Impact of c-Met expression on angiogenesis in soft tissue sarcomas: correlation to microvessel-density

  • Cornelius Kuhnen
  • Thomas Muehlberger
  • Maria Honsel
  • Edina Tolnay
  • Hans Ulrich Steinau
  • Klaus-Michael Müller
Original Paper

Abstract

Purpose and methods

The c-Met protein is significant for oncogenesis and angiogenesis within the c-Met/HGF/SF-mediator system. The aim of this study was the analysis of c-Met immunoexpression/-synthesis and microvessel density as parameters for angiogenesis and prognosis in 115 soft tissue sarcomas.

Results

C-Met could be detected by immunohistochemistry in 87% of sarcomas. In all, 60.9% of cases exhibited absent or faint expression of c-Met protein, and 39.1% high expression of c-Met protein with a correlation between tumor grading and c-Met immunoexpression. Using in situ hybridization with detection of c-met-mRNA-transcripts, c-Met protein synthesis within tumor cells could be demonstrated. A statistically significant correlation between c-Met immunoexpression and tumor microvessel density was found. No prognostic value of c-Met expression and microvessel density could be detected in 56 patients with clinical follow-up (P=0.8506 and P=0.9329 for disease-free survival).

Conclusions

The results underline a role of c-Met as an oncoprotein in soft tissue sarcomas with correlation between immunoexpression and grading. The statistically significant correlation between c-Met expression and microvessel density (as a parameter of tumor angiogenesis) suggests an angiogenic function of the c-Met/HGF/SF mediator system in malignant mesenchymal tumors.

Keywords

Angiogenesis Soft tissue sarcoma c-Met oncoprotein Microvessel density 

Notes

Acknowledgements

The authors gratefully acknowledge the excellent technical assistance of Susanne Schaub-Kuhnen and Cornelia Troske (Institute for Pathology, University Hospital Bergmannsheil, Bochum).

References

  1. Alami J, Williams BR, Yeger H (2002) Expression and localization of HGF and met in Wilms' tumours. J Pathol 196:76–84CrossRefPubMedGoogle Scholar
  2. Camp RL, Rimm EB, Rimm DL (1999) Met expression is associated with poor outcome in patients with axillary lymph node negative breast cancer. Cancer 86:2259–2265CrossRefPubMedGoogle Scholar
  3. Collett D (1994) Modelling survival data in medical research, 1st edn. Chapman & Hall, London, 1994Google Scholar
  4. Cordell JL, Falini B, Erber WN (1984) Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal antialkaline phosphatase (APAAP) complexes. J Histochem Cytochem 32:219–229PubMedGoogle Scholar
  5. Cortner J, Vande Woude GF, Rong S (1995) The Met-HGF/SF autocrine signaling mechanism is involved in sarcomagenesis. In: Goldberg ID, Rosen EM (eds) Epithelial-mesenchymal interactions in cancer. Birkhäuser, Basel, pp 89–121Google Scholar
  6. Costello P, McCann A, Carney DN, Dervan PA (1995) Prognostic significance of microvessel density in lymph node negative breast carcinoma. Hum Pathol 26:1173–1174PubMedGoogle Scholar
  7. Dean M, O'Connell P, Leppert M, Park M, Amos JA, Phillips DG, White R, Vande Woude GF (1987) Three additional DNA polymorphisms in the met gene and D7S8 locus: use in prenatal diagnosis of cystic fibrosis. J Pediatr 111:490–495PubMedGoogle Scholar
  8. De Young BR, Wick MR, Fitzgibbon FJ, Sirgi KE, Swanson PR (1993) CD31: an immunospecific marker for endothelial differentiation in human neoplasms. Appl Immunohistochem 1:97–100Google Scholar
  9. Ebert M, Yokoyama M, Friess H, Büchler MW, Korc M (1994) Coexpression of the c-met proto-oncogene and hepatocyte growth factor in human pancreatic cancer. Cancer Res 54:5775–5778PubMedGoogle Scholar
  10. Ferracini R, Oliviero M, Di Renzo MF, Martano M, De Giovanni C, Nanni P, Basso G, Scotlandi K, Lollini PL, Comoglio PM (1996) Retrogenic expression of the MET proto-oncogene correlates with the invasive phenotype of human rhabdomyosarcomas. Oncogene 12:1697–1705PubMedGoogle Scholar
  11. Fletcher CDM, Unni KK, Mertens F (eds) (2002) World Health Organization classification of tumours. Pathology and genetics of tumours of soft tissue and bone. IARC, Lyon, FranceGoogle Scholar
  12. Folkman J (1995) Tumor angiogenesis. In: Mendelsohn J (ed) The molecular basis of cancer. Saunders, Philadelphia London Toronto, pp 207–232Google Scholar
  13. Fukuda T, Ichimura E, Shinozaki T, Sano T, Kashiwabara K, Oyama T, Nakajima T, Nakumara T (1998) Coexpression of HGF and c-Met/HGF receptor in human bone and soft tissue tumors. Pathol Int 48:757–762PubMedGoogle Scholar
  14. Furukawa T, Duguid WP, Kobari M, Matsuno S, Tsao MS (1995) Hepatocyte growth factor and Met receptor expression in human pancreatic carcinogenesis. Am J Pathol 147:889–895PubMedGoogle Scholar
  15. Ghoussoub RA, Dillon DA, D´Aquila T, Rimm EB, Fearon ER, Rimm DL (1998) Expression of c-met is a strong independent prognostic factor in breast carcinoma. Cancer 82:1513–1520CrossRefPubMedGoogle Scholar
  16. Guillou L, Coindre JM, Bonichon F, Binh Bui N, Terrier P, Collin P, Vilain MO, Mandard AM, Le Doussal V, Leroux A, Jacquemier J, Duplay H, Sastre-Garau X, Costa J (1997) Comparative study of the national cancer institute and french federation of cancer centers sarcoma group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 15:350–362PubMedGoogle Scholar
  17. Helou K, Wallenius V, Qiu Y, Ohman F, Stahl F, Klinga-Levan K, Kindblom LG, Mandahl N, Jansson JO, Levan G (1999) Amplification and overexpression of the hepatocyte growth factor receptor (HGFR/MET) in rat DMBA sarcomas. Oncogene 18:3226–3234CrossRefPubMedGoogle Scholar
  18. Hirose Y, Kojima M, Sagoh M, Hayashi T, Murakami H, Shimazaki K, Yoshida K, Kawase T (1998) Clinical importance of c-Met protein expression in high grade astrocytic tumors. Neurol Med Chir Tokyo 38:851–858PubMedGoogle Scholar
  19. Jin L, Fuchs A, Schnitt SJ, Yao Y, Joseph A, Lamszus K, Park M, Goldberg ID, Rosen EM (1997) Expression of scatter factor and c-met receptor in benign and malignant breast cancer. Cancer 79:749–760CrossRefPubMedGoogle Scholar
  20. Johnson GD, De Noguera C, Aranjo JGM (1986) A simple method for reducing the fading of immunfluorescence during microscopy. J Immunol Methods 43:349–350CrossRefGoogle Scholar
  21. Kleinbaum DG (1994) Logistic regression, 1st edn. Springer, New YorkGoogle Scholar
  22. Koochekpour S, Jeffers M, Rulong S, Taylor G, Klineberg E, Hudson EA, Resau JH, Vande Woude GF (1997) Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res 57:5391–5398PubMedGoogle Scholar
  23. Kuhnen C, Tolnay E, Steinau HU, Voss B, Müller KM (1998) Expression of c-Met receptor and hepatocyte growth factor/scatter factor in synovial sarcoma and epithelioid sarcoma. Virchows Arch 432:337–342CrossRefPubMedGoogle Scholar
  24. Mandard AM, Petiot JF, Marnay J, Mandard JC, Chasle J, De Ranieri E, Dupin P, Herlin P, De Ranieri J, Tanguy A, Boulier N, Abbatucci JS (1989) Prognostic factors in soft tissue sarcomas. Cancer 63:1437–1451PubMedGoogle Scholar
  25. Maulik G, Shrikhande A, Kijima T, Ma PC, Morrison PT, Salgia R (2002) Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev 13:41–59CrossRefPubMedGoogle Scholar
  26. Mentzel T, Calonje E, Wadden C, Camplejohn RS, Beham A, Smith MA, Fletcher CDM (1996) Myxofibrosarcoma: clinicopathologic analysis of 75 cases with emphasis on the low-grade variant. Am J Surg Pathol 20:391–405CrossRefPubMedGoogle Scholar
  27. Miracco C, Montesco MC, Santopietro R, Spina D, d'Amore ESG, Tosi P, Ninfo V (1996) Proliferative activity, angiogenesis, and necrosis in peripheral nerve sheath tumors: a quantitative evaluation for prognosis. Mod Pathol 9:1108–1117PubMedGoogle Scholar
  28. Nabeshima K, Shimao Y, Sato S, Kataoka H, Moriyama T, Kawano H, Wakisaka S, Koono M (1997) Expression of c-Met correlates with grade of malignancy in human astrocytic tumours: an immunohistochemical study. Histopathology 31:436–443PubMedGoogle Scholar
  29. Naka T, Iwamoto Y, Shinohara N, Ushijima M, Chuman H, Tsuneyoshi M (1997) Expression of c-met proto-oncogene product (c-MET) in benign and malignant bone tumors. Mod Pathol 10:832–838PubMedGoogle Scholar
  30. Natali PG, Prat M, Nicotra MR, Bigotti A, Oliviero M, Comoglio PM, Di Renzo MF (1996) Overexpression of the met/HGF receptor in renal cell carcinomas. Int J Cancer (Pred Oncol) 69:212–217Google Scholar
  31. Oda Y, Sakamoto A, Saito T, Kinukawa N, Iwamoto Y, Tsuneyoshi M (2000) Expression of hepatocyte growth factor (HGF)/scatter factor and its receptor c-Met correlates with poor prognosis in synovial sarcoma. Hum Pathol 31:185–192PubMedGoogle Scholar
  32. Parmar MKB, Machin D (1995) Survival analysis, 1st edn. Wiley, ChichesterGoogle Scholar
  33. Pavlopoulos PM, Konstantinidou AE, Agapitos E, Kavantzas N, Nikolopoulou P, Davaris P (1998) A morphometric study of neovascularization in colorectal carcinoma. Cancer 83:2067–2075PubMedGoogle Scholar
  34. Perosio PM, Brooks JJ (1989) Expression of growth factors and growth factor receptors in soft tissue tumors. Lab Invest 60:245–253PubMedGoogle Scholar
  35. Pisters LL, Troncoso P, Zhau HE, Li W, von Eschenbach AC, Chung LWK (1995) C-met proto-oncogene expression in benign and malignant human prostate tissues. J Urology 154:293–298Google Scholar
  36. Polverini PJ, Nickoloff BJ (1995) Role of scatter factor and the c-met protooncogene in the pathogenesis of AIDS-associated Kaposi´s sarcoma. Adv Cancer Res 66:235–253PubMedGoogle Scholar
  37. Qian CN, Guo X, Cao B, Kort EJ, Lee CC, Chen J, Wang LM, Mai WY, Min HQ, Hong MH, Vande Woude GF, Resau JH, The BT (2002) Met protein expression level correlates with survival in patients with late-stage nasopharyngeal carcinoma. Cancer Res 62:589–596PubMedGoogle Scholar
  38. Rong S, Bodescot M, Blair D, Dunn J, Nakamura T, Mizuno K, Park M, Chan A, Aaronson S, Vande Woude GF (1992) Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor. Mol Cell Biol 12:5152–5158PubMedGoogle Scholar
  39. Rong S, Jeffers M, Resau JH, Tsarfaty I, Oskarsson M, Vande Woude GF (1993) Met expression and sarcoma tumorigenicity. Cancer Res 53:5355–5360PubMedGoogle Scholar
  40. Rosen EM, Goldberg ID (1994) Scatter factor and angiogenesis. Adv Cancer Res 67:257–279Google Scholar
  41. Roychowdhury DF, Tseng A, Fu KK, Weinberg V, Weidner N (1996) New prognostic factors in nasopharyngeal carcinoma: tumor angiogenesis and c-erbB2 expression. Cancer 77:1419–1426CrossRefPubMedGoogle Scholar
  42. Saeki H, Oda S, Kawaguchi H, Ohno S, Kuwano H, Maehara Y, Sugimachi K (2002) Concurrent overexpression of Ets-1 and c-Met correlates with a phenotype of high cellular motility in human esophageal cancer. Int J Cancer 98:8–13CrossRefPubMedGoogle Scholar
  43. Scotlandi K, Baldini N, Oliviero M, Di Renzo MF, Martano M, Serra M, Manara MC, Comoglio PM, Ferracini R (1996) Expression of Met/hepatocyte growth factor receptor gene and malignant behavior of musculoskeletal tumors. Am J Pathol 149:1209–1219PubMedGoogle Scholar
  44. Tokunou M, Niki T, Eguchi K, Iba S, Tsuda H, Yamada T, Matsuno Y, Kondo H, Saitoh Y, Inamura H, Hirohashi S (2001) c-MET expression in myofibroblasts: role in autocrine activation and prognostic significance in lung adenocarcinoma. Am J Pathol 158:1451–1463PubMedGoogle Scholar
  45. Tolnay E, Kuhnen C, Wiethege T, König JE, Voss B, Müller KM (1998) 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 124:291–296CrossRefPubMedGoogle Scholar
  46. Tynninen O, von Boguslawski K, Aronen HJ, Paavonen T (1999) Prognostic value of vascular density and cell proliferation in breast cancer patients. Pathol Res Pract 195:31–37PubMedGoogle Scholar
  47. Vermeulen PB, Gasparini G, Fox SB, Toi M, Martin L, McGulloch P, Pezzala F, Viale G, Weidner N, Harris AL, Dirix LY (1996) Quantification of angiogenesis in solid human tumors:an international consensus on the methodology and criteria of evaluation. Eur J Cancer 32:2474–2478CrossRefGoogle Scholar
  48. Wagatsuma S, Konno R, Sato S, Yamjima A (1998) Tumor angiogenesis, hepatocyte growth factor, and c-Met expression in endometrial carcinoma. Cancer 82:520–530CrossRefPubMedGoogle Scholar
  49. Wallenius V, Hisaoka M, Helou K, Levan G, Mandahl N, Meis-Kindblom JM, Kindblom LG, Jansson JO (2000) Overrexpression 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 156:821–829PubMedGoogle Scholar
  50. Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med 324:1–8PubMedGoogle Scholar
  51. Weidner N, Folkman J, Pozza F (1992) Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 84:1875CrossRefPubMedGoogle Scholar
  52. Weiss SW, Goldblum JR (2001) Enzinger and Weiss's soft tissue tumors, 4th edn. Mosby, St. Louis Baltimore BerlinGoogle Scholar
  53. Wiethege T, Voss B, Pohle T, Fisseler-Eckhoff A, Müller KM (1991) Localization of elastase and tumor necrosis factor α mRNA by non-radiactive in situ hybridization in cultures of alveolar macrophages. Path Res Pract 187:912–915PubMedGoogle Scholar
  54. Yamazaki K, Abe S, Takekawa H, Sukoh N, Watanabe N, Ogura S (1994) Tumor angiogenesis in human lung adenocarcinoma. Cancer 74:2245–2250PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Cornelius Kuhnen
    • 1
  • Thomas Muehlberger
    • 2
  • Maria Honsel
    • 1
  • Edina Tolnay
    • 1
  • Hans Ulrich Steinau
    • 3
  • Klaus-Michael Müller
    • 1
  1. 1.Institute for Pathology, Limb tumor registryUniversity Hospital BergmannsheilBochumGermany
  2. 2.Department of Plastic and Reconstructive Surgery, University HospitalHannover Medical SchoolHannoverGermany
  3. 3.Department of Plastic Reconstructive and Hand Surgery-Burn Centre, Limb tumor registryUniversity Hospital Bergmannsheil44789 BochumGermany

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