Acta Neuropathologica

, Volume 108, Issue 2, pp 135–142 | Cite as

Epidermal growth factor receptor family (EGFR, ErbB2–4) in gliomas and meningiomas

  • Ulrika Andersson
  • Dongsheng Guo
  • Beatrice Malmer
  • A. Tommy Bergenheim
  • Thomas Brännström
  • Håkan Hedman
  • Roger Henriksson
Regular Paper


Overexpression of epidermal growth factor receptor (EGFR, ErbB1) correlates with enhanced malignant potential of many human tumor types including glioblastoma multiforme. The significance of EGFR expression in meningiomas is, however, unclear. Reports regarding the other EGFR family members, ErbB2–4, in brain tumors are sparse. In this study, the expression of the EGFR family members was analyzed in relation to various parameters for the clinical importance of these receptors in 44 gliomas and 26 meningiomas. In gliomas, quantitative real-time reverse transcription (RT)-PCR revealed the highest EGFR mRNA expression in high-grade gliomas, while ErbB2 and ErbB3 mRNA were detected only in a few high-grade gliomas. In contrast, ErbB4 expression was most pronounced in low-grade gliomas. Immunohistochemistry showed significantly higher EGFR protein expression in high-grade gliomas compared to low-grade gliomas (P=0.004). ErbB2 protein expression was mainly seen in high-grade gliomas. ErbB3 protein expression was low in all gliomas analyzed. ErbB4 protein expression was significantly higher in low-grade gliomas than in high-grade gliomas (P=0.007). In meningiomas, quantitative real-time RT-PCR revealed expression of EGFR, ErbB2, and ErbB4 mRNA in the majority of the tumors. ErbB3 was detected in only one of the meningiomas analyzed. Immunohistochemistry demonstrated high ErbB2 protein expression in meningiomas. An intriguing observation in astrocytomas and oligodendrogliomas grade II, was a significantly decreased overall survival for patients with high EGFR protein expression (P=0.04). The high ErbB4 expression in low-grade compared to high-grade gliomas might suggest that ErbB4 acts as a suppressor of malignant transformation in brain tumors, which is in line with previous studies in other tumor types.


Epidermal growth factor receptor ErbB2 ErbB3 ErbB4 Gliomas Meningiomas 



This study was supported by grants from the Swedish Cancer Society and the Lion’s Cancer Research Foundation, Umeå University, Sweden. Kerstin Bergh is acknowledged for her excellent assistance with the immunohistochemical staining. We also thank Karin Andersson for secretarial assistance and Björn Tavelin for statistical help and advice.


  1. 1.
    Barker FG, Simmons ML, Chang SM, Prados MD, Larson DA, Sneed PK, Wara WM, Berger MS, Chen P, Israel MA, Aldape KD (2001) EGFR overexpression and radiation response in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 51:410–418CrossRefPubMedGoogle Scholar
  2. 2.
    Chozick BS, Benzil DL, Stopa EG, Pezzullo JC, Knuckey NW, Epstein MH, Finkelstein SD, Finch PW (1996) Immunohistochemical evaluation of erb-2 and p53 protein expression in benign and atypical human meningiomas. J Neurooncol 27:117–126PubMedGoogle Scholar
  3. 3.
    Etienne MC, Formento JL, Lebrun-Frenay C, Gioanni J, Chatel M, Paquis P, Bernard C, Courdi A, Bensadoun RJ, Pignol JP, Francoual M, Grellier P, Frenay M, Milano G (1998) Epidermal growth factor receptor and labelling index are independent prognostic factors in glial tumor outcome. Clin Cancer Res 4:2383–2390PubMedGoogle Scholar
  4. 4.
    Gilbertson RJ, Pearson AD, Perry RH, Jaros E, Kelly PJ (1995) Prognostic significance of the c-erbB-2 oncogene product in childhood medulloblastoma. Br J Cancer 71:473–477PubMedGoogle Scholar
  5. 5.
    Gilbertson R, Perry RH, Kelly PJ, Pearson AD, Lunec J (1997) Prognostic significance of HER2 and HER4 co-expression in childhood medulloblastoma. Cancer Res 57:3272–3280PubMedGoogle Scholar
  6. 6.
    Gilbertson R, Wickramasinghe C, Hernan R, Balaji V, Hunt D, Jones-Wallace D, Crolla J, Perry R, Lunec J, Pearson A, Ellison D (2001) Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer 85:705–712CrossRefPubMedGoogle Scholar
  7. 7.
    Graber HU, Friess H, Kaufmann B, Willi D, Zimmermann A, Korc M, Buchler MW (1999) ErbB-4 mRNA expression is decreased in non-metastatic pancreatic cancer. Int J Cancer 84:24–27CrossRefPubMedGoogle Scholar
  8. 8.
    Haapasalo H, Hyytinen E, Sallinen P, Helin H, Kallioniemi OP, Isola J (1996) c-erb-2 in astrocytomas: infrequent overexpression by immunohistochemistry and absence of gene amplification by fluorescence in situ hybridisation. Br J Cancer 73:620–623PubMedGoogle Scholar
  9. 9.
    Haugen DR, Akslen LA, Varhaug JE, Lillehaug JR (1996) Expression of c-erbB3 and c-erbB4 in papillary thyroid carcinomas. Cancer Res 57:1184–1188Google Scholar
  10. 10.
    Herms JW, Behnke J, Bergmann M, Christen HJ, Kolb R, Wilkening M, Markakis E, Hanefeld F, Kretzschmar HA (1997) Potential prognostic value of c-erbB-2 in medulloblastoma in very young children. J Pediatr Hematol Oncol 19:510–515CrossRefPubMedGoogle Scholar
  11. 11.
    Hiesiger EM, Hayes RL, Pierz DM, Budzilovich GN (1993) Prognostic relevance of epidermal growth factor receptor (EGF-R) and c-neu/erbB2 expression in glioblastomas (GBMs). J Neurooncol 16: 93–104PubMedGoogle Scholar
  12. 12.
    Hoang-Xuan K, He J, Huguet S, Mokhtari K, Marie Y, Kujas M, Leuraud P, Capelle L, Delattre JY, Poirier J, Broet P, Sanson M (2001) Molecular heterogeneity of oligodendrogliomas suggests alternative pathways in tumor progression. Neurology 9:1278–1281Google Scholar
  13. 13.
    Hwang S-L, Hong Y-R, Chai C-Y, Lin H-J, Howng S-L (1998) Prognostic evaluation in supratentorial astrocytic tumors using p53, epidermal growth factor receptor, c-erbB-2 immunostaining. Kaohsiung J Med Sci 14:607–615PubMedGoogle Scholar
  14. 14.
    Jaros E, Perry RH, Adam L, Kelly PJ, Crawford PJ, Kalbag RM, Mendelow AD, Sengupta RP, Pearson ADJ (1992) Prognostic implications of p53 protein, epidermal growth factor receptor, and Ki-67 labelling in brain tumours. Br J Cancer 66:373–385PubMedGoogle Scholar
  15. 15.
    Junttila TT, Sundvall M, Maatta JA, Elenius K (2000) Erbb4 and its isoforms: selective regulation of growth factor responses by naturally occurring receptor variants. Trends Cardiovasc Med 10:304–310Google Scholar
  16. 16.
    Kataoka H, Joh T, Kasugai K, Okayama N, Moriyama A, Asai K, Kato T (1998) Expression of mRNA for heregulin and its receptor, ErbB-3 and ErbB-4, in human upper gastrointestinal mucosa. Life Sci 63:553–564CrossRefPubMedGoogle Scholar
  17. 17.
    Kew TY, Bell JA, Pinder SE, Denley H, Srinivasan R, Gullick WJ, Nicholson RI, Blamey RW, Ellis IO (2000) c-erbB-4 protein expression in human breast cancer. Br J Cancer 82:1163–1170CrossRefPubMedGoogle Scholar
  18. 18.
    Kleihues P, Cavenee WK (eds) (2000) WHO Health Organization classification of tumours: tumours of the nervous system. IARC Press, LyonGoogle Scholar
  19. 19.
    Lee JC, Wang ST, Chow NH, Yang HB (2002) Investigation of the prognostic value of co-expressed erbB family members for the survival of colorectal cancer patients after curative surgery. Eur J Cancer 38:1065–1071Google Scholar
  20. 20.
    Lyne JC, Melhem MF, Finley GG, Wen D, Liu N, Deng DH, Salup R (1997) Tissue expression of neu differentiation factor/heregulin and its receptor complex in prostate cancer and its biologic effects on prostate cancer cells in vitro. Cancer J Sci Am 3:21–30PubMedGoogle Scholar
  21. 21.
    Nilsson J, Vallbo C, Dongsheng G, Golovleva I, Hallberg B, Henriksson R, Hedman H (2001) Cloning, characterization, and expression of human LIG1. Biochem Biophys Res Commun 284:1155–1161CrossRefPubMedGoogle Scholar
  22. 22.
    Olson JJ, Barnett D, Yang J, Assietti R, Cotsonis G, James CD (1998) Gene amplification as a prognostic factor in primary brain tumours. Clin Cancer Res 4:215–222PubMedGoogle Scholar
  23. 23.
    Riese DJ 2nd, Stern DF (1998) Specificity within the EGF family/ErbB receptor family signalling network. BioEssays 20:41–48CrossRefPubMedGoogle Scholar
  24. 24.
    Schlegel J, Merdes A, Stumm G, Albert FK, Forsting M, Hynes N, Kiessling M (1994) Amplification of the epidermal growth factor receptor gene correlates with different growth behaviour in human glioblastoma. Int J Cancer 56:72–77PubMedGoogle Scholar
  25. 25.
    Schwechheimer K, Läufle RM, Schmahl W, Knödlseder M, Fischer H, Höfler H (1994) Expression of Neu/c-erbB-2 in human brain tumors. Hum Pathol 25:772–780CrossRefPubMedGoogle Scholar
  26. 26.
    Simmons ML, Lamborn KR, Takahashi M, Chen P, Israel MA, Berger MS, Godfrey T, Nigro J, Prados M, Chang S, Barker FG, Aldape K (2001) Analysis of complex relationships between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients. Cancer Res 61:1122–1128PubMedGoogle Scholar
  27. 27.
    Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, O’Fallon JR, Schaefer PL, Scheithauer BW, James CD, Buckner JC, Jenkins RB (2001) PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 93:1246–1256CrossRefPubMedGoogle Scholar
  28. 28.
    Thomasson M, Hedman H, Junttila TT, Elenius K, Ljungberg B, Henriksson R (2004) ErbB4 is down-regulated in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis of the epidermal growth factor receptor family. Acta Oncol (in press)Google Scholar
  29. 29.
    Yarden Y, Sliwkowsky MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137CrossRefPubMedGoogle Scholar
  30. 30.
    Zenhe S, Risberg B, Karlsson MG, Willman K, Tierens A, Skovlund E, Nesland JM (2002) EGFR family expression in breast carcinomas. c-erbB-2 and c-erbB-4 receptors have different effects on survival. J Pathol 196:17–25CrossRefPubMedGoogle Scholar
  31. 31.
    Zhu A, Shaeffer J, Leslie S, Kolm P, El-Mahdi AM (1996) Epidermal growth factor receptor: an independent predictor of survival in astrocytic tumors given definitive irradiation. Int J Radiat Oncol Biol Phys 34:809–815CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Ulrika Andersson
    • 1
  • Dongsheng Guo
    • 1
  • Beatrice Malmer
    • 1
  • A. Tommy Bergenheim
    • 2
  • Thomas Brännström
    • 3
  • Håkan Hedman
    • 1
  • Roger Henriksson
    • 1
  1. 1.Department of Radiation Sciences, OncologyUmeå UniversityUmeåSweden
  2. 2.Department of Pharmacology and Clinical Neuroscience, NeurosurgeryUmeå UniversityUmeåSweden
  3. 3.Department of Medical Bioscience, PathologyUmeå UniversityUmeåSweden

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