulmonary adenocarcinomas: an evaluation of their expression as prognostic markers. Oncology. 1996;53:392–397
  177. Tsao MS, Liu N, Chen JR, Pappas J, Ho J, To C, et al. Differential expression of Met/hepatocyte growth factor receptor in subtypes of non-small cell lung cancers. Lung Cancer. 1998;20:1–16
  178. Olivero M, Rizzo M, Madeddu R, Casadio C, Pennacchietti S, Nicotra MR, et al. Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas. Br. J. Cancer. 1996;74:1862–1868
  179. Liu C, Tsao MS. 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. 1993;142:1155–1162
  180. Stabile LP, Lyker JS, Huang L, Siegfried JM. Inhibition of human non-small cell lung tumors by a c-Met antisense/U6 expression plasmid strategy. Gene Ther. 2004;11:325–335
  181. Ajisaka H, Nishimura G, Tsuneda A, Fujita H, Michiwa Y, Kawamura T, et al. The expression of cMET/hepatocyte growth factor receptor in colorectal cancer. Jpn. J. Gastroenterol. 1998;95:750–754
  182. Takeuchi H, Bilchik A, Saha S, Turner R, Wiese D, Tanaka M, et al. c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin. Cancer Res. 2003;9:1480–1488
  183. Schmidt L, Junker K, Nakaigawa N, Kinjerski T, Weirich G, Miller M, et al. Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene. 1999;18:2343–2350
  184. Parr C, Hiscox S, Nakamura T, Matsumoto K, Jiang WG. 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. 2000;85:563–570
  185. Camp RL, Rimm EB, Rimm DL. Met expression is associated with poor outcome in patients with axillary lymph node negative breast carcinoma. Cancer. 1999;86:2259–2265
  186. Nakopoulou L, Gakiopoulou H, Keramopoulos A, Giannopoulou I, Athanassiadou P, Mavrommatis J, et al. c-met tyrosine kinase receptor expression is associated with abnormal beta-catenin expression and favourable prognostic factors in invasive breast carcinoma. Histopathology. 2000;36:313–325
  187. Nagy J, Curry GW, Hillan KJ, McKay IC, Mallon E, Purushotham AD, et al. Hepatocyte growth factor/scatter factor expression and c-met in primary breast cancer. Surg. Oncol. 1996;5:15–21
  188. Ghoussoub RA, Dillon DA, D'Aquila T, Rimm EB, Fearon ER, Rimm DL. Expression of c-met is a strong independent prognostic factor in breast carcinoma. Cancer. 1998;82:1513–1520
  189. Bieche I, Champeme MH, Lidereau R. Infrequent mutations of the MET gene in sporadic breast tumours. Int. J. Cancer. 1999;82:908–910
  190. Jiang WG, Grimshaw D, Lane J, Martin TA, Abounader R, Laterra J, et al. A hammerhead ribozyme suppresses expression of hepatocyte growth factor/scatter factor receptor c-MET and reduces migration and invasiveness of breast cancer cells [erratum appears in Clin Cancer Res 2002 Jan;8(1):300 Note: Abounder R [corrected to Abounader R]]. Clin. Cancer Res. 2001;7:2555–2562
  191. Hiscox S, Parr C, Nakamura T, Matsumoto K, Mansel RE, Jiang WG. Inhibition of HGF/SF-induced breast cancer cell motility and invasion by the HGF/SF variant, NK4. Breast Cancer Res. Treat. 2000;59:245–254
  192. Inoue K, Chikazawa M, Karashima T, Iiyama T, Kamada M, Shuin T, et al. Overexpression of c-Met/hepatocyte growth factor receptors in human prostatic adenocarcinoma. Acta Med. Okayama. 1998;52:305–310
  193. Pisters LL, Troncoso P, Zhau HE, Li W, von Eschenbach AC, Chung LW. c-met proto-oncogene expression in benign and malignant human prostate tissues. J. Urol. 1995;154:293–298
  194. Humphrey PA, Zhu X, Zarnegar R, Swanson PE, Ratliff TL, Vollmer RT, et al. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am. J. Pathol. 1995;147:386–396
  195. Knudsen BS, Gmyrek GA, Inra J, Scherr DS, Vaughan ED, Nanus DM, et al. High expression of the Met receptor in prostate cancer metastasis to bone. Urology. 2002;60:1113–1117
  196. Parr C, Davies G, Nakamura T, Matsumoto K, Mason MD, Jiang WG. 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. 2001;285:1330–1337
  197. La Rosa S, Uccella S, Capella C, Erba S, Sessa F. Localization of hepatocyte growth factor and its receptor met in endocrine cells and related tumors of the gut and pancreas: an immunohistochemical study. Endocr. Pathol. 2000;11:315–329
  198. Paciucci R, Vila MR, Adell T, Diaz VM, Tora M, Nakamura T, et al. Activation of the urokinase plasminogen activator/urokinase plasminogen activator receptor system and redistribution of E-cadherin are associated with hepatocyte growth factor-induced motility of pancreas tumor cells overexpressing. Met. Am. J. Pathol. 1998;153:201–212
  199. Di Renzo MF, Poulsom R, Olivero M, Comoglio PM, Lemoine NR. Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res. 1995;55:1129–1138
  200. Maehara N, Matsumoto K, Kuba K, Mizumoto K, Tanaka M, Nakamura T. NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells. Br. J. Cancer. 2001;84:864–873
  201. Wagatsuma S, Konno R, Sato S, Yajima A. Tumor angiogenesis, hepatocyte growth factor, and c-Met expression in endometrial carcinoma. Cancer. 1998;82:520–530
  202. Huntsman D, Resau JH, Klineberg E, Auersperg N. Comparison of c-met expression in ovarian epithelial tumors and normal epithelia of the female reproductive tract by quantitative laser scan microscopy. Am. J. Pathol. 1999;155:343–348
  203. Di Renzo MF, Olivero M, Katsaros D, Crepaldi T, Gaglia P, Zola P, et al. Overexpression of the Met/HGF receptor in ovarian cancer. Int. J. Cancer. 1994;58:658–662
  204. Sawatsubashi M, Sasatomi E, Mizokami H, Tokunaga O, Shin T. Expression of c-Met in laryngeal carcinoma. Virchows Arch. 1998;432:331–335
  205. Suzuki K, Cheng J, Watanabe Y. Hepatocyte growth factor and c-Met (HGF/c-Met) in adenoid cystic carcinoma of the human salivary gland. J. Oral Pathol. Med. 2003;32:84–89
  206. Galeazzi E, Olivero M, Gervasio FC, De Stefani A, Valente G, Comoglio PM, et al. Detection of MET oncogene/hepatocyte growth factor receptor in lymph node metastases from head and neck squamous cell carcinomas. Eur. Arch. Otorhinolaryngol. 1997;254:S138–S143
  207. Qian CN, Guo X, Cao B, Kort EJ, Lee CC, Chen J, et al. Met protein expression level correlates with survival in patients with late-stage nasopharyngeal carcinoma. Cancer Res. 2002;62:589–596
  208. Kiss A, Wang NJ, Xie JP, Thorgeirsson SS. Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth Factor/c-met,TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin. Cancer Res. 1997;3:1059–1066
  209. Suzuki K, Hayashi N, Yamada Y, Yoshihara H, Miyamoto Y, Ito Y, et al. Expression of the c-met protooncogene in human hepatocellular carcinoma. Hepatology. 1994;20:1231–1236
  210. Nabeshima K, Shimao Y, Sato S, Kataoka H, Moriyama T, Kawano H, et al. Expression of c-Met correlates with grade of malignancy in human astrocytic tumours: an immunohistochemical study. Histopathology. 1997;31:436–443
  211. Hirose Y, Kojima M, Sagoh M, Murakami H, Yoshida K, Shimazaki K, et al. Immunohistochemical examination of c-Met protein expression in astrocytic tumors. Acta Neuropathol. 1998;95:345–351
  212. Moon YW, Weil RJ, Pack SD, Park WS, Pak E, Pham T, et al. Missense mutation of the MET gene detected in human glioma. Mod. Pathol. 2000;13:973–977
  213. Abounader R, Lal B, Luddy C, Koe G, Davidson B, Rosen EM, et al. In vivo targeting of SF/HGF and c-met expression via U1snRNA/ribozymes inhibits glioma growth and angiogenesis and promotes apoptosis. Fed. Am. Soc. Exp. Biol. J. 2002;16:108–110
  214. Nakopoulou L, Vouriakou C, Papaliodi E, Lazaris AC, Stefanaski K, Michalopoulos G. Immunodetection of c-met-oncogene's protein product in renal cell neoplasia. Pathol. Res. Pract. 1997;193:299–304
  215. Sweeney P, El-Naggar AK, Lin SH, Pisters LL. Biological significance of c-met over expression in papillary renal cell carcinoma. J. Urol. 2002;168:51–55
  216. Natali PG, Prat M, Nicotra MR, Bigotti A, Olivero M, Comoglio PM, et al. Overexpression of the met/HGF receptor in renal cell carcinomas. Int. J. Cancer. 1996;69:212–217
  217. Inoue K, Karashima T, Chikazawa M, Iiyama T, Yoshikawa C, Furihata M, et al. Overexpression of c-met proto-oncogene associated with chromophilic renal cell carcinoma with papillary growth. Virchows Arch. 1998;433:511–515
  218. Park WS, Oh RR, Kim YS, Park JY, Shin MS, Lee HK, et al. Absence of mutations in the kinase domain of the Met gene and frequent expression of Met and HGF/SF protein in primary gastric carcinomas. Acta Pathol. Microbiol. Immunol. Scand. 2000;108:195–200
  219. Wu CW, Li AF, Chi CW, Chung WW, Liu TY, Lui WY, et al. Hepatocyte growth factor and Met/HGF receptors in patients with gastric adenocarcinoma. Oncol. Rep. 1998;5:817–822
  220. Nakajima M, Sawada H, Yamada Y, Watanabe A, Tatsumi M, Yamashita J, et al. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas [see comment]. Cancer. 1999;85:1894–1902
  221. Taniguchi K, Yonemura Y, Nojima N, Hirono Y, Fushida S, Fujimura T, et al. The relation between the growth patterns of gastric carcinoma and the expression of hepatocyte growth factor receptor (c-met), autocrine motility factor receptor, and urokinase-type plasminogen activator receptor. Cancer. 1998;82:2112–2122
  222. Tsugawa K, Yonemura Y, Hirono Y, Fushida S, Kaji M, Miwa K, et al. Amplification of the c-met, c-erbB-2 and epidermal growth factor receptor gene in human gastric cancers: correlation to clinical features. Oncology. 1998;55:475–481
  223. Gao C, Lu Y. Correlation of multiple gene changes with malignant phenotype of human gastric carcinoma. Chung-Hua i Hsueh Tsa Chih. 1996;76:671–675
  224. Kaji M, Yonemura Y, Harada S, Liu X, Terada I, Yamamoto H. 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. 1996;3:393–404

PII: S0304-3835(04)00765-7

doi: 10.1016/j.canlet.2004.09.044

Cancer Letters
Volume 225, Issue 1 , Pages 1-26 , 8 July 2005

Article Tools

* Image Usage & Resolution