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COX2 Expression Predicts Resistance to Chemoradiotherapy in Esophageal Squamous Cell Carcinoma

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

The overexpression of cyclooxygenase (COX)2 is correlated with carcinogenesis, tumor progression, and prognosis, and increased COX2 expression is correlated with radiation resistance. However, no correlation between the COX2 expression and resistance to chemoradiotherapy for esophageal squamous cell carcinoma has been characterized. The purpose of the present study was to evaluate whether COX2 expression is an indicator of resistance to chemoradiotherapy in esophageal squamous cell carcinoma and the feasibility of COX2 as a biomarker for CRT.

Methods

Fifty-eight patients who were diagnosed with esophageal squamous cell carcinoma from biopsy samples were enrolled in the present series. All patients underwent concurrent chemoradiotherapy in a neoadjuvant setting, followed by radical esophagectomy. COX2 expression was evaluated by immunohistochemical staining and statistically compared with the histopathologic findings in surgically resected specimens.

Results

The rate of responders was 87% for weak expression of COX2, 62% for moderate expression, and 30% for strong expression, and there was a close correlation between COX2 expression and the response rate (Kendall’s τb = 0.396, P = 0.001). In the univariate analysis, negative or weak expression of COX2 was found to correlate significantly with CRT response (odds ratio, 6.296; 95% confidence interval (CI), 1.58–25.096; P = 0.010). In the multivariate analysis, weak expression of COX2 (30% or less) was found to be an independent prognostic factor (odds ratio, 6.534; 95% CI, 1.535–27.803; P = 0.011).

Conclusions

The COX2 expression predicts resistance to chemoradiotherapy in esophageal squamous cell carcinoma, and it also is a feasible biomarker for evaluating the CRT response.

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References

  1. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349(23):2241–52.

    Article  PubMed  CAS  Google Scholar 

  2. Akutsu Y, Matsubara H, Shuto K, et al. Clinical and pathologic evaluation of the effectiveness of neoadjuvant chemoradiation therapy in advanced esophageal cancer patients. World J Surg. 2009;33(5):1002–9.

    Article  PubMed  Google Scholar 

  3. Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem. 2000;69:145–82.

    Article  PubMed  CAS  Google Scholar 

  4. Dempke W, Rie C, Grothey A, et al. Cyclooxygenase-2: a novel target for cancer chemotherapy? J Cancer Res Clin Oncol. 2001;127(7):411–7.

    Article  PubMed  CAS  Google Scholar 

  5. Shamma A, Yamamoto H, Doki Y, et al. Up-regulation of cyclooxygenase-2 in squamous carcinogenesis of the esophagus. Clin Cancer Res. 2000;6(4):1229–38.

    PubMed  CAS  Google Scholar 

  6. Lucci A, Krishnamurthy S, Singh B, et al. Cyclooxygenase-2 expression in primary breast cancers predicts dissemination of cancer cells to the bone marrow. Breast Cancer Res Treat. 2009;117(1):61–8.

    Article  PubMed  CAS  Google Scholar 

  7. Hashimoto N, Inayama M, Fujishima M, et al. Clinicopathologic significance of expression of cyclooxygenase-2 in human esophageal squamous cell carcinoma. Hepatogastroenterology. 2007;54(75):758–60.

    PubMed  CAS  Google Scholar 

  8. van Nes JG, de Kruijf EM, Faratian D, et al. COX2 expression in prognosis and in prediction to endocrine therapy in early breast cancer patients. Breast Cancer Res Treat. 2011;125(3):671–85.

    Article  PubMed  CAS  Google Scholar 

  9. Pai R, Soreghan B, Szabo IL, et al. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med. 2002;8(3):289–93.

    Article  PubMed  CAS  Google Scholar 

  10. Yasumaru M, Tsuji S, Tsujii M, et al. Inhibition of angiotensin II activity enhanced the antitumor effect of cyclooxygenase-2 inhibitors via insulin-like growth factor I receptor pathway. Cancer Res. 2003;63(20):6726–34.

    PubMed  CAS  Google Scholar 

  11. Anai S, Tanaka M, Shiverick KT, et al. Increased expression of cyclooxygenase-2 correlates with resistance to radiation in human prostate adenocarcinoma cells. J Urol. 2007;177(5):1913–7.

    Article  PubMed  CAS  Google Scholar 

  12. Takubo K, Makuuchi H, Hujita H, et al. Japanese classification of esophageal cancer, 10th edn: part I. Esophagus. 2009;6(1):1–25.

    Article  Google Scholar 

  13. Baron JA. Epidemiology of non-steroidal anti-inflammatory drugs and cancer. Prog Exp Tumor Res. 2003;37:1–24.

    Article  PubMed  CAS  Google Scholar 

  14. Nikitakis NG, Hebert C, Lopes MA, et al. PPARgamma-mediated antineoplastic effect of NSAID sulindac on human oral squamous carcinoma cells. Int J Cancer. 2002;98(6):817–23.

    Article  PubMed  CAS  Google Scholar 

  15. Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA. 1997;94(7):3336–40.

    Article  PubMed  CAS  Google Scholar 

  16. Boolbol SK, Dannenberg AJ, Chadburn A, et al. Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res. 1996;56(11):2556–60.

    PubMed  CAS  Google Scholar 

  17. Wild PJ, Kunz-Schughart LA, Stoehr R, et al. High-throughput tissue microarray analysis of COX2 expression in urinary bladder cancer. Int J Oncol. 2005;27(2):385–91.

    PubMed  CAS  Google Scholar 

  18. Witton CJ, Hawe SJ, Cooke TG, et al. Cyclooxygenase 2 (COX2) expression is associated with poor outcome in ER-negative, but not ER-positive, breast cancer. Histopathology. 2004;45(1):47–54.

    Article  PubMed  CAS  Google Scholar 

  19. Edwards J, Mukherjee R, Munro AF, et al. HER2 and COX2 expression in human prostate cancer. Eur J Cancer. 2004;40(1):50–5.

    Article  PubMed  CAS  Google Scholar 

  20. Fux R, Schwab M, Thon KP, et al. Cyclooxygenase-2 expression in human colorectal cancer is unrelated to overall patient survival. Clin Cancer Res. 2005;11(13):4754–60.

    Article  PubMed  CAS  Google Scholar 

  21. Wijnhoven BP, van Lanschot JJ, Tilanus HW, et al. Neoadjuvant chemoradiotherapy for esophageal cancer: a review of meta-analyses. World J Surg. 2009;33(12):2606–14.

    Article  PubMed  Google Scholar 

  22. Li Y, Niu Y, Wu H, et al. PC-407, a celecoxib derivative, inhibited the growth of colorectal tumor in vitro and in vivo. Cancer Sci. 2009;100(12):2451–8.

    Article  PubMed  CAS  Google Scholar 

  23. Tendo M, Yashiro M, Nakazawa K, et al. Inhibitory effect of a selective cyclooxygenase inhibitor on the invasion-stimulating activity of orthotopic fibroblasts for scirrhous gastric cancer cells. Cancer Sci. 2005;96(7):451–5.

    Article  PubMed  CAS  Google Scholar 

  24. Kaneko M, Kaneko S, Suzuki K. Prolonged low-dose administration of the cyclooxygenase-2 inhibitor celecoxib enhances the antitumor activity of irinotecan against neuroblastoma xenografts. Cancer Sci. 2009;100(11):2193–201.

    Article  PubMed  CAS  Google Scholar 

  25. Zhao S, Cai J, Bian H, et al. Synergistic inhibition effect of tumor growth by using celecoxib in combination with oxaliplatin. Cancer Invest. 2009;27(6):636–40.

    Article  PubMed  CAS  Google Scholar 

  26. Palayoor ST, Bump EA, Calderwood SK, et al. Combined antitumor effect of radiation and ibuprofen in human prostate carcinoma cells. Clin Cancer Res. 1998;4(3):763–71.

    PubMed  CAS  Google Scholar 

  27. Irie T, Tsujii M, Tsuji S, et al. Synergistic antitumor effects of celecoxib with 5-fluorouracil depend on IFN-gamma. Int J Cancer. 2007;121(4):878–83.

    Article  PubMed  CAS  Google Scholar 

  28. Kang KB, Wang TT, Woon CT, et al. Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: inhibition of tumor angiogenesis with extensive tumor necrosis. Int J Radiat Oncol Biol Phys. 2007;67(3):888–96.

    Article  PubMed  CAS  Google Scholar 

  29. Kuipers GK, Slotman BJ, Wedekind LE, et al. Radiosensitization of human glioma cells by cyclooxygenase-2 (COX-2) inhibition: independent on COX-2 expression and dependent on the COX-2 inhibitor and sequence of administration. Int J Radiat Biol. 2007;83(10):677–85.

    Article  PubMed  CAS  Google Scholar 

  30. Shin YK, Park JS, Kim HS, et al. Radiosensitivity enhancement by celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, via COX-2-dependent cell cycle regulation on human cancer cells expressing differential COX-2 levels. Cancer Res. 2005;65(20):9501–9.

    Article  PubMed  CAS  Google Scholar 

  31. Jun HJ, Kim YM, Park SY, et al. Modulation of ionizing radiation-induced G2 arrest by cyclooxygenase-2 and its inhibitor celecoxib. Int J Radiat Oncol Biol Phys. 2009;75(1):225–34.

    Article  PubMed  CAS  Google Scholar 

  32. Raju U, Ariga H, Dittmann K, et al. Inhibition of DNA repair as a mechanism of enhanced radioresponse of head and neck carcinoma cells by a selective cyclooxygenase-2 inhibitor, celecoxib. Int J Radiat Oncol Biol Phys. 2005;63(2):520–8.

    Article  PubMed  CAS  Google Scholar 

  33. Kim BM, Won J, Maeng KA, et al. Nimesulide, a selective COX-2 inhibitor, acts synergistically with ionizing radiation against A549 human lung cancer cells through the activation of caspase-8 and caspase-3. Int J Oncol. 2009;34(5):1467–73.

    PubMed  CAS  Google Scholar 

  34. Dawson SJ, Michael M, Biagi J, et al. A phase I/II trial of celecoxib with chemotherapy and radiotherapy in the treatment of patients with locally advanced oesophageal cancer. Invest New Drugs. 2007;25(2):123–9.

    Article  PubMed  CAS  Google Scholar 

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The authors declare that there are no conflicts of interest in this article and no funding has been received.

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Correspondence to Yasunori Akutsu MD, PhD.

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Akutsu, Y., Hanari, N., Yusup, G. et al. COX2 Expression Predicts Resistance to Chemoradiotherapy in Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 18, 2946–2951 (2011). https://doi.org/10.1245/s10434-011-1645-z

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  • DOI: https://doi.org/10.1245/s10434-011-1645-z

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