Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Amplification and overexpression of the hepatocyte growth factor receptor (HGFR/MET) in rat DMBA sarcomas

Oncogene volume 18, pages 3226–3234 (1999)Cite this article

Abstract

In the present study subcutaneous fibrosarcomas were induced by the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) in rats from F1 generation cross breedings of two different inbred strains. Comparative genomic hybridization (CGH) analysis, which allows detection of DNA sequence copy changes, was applied to one of the tumors and it was found that there were increased copy numbers of sequences at chromosome 4q12-q21 in this tumor. We have previously determined that the loci for the hepatocyte growth factor (Hgf) and hepatocyte growth factor receptor (Hgfr/Met), a protooncogene, are situated in this particular chromosome region. Using probes for the two genes in FISH (fluorescence in situ hybridization) and in Southern blots we found that the Hgfr/Met gene was amplified in five of the 19 sarcomas studied, and that the Hgf gene was coamplified in two of them. Northern and Western blots and tyrosine phosphorylation analysis showed that the HGF receptor was overexpressed and functional in all five tumors, as well as in two additional tumors. In summary, both amplification and overexpression of the Hgfr/Met gene was found in about 25% of DMBA-induced experimental rat sarcomas, and HGF receptor overexpression alone was seen in two additional tumors. Possibly this reflects an involvement in paracrine or autocrine stimulation of growth and invasiveness by HGF. Our finding could provide a rodent model system to increased knowledge about causality and therapy, which may be applicable to the sizeable fraction of human musculoskeletal tumors displaying MET overexpression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 5
Figure 3
Figure 4

Similar content being viewed by others

References

  • Biedler JL and Spengler BA. . 1976 Science 19: 185–187.

  • Comoglio PM and Boccaccio C. . 1996 Genes to Cells 1: 347–354.

  • Di Renzo MF, Olivero M, Katsaros D, Crepaldi T, Gaglia P, Zola P, Sismondi P and Comoglio PM. . 1994 Int. J. Cancer 58: 658–662.

  • du Manoir S, Speicher MR, Joos S, Schröck E, Popp S, Döhner H, Kovacs G, Robert-Nicoud M, Lichter P and Cremer T. . 1993 Hum. Genet. 90: 590–610.

  • Ferracini R, Olivero M, Di Renzo MF, Martano M, De Giovanni C, Nanni P, Basso G, Scotlandi K, Lollini PL and Comoglio PM. . 1996 Oncogene 12: 1697–1705.

  • Fischer U, Müller H-W, Sattler H-P, Feiden K, Zang KD and Meese E. . 1995 Genes Chromosom. Cancer 12: 63–65.

  • Galeazzi E, Olivero M, Gervasio FC, De Stefani A, Valente G, Comoglio PM, Di Renzo MF and Cortesina G. . 1997 Eur. Arch. Otorhinolaryngol. 254: (suppl 1) S138–S143.

  • Houldsworth J, Cordon-Cardo C, Ladanyi M, Kelsen DP and Chaganti RS. . 1990 Cancer Res. 50: 6417–6422.

  • Islam MQ and Levan G. . 1987 Hereditas 107: 127–130.

  • Iwazawa T, Shiozaki H, Doki Y, Inoue M, Tamura S, Matsui S, Monden T, Matsumoto K, Nakamura T and Monden M. . 1996 Jpn. J. Cancer Res. 87: 1134–1142.

  • Jeffers M, Rong S and Vande Woude GF. . 1996 Mol. Cell. Biol. 16: 1115–1125.

  • Kallioniemi O-P, Kallioniemi A, Piper J, Isola J, Waldman FM, Gray JW and Pinkel D. . 1994 Genes Chromosom. Cancer 10: 231–243.

  • Kito K, Kihana T, Sugita A, Murao S, Akehi S, Sato M, Tachibana M, Kimura S and Ueda N. . 1996 Mol. Carcinog. 17: 78–83.

  • Kuniyasu H, Yasui W, Kitadai Y, Yokozaki H, Ito H and Tahara E. . 1992 Biochem. Biophys. Res. Commun. 189: 227–232.

  • Levan G, Mandahl N, Bregula U, Klein G and Levan A. . 1976 Hereditas 83: 83–90.

  • Maggiora P, Gambarotta G, Olivero M, Giodano S, Di Renzo MF and Comoglio PM. . 1997 J. Cell. Physiol. 173: 183–186.

  • Maniatis T, Fritsch EF and Sambrook J. . 1982 Molecular cloning: A Laboratory Manual. Cold Spring Harbor Laboratory: Cold Spring Harbor, New York.

    Google Scholar 

  • Matsumoto K and Nakamura T. . 1996 J. Biochem. 119: 519–600.

  • Mitelman F, Johansson B, Mandahl N and Mertens F. . 1997 Cancer Genet. Cytogenet. 95: 1–8.

  • Mitelman F and Levan G. . 1972 Hereditas 71: 325–334.

  • Mitelman F, Mark J, Levan G and Levan A. . 1972 Science 176: 1340–1341.

  • Naka T, Iwamoto Y, Shinohara N, Ushijima M, Chuman H and Tsuneyoshi M. . 1997 Modern Pathology 10: 832–838.

  • Nisson PE, Watkins PC and Boyle A. . 1992 Focus 14: 119–122.

  • Nunberg JH, Kaufman RJ, Schimke RT, Urlaub G and Chasin LA. . 1978 Proc. Natl. Acad. Sci. USA 75: 5553–5556.

  • Quintanilla M, Brown K, Ramsden M and Balmain A. . 1986 Nature 322: 78–80.

  • Rong S, Segal S, Anver M, Resau JH and Vande Woude GF. . 1994 Proc. Natl. Acad. Sci. USA 91: 4731–4735.

  • Rubin JS, Bottaro DB and Aaronson SA. . 1993 Biochem. Biophys. Acta 1155: 357–371.

  • Ruggeri B, DiRado M, Zhang SY, Bauer B, Goodrow T and Klein-Szanto AJP. . 1993 Proc. Natl. Acad. Sci. USA 90: 1013–1017.

  • Schwab M, Ramsay G, Alitalo K, Varmus HE, Bishop JM, Martinsson T, Levan G and Levan A. . 1985 Nature 315: 345–347.

  • Scotlandi K, Baldini N, Oliviero M, Di Renzo MF, Martano M, Serra M, Manara MC, Comoglio PM and Ferracini R. . 1996 Am. J. Pathol. 149: 1209–1219.

  • Southern EM. . 1975 J. Mol. Biol. 98: 503–517.

  • Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM and Sonenhseim GE. . 1997 J. Clin. Invest. 100: 2952–2960.

  • Stark GR and Wahl GM. . 1984 Ann. Rev. Biochem. 53: 447–491.

  • Wallenius VR, Rawet H, Skrtic S, Helou K, Qiu Y, Levan G, Ekberg S, Carlsson B, Isaksson OGP, Nakamura T and Jansson J-O. . 1997 Mamm. Genome 8: 661–667.

  • Yamada A, Matsumoto K, Iwanari H, Sekiguchi K, Kawata S, Matsuzawa Y and Nakamura T. . 1995 Biomed. Res. 16: 105–114.

  • Zarbl H, Sukumar S, Arthur AV, Martin-Zanca D and Barbacid M. . 1985 Nature 315: 382–385.

Download references

Acknowledgements

This work was supported by grants from the Swedish Cancer Society, the Swedish Medical Research Council (Nos 9894 and 10998), the IngaBritt and Arne Lundberg Research Foundation, the Wilhelm and Martina Lundgren Foundation, the Royal Swedish Academy of Sciences, the Royal and Hvitfeldtska Foundation, the Söderberg Foundation, the Bergwall Foundation, Nordisk Insulin Foundation, Swedish Medical Society and Göteborg Medical Society.

Author information

Authors and Affiliations

  1. >Department of Cell and Molecular Biology – Genetics, Göteborg University, Gothenburg, Sweden

    Khalil Helou, Yan Qiu, Fredrik Öhman, Fredrik Ståhl, Karin Klinga-Levan & Göran Levan

  2. Research Centre for Endocrinology and Metabolism (RCEM), Göteborg University, Gothenburg, Sweden

    Ville Wallenius & John-Olov Jansson

  3. Department of Pathology, Göteborg University, Gothenburg, Sweden

    Lars-Gunnar Kindblom

  4. Department of Clinical Genetics, University Hospital, Lund, Sweden

    Nils Mandahl

Authors
  1. Khalil Helou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ville Wallenius
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fredrik Öhman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fredrik Ståhl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karin Klinga-Levan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lars-Gunnar Kindblom
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nils Mandahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. John-Olov Jansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Göran Levan
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Helou, K., Wallenius, V., Qiu, Y. et al. Amplification and overexpression of the hepatocyte growth factor receptor (HGFR/MET) in rat DMBA sarcomas. Oncogene 18, 3226–3234 (1999). https://doi.org/10.1038/sj.onc.1202658

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202658

Keywords

This article is cited by

Search

Advanced search

Quick links