Hepatocyte growth factor/scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinases


Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional factor involved both in development and tissue repair, as well as pathological processes such as cancer and metastasis. It has been identified in vivo in many types of tumours together with its tyrosine kinase receptor, Met. We show here that exogenous HGF/SF acts as a strong chemoattractant for human mesothelioma cell lines. The factor also enhanced cell adhesion to and invasion into Matrigel. The mesothelioma cell lines synthesized a panel of matrix metalloproteinases critical for tumour progression such as MMP-1, 2, 3, 9 and membrane-bound MT1-MMP. HGF/SF stimulated the expression of MMP-1, 9 and MT1-MMP and had a slight effect on expression of the MMP inhibitor TIMP-1 but not TIMP-2. However, there was no simple correlation between the levels of MMPs and TIMPs of the cell lines and their different invasion properties or between HGF/SF stimulatory effects on MMP expression and invasion. In addition, effects of protease inhibitors on invasion suggested that serine proteases were also expressed in human mesothelioma cell lines and were involved in HGF/SF-induced invasion. The results show a predominant role for HGF/SF in mesothelioma cell invasion, stimulating simultaneously adhesion, motility, invasion and regulation of MMP and TIMP levels. © 2000 Cancer Research Campaign

Change history

  • 16 November 2011

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication


  1. Allan JA, Hembry RM, Angal S, Reynolds JJ and Murphy G (1991) Binding of latent and high M active forms of stromelysin to collagen is mediated by the c-terminal domain. J Cell Sci 99: 789–795

  2. Attanoos RL and Gibbs AR (1997) Pathology of malignant mesothelioma. Histopathol 30: 403–418

  3. Beviglia L and Kramer RH (1999) HGF induces FAK activation and integrin-mediated adhesion in MTLn3 breast carcinoma cells. Int J Cancer 83: 640–649

  4. Bottaro DP, Rubin JS, Faletto DL, Chan AM-L, Kimiecick TE, Vande Woude GF and Aaronson SA (1991) Identification of the hepatocyte growth factor receptor as the c-met protooncogene product. Science 251: 802–804

  5. Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, Tamagnone L, Coffer A and Comoglio PM (1992) Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119: 629–641

  6. Clark IM, Powell LK, Wright JK, Cawston TE and Hazleman BL (1992) Monoclonal antibodies against human fibroblast collagenase and the design of an enzyme-linked immunosorbent assay to measure total collagenase. Matrix 12: 475–480

  7. Coussens LM and Werb Z (1996) Matrix metalloproteinases and the development of cancer. Chem Biol 3: 895–904

  8. Di Renzo MF, Narsimhan RP, Olivero M, Bretti S, Giordano S, Medico E, Gaglia P, Zara P and Comoglio PM (1991) Expression of the met/HGF receptor in normal and neoplastic tissues. Oncogene 6: 1997–2003

  9. D'Ortho MP, Stanton H, Butler M, Atkinson SJ, Murphy G and Hembry RM (1998) MT1-MMP on the cell surface causes focal degradation of gelatin films. FEBS Lett 421: 159–164

  10. Dunsmore SE, Rubin JS, Kovacs SO, Chedid M, Parks WC and Welgus HG (1996) Mechanisms of hepatocyte growth factor stimulation of keratinocyte metalloproteinase production. J Biol Chem 271: 24576–24582

  11. Eagles G, Warn A, Ball RY, Baillie-Johnson H, Arakaki N, Daikuhara Y and Warn RM (1996) Hepatocyte growth factor/scatter factor is present in most pleural effusion fluids from cancer patients. Br J Cancer 73: 377–381

  12. Edwards DR, Leco KJ, Beaudry PP, Atadja PW, Veillette C and Riabowol KT (1996) Differential effects of transforming growth factor-β1 on the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in young and old human fibroblasts. Experimental Gerontology 31: 207–223

  13. Gherardi E, Sharpe M, Lane K, Sirulnik A and Stoker M (1993) Hepatocyte growth factor/scatter factor (HGF/SF), the c-Met receptor and the behaviour of epithelial cells. Symp. Soc Exp Biol 47: 163–181

  14. Grant DS, Kleinman HK, Goldberg ID, Bhargava M, Nickoloff BJ, Kinsella JL, Polverini PJ and Rosen EM (1993) Scatter factor induces blood vessel formation in vivo. Proc Natl Acad Sci USA 90: 1937–1941

  15. Hamasuna R, Kataoka H, Moriyama T, Itoh H, Seiki M and Koono M (1999) Regulation of matrix metalloproteinase-2 (MMP-2) by hepatocyte growth factor/scatter factor (HGF/SF) in human glioma cells: HGF/SF enhances MMP-2 expression and activation accompanying up-regulation of membrane type-1 MMP. Int J Cancer 82: 274–281

  16. Harvey P, Warn A, Newman P, Perry LJ, Ball RY and Warn RM (1996) Immunoreactivity for hepatocyte growth factor and its receptor, Met, in human lung carcinoma and malignant mesothelioma. J Pathol 180: 389–394

  17. Harvey P, Warn A, Dobbin S, Arakaki N, Daikuhara Y, Jaurand MC and Warn RM (1998) Expression of HGF/SF in mesothelioma cell lines and its effects on cell motility, proliferation and morphology. Br J Cancer 77: 1052–1059

  18. Jeffers M, Rong S, Anver M and Vande Woude GF (1996a) Autocrine hepatocyte growth factor/scatter factor-Met signalling induces transformation and the invasive/metastatic phenotype in C127 cells. Oncogene 13: 853–861

  19. Jeffers M, Rong S and Vande Woude GF (1996b) 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

  20. Johnson LL, Dyer R and Hupe DJ (1998) Matrix metalloproteinases. Curr Opin Chem Biol 2: 466–471

  21. Kheradmand F, Werner E, Tremble P, Symons M and Werb Z (1998) Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science 280: 898–902

  22. Klominek J, Sumitran Karuppan S and Hauzenberger D (1997) Differential motile response of human mesothelioma cells to fibronectin, laminin and collagen type IV: the role of β1 integrins. Int J Cancer 72: 1034–1044

  23. Klominek J, Baskin B, Liu Z and Hauzenberger D (1998) Hepatocyte growth factor/scatter factor stimulates chemotaxis and growth of malignant mesothelioma cells through c-met receptor. Int J Cancer 76: 240–249

  24. Lohi J, Lehti K, Westermarck J, Kähäri V and Keski-Oja J (1996) Regulation of membrane type matrix metalloproteinase-1 expression by growth factors and phorbol 12-myristate 13-acetate. Eur J Biochem 239: 239–247

  25. Marshall BC, Santana A, Xu Q-P, Petersen M, Campbell EJ, Hoidal JR and Welgus HG (1993) Metalloproteinases and tissue inhibitor of metalloproteinases in mesothelial cells. Cellular differentiation influences expression. J Clin Invest 91: 1792–1799

  26. Messent AJ, Tuckwell DS, Knäuper Humphries MJ, Murphy G and Gavrilovic J (1998) Effects of collagenase-cleavage of type 1 collagen on α2β1 integrin-mediated cell adhesion. J Cell Sc 111: 1127–1135

  27. Miyazawa K, Shimomura T, Kitamura A, Kondo J, Morimoto Y and Kitamura N (1993) Molecular cloning and sequence analysis of the cDNA for a human serine protease responsible for activation of hepatocyte growth factor. J Biol Chem 268: 10024–10028

  28. Moriyama T, Kataoka H, Seguchi Tsubouchi H and Koono M (1996) Effects of hepatocyte growth factor (HGF) on human glioma cells in vitro: HGF acts as a motility factor in glioma cells. Int J Cancer 66: 678–685

  29. Murphy G and Knäuper V (1997) Relating matrix metalloproteinase structure to function: why the ‘hemopexin’ domain? Matrix Biol 15: 511–518

  30. Murphy G and Gavrilovic J (1999) Proteolysis and cell migration: creating a path? Curr Opin Cell Biol 11: 914–621

  31. Nakahara H, Howard L, Thompson EW, Sato H, Seiki M, Yeh Y and Chen WT (1997) Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion. Proc Natl Acad Sci USA 94: 7959–7964

  32. Nakayama Y, Kohno K, Nomural Y, Naito S, Ono M, Shimizu K, Osato K and Kuwano M (1993) Enhanced invasive activity and decreased expression of tissue inhibitors of metalloproteinases by hepatocyte growth factor in human renal cancer cells. The Cancer Journal 6: 213–219

  33. Naldini L, Vigna E, Narsimham R, Gaudino G, Zarnegar R, Michalopoulos GK and Comoglio PM (1991) Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-met. Oncogene 6: 501–504

  34. Naldini L, Tamagnone L, Vigna E, Sachs M, Hartmann G, Birchmeier W, Daikuhara Y, Tsubouchi H, Blasi F and Comoglio PM (1992) Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor. EMBO J 11: 4825–4833

  35. Peacock A, Dawes K, Shock A, Gray A, Reeves J and Laurent G (1992) Endothelin-1 and endothelin-3 induce chemotaxis and replication of pulmonary artery fibroblasts. Am J Respir Cell Mol Biol 7: 492–499

  36. Peto J, Hodgson J, Matthews F and Jones J (1995) Continuing increase in mesothelioma mortality in Britain. Lancet 345: 53–539

  37. Prat M, Narsimhan RP, Crepaldi T, Nicotra MR, Natali P and Comoglio PM (1991) The receptor encoded by the human c-Met oncogene is expressed in hepatocytes, epithelial cells and solid tumors. Int J Cancer 49: 323–328

  38. Rong S, Bodescot M, Blair D, Dunn J, Nakamura T, Mizuno K, Park M, Chan A, Aaronson S and Vande Woude GF (1992) Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor. Mol Cell Biol 12: 5152–5158

  39. Rong S, Jeffers M, Resau JH, Tsarfaty I, Oskarsson M and Vande Woude GF (1993) Met expression and sarcoma tumorigenicity. Cancer Res 53: 5355–5360

  40. Rong S, Segal S, Anver M, Resau JH and Vande Woude GF (1994) Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. PNAS 91: 4731–4735

  41. Rosen EM, Knesel J, Goldberg ID, Jin L, Bhargava M, Joseph A, Zitnik R, Wines J, Kelley M and Rockwell S (1994) Scatter factor modulates the metastatic phenotype of the EMT6 mouse mammary tumor. Int J Cancer 57: 706–714

  42. Shetty S, Kumar A, Johnson A, Pueblitz S and Idell S (1995) Urokinase receptor in human malignant mesothelioma cells: role in tumor cell mitogenesis and proteolysis. Am J Physiol 268: L972–L982

  43. Sonnenberg E, Meyer D, Weidner KM and Birchmeier C (1993) 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 123: 223–235

  44. Stoker M, Gherardi E, Perryman M and Gray J (1987) Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327: 239–242

  45. Thirkettle I, Harvey P, Hasleton PS, Ball RY and Warn RM (2000) Immunoreactivity for cadherins, HGF/SF, met, and erbB-2 in pleural malignant mesotheliomas. Histopathology 36: 522–528

  46. Weidner K, Behrens J, Vandekerckhove J and Birchmeier W (1990) Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells. J Cell Biol 111: 2097–2108

  47. Weimar IS, de Jong D, Muller EJ, Nakamura T, van Gorp JM, de Gast GC and Gerritsen WR (1997) Hepatocyte growth factor/scatter factor promotes adhesion of lymphoma cells to extracellular matrix molecules via alpha 4 beta 1 and alpha 5 beta 1 integrins. Blood 89: 990–1000

  48. Yamashita K, Suzuki M, Iwata H, Koike T, Hamaguchi M, Shinagawa A, Noguchi T and Hayakawa T (1996) Tyrosine phosphorylation is crucial for growth signaling by tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2). FEBS Lett 396: 103–107

  49. Zeng L, Fleury-Feith J, Monnet I, Boutin C, Bignon J and Jaurand MC (1994) Hum Pathol 25: 227–234

Download references

Author information

Rights and permissions

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

Reprints and Permissions

About this article

Cite this article

Harvey, P., Clark, I., Jaurand, M. et al. Hepatocyte growth factor/scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinases. Br J Cancer 83, 1147–1153 (2000). https://doi.org/10.1054/bjoc.2000.1445

Download citation


  • HGF/SF
  • mesothelioma
  • cell motility
  • invasion
  • MMP
  • TIMP

Further reading