Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Expression of cyclooxygenase-2 and epidermal growth factor receptor in primary and recurrent glioblastoma multiforme


Purpose: To investigate the pattern and level of cyclooxygenase-2 (COX-2) expression in a series of high grade primary and recurrent glioblastoma multiforme (GBM) and correlation with time to recurrence and patients’ survival following therapy. The relationship between COX-2 and epidermal growth factor receptor (EGFR) immunoreactivities was evaluated. Materials and methods: Specimens of 14 primary and 14 recurrent GBMs (eight pairs) following surgery and full course radiation therapy were processed for immunostaining on COX-2 and EGFR. Tumor cell positivity was semi-quantitatively scored. COX-2 scores of the primary tumor and recurrence were correlated with the time to radiological tumor progression and patients’ survival. Results: COX-2 positive tumor cells were disseminated throughout the tumor parenchyma. The intensity and pattern of COX-2 expression were heterogeneous, with predominant expression in areas surrounding tumor necrosis. Scoring of COX-2 positivity revealed values between 1 and 80% of the cells. Primary GBMs with COX-2 expression levels between 25% and 70% of the tumor cells showed a shorter time to radiological recurrence than GBMs with <10% COX-2 positive tumor cells (respectively, 219±50 and 382±77 days). No correlation was found between the COX-2 expression in the primary tumor and patients’ survival (r s=−0.073) following therapy. No correlation was found either between COX-2 and EGFR immunoreactivity. Conclusions: Immunohistochemical expression of COX-2 in GBM showed large variation. Hence, determination of COX-2 expression in tumor specimen for each individual might be relevant for selection of those patients, who could benefit from adjuvant therapy with selective COX-2 inhibitors.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. Badie B, Schartner JM, Hagar AR, Prabakaran S, Peebles TR, Bartley B, Lapsiwala S, Resnick DK, Vorpahl J (2003) Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation. Clin Cancer Res 9:872–877

  2. Barker FG 2nd, 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 51:410–418

  3. Brada M (1999) Current approaches to radiation therapy for malignant gliomas. Front Radiat Ther Oncol 33:139–149

  4. Brain Tumor Committee (2001) Int J Radiat Oncol Biol Phys 51:11–18

  5. Buccoliero AM, Caldarella A, Arganini L, Mennonna P, Gallina P, Taddei A, Taddei GL (2004) Cyclooxygenase-2 in oligodendroglioma: possible prognostic significance. Neuropathology 24:201–207

  6. Chakravarti A, Dicker A, Mehta M (2004) The contribution of epidermal growth factor receptor (EGFR) signaling pathway to radioresistance in human gliomas: a review of preclinical and correlative clinical data. Int J Radiat Oncol Biol Phys 58:927–931

  7. Chakravarti A, Seiferheld W, Tu X, Wang H, Zhang HZ, Ang KK, Hammond E, Curran W Jr, Mehta M (2005) Immunohistochemically determined total epidermal growth factor receptor levels not of prognostic value in newly diagnosed glioblastoma multiforme: report from the radiation therapy oncology group. Int J Radiat Oncol Biol Phys 62:318–327

  8. Choy H, Milas L (2003) Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance? J Natl Cancer Inst 95:1440–1452

  9. Coffey RJ, Hawkey CJ, Damstrup L, Graves-Deal R, Daniel VC, Dempsey PJ, Chinery R, Kirkland SC, DuBois RN, Jetton TL, Morrow JD (1997) Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenesis in polarizing colon cancer cells. Proc Natl Acad Sci USA 94:657–662

  10. Colgan SP, Taylor CT, Narravula S, Synnestvedt K, Blume ED (2002) Endothelial COX-2 induction by hypoxia liberates 6-keto-PGF1 alpha, a potent epithelial secretagogue. Adv Exp Med Biol 507:107–112

  11. Davis TW, O’Neal JM, Pagel MD, Zweifel BS, Mehta PP, Heuvelman DM, Masferrer JL (2004). Synergy between celecoxib and radiotherapy results from inhibition of cyclooxygenase-2-derived prostaglandin E2, a survival factor for tumor and associated vasculature. Cancer Res 64:279–285

  12. Deininger MH, Weller M, Streffer J, Mittelbronn M, Meyermann R (1999) Patterns of cyclooxygenase-1 and -2 expression in human gliomas in vivo. Acta Neuropathol 98:240–244

  13. Garewal H, Ramsey L, Fass R, Hart NK, Payne CM, Bernstein H, Bernstein C (2003) Perils of immunohistochemistry: variability in staining specificity of commercially available COX-2 antibodies on human colon tissue. Dig Dis Sci 48:197–202

  14. Hara A, Okayasu I (2004) Cyclooxygenase-2 and inducible nitric oxide synthase expression in human astrocytic gliomas: correlation with angiogenesis and prognostic significance. Acta Neuropathol (Berl) 108:43–48

  15. Hoozemans J, Veerhuis R, Janssen I, Van Elk EJ, Rozemuller AJ, Eikelenboom P (2002) The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia: implications for Alzheimer’s disease. Brain Res 951:218–226

  16. Hulsebos TJ, Troost D, Leenstra S (2004) Molecular-genetic characterisation of gliomas that recur as same grade or higher grade tumors. J Neurol Neurosurg Psychiatry 75:723–726

  17. Hulshof MCCM (2002) Modification of radiation effects in patients with glioblastoma multiforme. Ph.D. thesis, University of Amsterdam, Amsterdam, The Netherlands

  18. Joki T, Heese O, Nikas DC, Bello L, Zhang J, Kraeft SK, Seyfried NT, Abe T, Chen LB, Carroll RS, Black PM (2000) Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS-398. Cancer Res 60:4926–4931

  19. Kim GE, Kim YB, Cho NH, Chung HC, Pyo HR, Lee JD, Park TK, Koom WS, Chun M, Suh CO (2004) Synchronous coexpression of epidermal growth factor receptor and cyclooxygenase-2 in carcinomas of the uterine cervix: a potential predictor of poor survival. Clin Cancer Res 10:1366–1374

  20. Kinoshita T, Takahashi Y, Sakashita T, Inoue H, Tanabe T, Yoshimoto T (1999) Growth stimulation and induction of epidermal growth factor receptor by overexpression of cyclooxygenases 1 and 2 in human colon carcinoma cells. Biochim Biophys Acta 1438:120–130

  21. Kuipers GK, Sminia P, Wessel RH, Stoter TR, Hoozemans JJ, Veldman B, Geldof AA, Slotman BJ, Lafleur MVM (2003) The role of cyclooxygenase-2 (COX-2) and COX-2 modulation in radiosensitization of human malignant glioma. Int J Radiat Oncol Biol Phys 55:546–547

  22. Leenstra S, Oskam NT, Bijleveld EH, Bosch DA, Troost D, Hulsebos TJ (1998) Genetic sub-types of human malignant astrocytoma correlate with survival. Int J Cancer 79:159–165

  23. Li L, Steinauer KK, Dirks AJ, Husbeck B, Gibbs I, Knox SJ (2003) Radiation-induced cyclooxygenase 2 up-regulation is dependent on redox status in prostate cancer cells. Radiat Res 160:617–621

  24. Milas L (2001) Cyclooxygenase-2 (COX-2) enzyme inhibitors as potential enhancers of tumor radioresponse. Semin Radiat Oncol 11:290–299

  25. Nakata E, Mason KA, Hunter N, Husain A, Raju U, Liao Z, Ang KK, Milas L ( 2004) Potentiation of tumorresponse to radiation or chemoradiation by selective cyclooxygenase-2 enzyme inhibitors. Int J Radiat Oncol Biol Phys 58:369–375

  26. Nam DH, Park K, Park C, Im YH, Kim MH, Lee S, Hong SC, Shin HJ, Kim JH, Eoh W, McDonnell TJ (2004) Intracranial inhibition of glioma cell growth by cyclooxygenase-2 inhibitor celecoxib. Oncol Rep 11:263–268

  27. New P (2004) Cyclooxygenase in the treatment of glioma: its complex role in signal transduction. Cancer Control 11:152–164

  28. Nozoe T, Ezaki T, Kabashima A, Baba H, Maehara Y (2005) Significance of immunohistochemical expression of cyclooxygenase-2 in squamous cell carcinoma of the esophagus. Am J Surg 189:110–115

  29. Pachkoria K, Zhang H, Adell G, Jarlsfelt I, Sun X-F (2005) Significance of COX-2 expression in rectal cancers with or without preoperative. Int J Radiat Oncol Biol Phys (in press)

  30. Prayson RA, Castilla EA, Vogelbaum MA, Barnett GH (2002) Cyclooxygenase-2 (COX-2) expression by immunohistochemistry in glioblastoma multiforme. Ann Diagn Pathol 6:148–153

  31. Raju U, Nakata E, Yang P, Newman RA, Ang KK, Milas L (2002) In vitro enhancement of tumor cell radiosensitivity by a selective inhibitor of cyclooxygenase-2 enzyme: mechanistic considerations. Int J Radiat Oncol Biol Phys 54:886–894

  32. Reardon DA, Quinn JA, Vredenburgh J, Rich JN, Gururangan S, Badruddoja M, Herndon JE 2nd, Dowell JM, Friedman AH, Friedman HS (2005) Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma. Cancer 103:329–338

  33. Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, Joensuu H, Isola J (2002) Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62:632–635

  34. Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, Makino K, Saya H, Hirano H, Kuratsu J, Oka K, Ishimaru Y, Ushio Y (2003) Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res 63:6962–6970

  35. Shono T, Tofilon PJ, Bruner JM, Owolabi O, Lang FF (2001) Cyclooxygenase-2 expression in human gliomas: prognostic significance and molecular correlations. Cancer Res 61:4375–4381

  36. Slotman BJ, Kralendonk JH, Van Alphen HA, Kamphorst W, Karim AB (1996) Hypofractionated radiation therapy in patients with glioblastoma multiforme: results of treatment and impact of prognostic factors. Int J Radiat Oncol Biol Phys 34:895–898

  37. Sminia P, Kuipers GK, Geldof AA, Lafleur MVM, Slotman BJ (2005) COX-2 inhibitors act as radiosensitizer in tumor treatment. Biomed Pharmacother (in press)

  38. Tortora G, Ciardiello F (2003) Antisense targeting protein kinase A type I as a drug for integrated strategies of cancer therapy. Ann N Y Acad Sci 1002:236–243

  39. Trifan OC, Hla T (2003) Cyclooxygenase-2 modulates cellular growth and promotes tumorigenesis. J Cell Mol Med 7:207–222

  40. Tuettenberg J, Grobholz R, Korn T, Wenz F, Erber R, Vajkoczy P (2005) Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme. J Cancer Res Clin Oncol 131:31–40

  41. Turini ME, DuBois RN (2002) Cyclooxygenase-2: a therapeutic target. Annu Rev Med 53:35–57

  42. Williams CS, Mann M, DuBois RN (1999) The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 18:7908–7916

Download references


Prof. Dr. D. Troost and Ing. M. Ramkema (Department of Neuropathology, Academic Medical Center, Amsterdam, The Netherlands) are kindly acknowledged for providing tumor sections from two patients, and Dr. L.J.A. Stalpers (Department of Radiation Oncology, Academic Medical Center, Amsterdam, The Netherlands) for the follow-up data. Thanks are due to Dr. J.J. Hoozemans for expert advice on the immunostainings and to the division of Photography (Department of Pathology of the VU University medical center) for the microscopical photos.

T.R. Stoter was supported by the Vanderes Foundation (project #49).

Author information

Correspondence to Peter Sminia.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sminia, P., Stoter, T.R., van der Valk, P. et al. Expression of cyclooxygenase-2 and epidermal growth factor receptor in primary and recurrent glioblastoma multiforme. J Cancer Res Clin Oncol 131, 653–661 (2005).

Download citation


  • COX-2
  • EGFR
  • Primary and recurrent glioblastoma multiforme
  • Immunohistochemistry