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Biomarkers for predicting the response of esophageal squamous cell carcinoma to neoadjuvant chemoradiation therapy

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Abstract

This review summarizes and evaluates the literature regarding the biomarkers for predicting the response and/or prognosis of esophageal squamous cell carcinoma (ESCC) patients treated with neoadjuvant chemoradiation therapy (CRT). There are seven categories of molecules known to correlate with the response and/or prognosis: tumor suppressors (p53, p21), cell cycle regulators (Cyclin D1, CDC25B, 14-3-3sigma), DNA repair molecules (p53R2, ERCC1), drug resistance proteins [metallothionein (MT)], angiogenic factors (VEGF), molecules involved in cell proliferation/invasion/metastasis (Ki-67, COX-2) and hedgehog signaling molecules (Gli-1). Of the above molecules, the tumor suppressor p53 is expected to be a representative biomarker for predicting the response and prognosis. The cell cycle markers CDC25B and 14-3-3sigma have potential as response biomarkers independent of the p53 status. The DNA repair markers, p53R2 or ERCC1, angiogenic molecule (VEGF), and hedgehog signaling pathway factor Gli-1 also have potential to predict the response and prognosis of ESCC. However, there are still many unanswered questions with regard to predicting the clinical effects of neoadjuvant CRT.

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References

  1. Natsugoe S, Okumura H, Matsumoto M, et al. Randomized controlled study on preoperative chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer in a single institution. Dis Esophagus. 2006;19:468–72.

    Article  CAS  PubMed  Google Scholar 

  2. John MJ, Flam MS, Mowry PA, et al. Radiotherapy alone and chemoradiation for nonmetastatic esophageal carcinoma. A critical review of chemoradiation. Cancer. 1989;632:397–403.

    Google Scholar 

  3. Naunheim KS, Petruska P, Roy TS, et al. Preoperative chemotherapy and radiotherapy for esophageal carcinoma. J Thorac Cardiovasc Surg. 1992;103:887–93.

    CAS  PubMed  Google Scholar 

  4. Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, et al. p53 status and the efficacy of cancer therapy in vivo. Science. 1994;266:807–10.

    Article  CAS  PubMed  Google Scholar 

  5. Caelles C, Helmberg A, Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature. 1994;370:220–3.

    Article  CAS  PubMed  Google Scholar 

  6. Wagata T, Shibagaki I, Imamura M, Shimada Y, Toguchida J, Yandell DW, et al. Loss of 17p, mutation of the p53 gene, and overexpression of p53 protein in esophageal squamous cell carcinomas. Cancer Res. 1993;53:846–50.

    Google Scholar 

  7. Sarbia M, Stahl M, Fink U, Willers R, Seeber S, Gabbert HE. Expression of apoptosis-regulating proteins and outcome of esophageal cancer patients treated by combined therapy modalities. Clin Cancer Res. 1998;4:2991–7.

    CAS  PubMed  Google Scholar 

  8. Yang B, Rice TW, Adelstein DJ, Rybicki LA, Goldblum JR. Overexpression of p53 protein associates decreased response to chemoradiotherapy in patients with esophageal carcinoma. Mod Pathol. 1999;12:251–6.

    CAS  PubMed  Google Scholar 

  9. Krasna MJ, Mao YS, Sonett JR, Tamura G, Jones R, Suntharalingam M, et al. P53 gene protein overexpression predicts results of trimodality therapy in esophageal cancer patients. Ann Thorac Surg. 1999;68:2021–4.

    Article  CAS  PubMed  Google Scholar 

  10. Samejima R, Kitajima Y, Yunotani S, Miyazaki K. Cyclin D1 is a possible predictor of sensitivity to chemoradiotherapy for esophageal squamous cell carcinoma. Anticancer Res. 1999;19:5515–21.

    CAS  PubMed  Google Scholar 

  11. Yamamoto M, Tsujinaka T, Shiozaki H, Doki Y, Tamura S, Inoue M, et al. Metallothionein expression correlates with the pathological response of patients with esophageal cancer undergoing preoperative chemoradiation therapy. Oncology. 1999;56:332–7.

    Article  CAS  PubMed  Google Scholar 

  12. Kitamura K, Saeki H, Kawaguchi H, Araki K, Ohno S, Kuwano H, et al. Immunohistochemical status of the p53 protein and Ki-67 antigen using biopsied specimens can predict a sensitivity to neoadjuvant therapy in patients with esophageal cancer. Hepatogastroenterology. 2000;47:419–23.

    CAS  PubMed  Google Scholar 

  13. Miyata H, Doki Y, Shiozaki H, Inoue M, Yano M, Fujiwara Y, et al. CDC25B and p53 are independently implicated in radiation sensitivity for human esophageal cancers. Clin Cancer Res. 2000;6:4859–65.

    CAS  PubMed  Google Scholar 

  14. Shimada H, Hoshino T, Okazumi S, Matsubara H, Funami Y, Nabeya Y, et al. Expression of angiogenic factors predicts response to chemoradiotherapy and prognosis of oesophageal squamous cell carcinoma. Br J Cancer. 2002;86:552–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Kishi K, Doki Y, Miyata H, Yano M, Yasuda T, Monden M. Prediction of the response to chemoradiation and prognosis in oesophageal squamous cancer. Br J Surg. 2002;89:597–603.

    Article  CAS  PubMed  Google Scholar 

  16. Takeuchi H, Ozawa S, Ando N, Kitagawa Y, Ueda M, Kitajima M. Cell-cycle regulators and the Ki-67 labeling index can predict the response to chemoradiotherapy and the survival of patients with locally advanced squamous cell carcinoma of the esophagus. Ann Surg Oncol. 2003;10:792–800.

    Article  PubMed  Google Scholar 

  17. Okumura H, Natsugoe S, Matsumoto M, Mataki Y, Takatori H, Ishigami S, et al. The predictive value of p53, p53R2, and p21 for the effect of chemoradiation therapy on oesophageal squamous cell carcinoma. Br J Cancer. 2005;92:284–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Sunada F, Itabashi M, Ohkura H, Okumura T. p53 negativity, CDC25B positivity, and metallothionein negativity are predictors of a response of esophageal squamous cell carcinoma to chemoradiotherapy. World J Gastroenterol. 2005;11:5696–700.

    CAS  PubMed  Google Scholar 

  19. Sarbia M, Ott N, Pühringer-Oppermann F, Brücher BL. The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus. Br J Cancer. 2007;97:1404–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Makino T, Yamasaki M, Miyata H, Yoshioka S, Takiguchi S, Fujiwara Y, et al. p53 mutation status predicts pathological response to chemoradiotherapy in locally advanced esophageal cancer. Ann Surg Oncol. 2010;17:804–11.

    Article  PubMed  Google Scholar 

  21. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253:49–53.

    Article  CAS  PubMed  Google Scholar 

  22. Natsugoe S, Nakashima S, Matsumoto M, Xiangming C, Okumura H, Kijima F, et al. Expression of p21WAF1/Cip1 in the p53-dependent pathway is related to prognosis in patients with advanced esophageal carcinoma. Clin Cancer Res. 1999;5:2445–9.

    CAS  PubMed  Google Scholar 

  23. Shinozaki H, Ozawa S, Ando N, Tsuruta H, Terada M, Ueda M, et al. Cyclin D1 amplification as a new predictive classification for squamous cell carcinoma of the esophagus, adding gene information. Clin Cancer Res. 1996;2:1155–61.

    CAS  PubMed  Google Scholar 

  24. Brücher BL, Keller G, Werner M, Müller U, Lassmann S, Cabras AD, et al. Using Q-RT-PCR to measure cyclin D1, TS, TP, DPD, and Her-2/neu as predictors for response, survival, and recurrence in patients with esophageal squamous cell carcinoma following radiochemotherapy. Int J Colorectal Dis. 2009;24:69–77.

    Article  PubMed  Google Scholar 

  25. Nishijima H, Nishitani H, Seki T, Nishimoto T. A dual-specificity phosphatase cdc25B is an unstable protein and triggers p34cdc2/cyclinB activation in hamster BHK21 cells arrested with hydroxyurea. J Cell Biol. 1997;138:1105–16.

    Article  CAS  PubMed  Google Scholar 

  26. Lammer CL, Wagerer S, Saffrich R, Mertens D, Ansorge W, Hoffmann I. The cdc25B phosphatase is essential for the G2/M transition in human cells. J Cell Sci. 1998;111:2445–53.

    CAS  PubMed  Google Scholar 

  27. Chan TA, Hermeking H, Lengauer C, Kinzler KW, Vogelstein B. 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage. Nature. 1999;401:616–20.

    Article  CAS  PubMed  Google Scholar 

  28. Okumura H, Natsugoe S, Matsumoto M, Yokomakura N, Uchikado Y, Takatori H, et al. Predictive value of p53 and 14-3-3sigma for the effect of chemoradiation therapy on esophageal squamous cell carcinoma. J Surg Oncol. 2005;91:84–9.

    Article  CAS  PubMed  Google Scholar 

  29. Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K, et al. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature. 2000;404:42–9.

    Article  CAS  PubMed  Google Scholar 

  30. Yamaguchi T, Matsuda K, Sagiya Y, Iwadate M, Fujimoto MA, Nakamura Y, et al. p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint. Cancer Res. 2001;61:8256–62.

    CAS  PubMed  Google Scholar 

  31. Kwon HC, Roh M, Oh SY, Kim SH, Kim MC, Kim JS, et al. Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer. Ann Oncol. 2007;18:504–9.

    Article  PubMed  Google Scholar 

  32. Joshi MB, Shirota Y, Danenberg KD, Conlon DH, Salonga DS, Herndon JE 2nd, et al. High gene expression of TS1, GSTP1, and ERCC1are risk factors for survival in patients treated with trimodality therapy for esophageal cancer. Clin Cancer Res. 2005;11:2215–21.

    Article  PubMed  Google Scholar 

  33. Kim MK, Cho KJ, Kwon GY, Park SI, Kim YH, Kim JH, et al. ERCC1 predicting chemoradiation resistance and poor outcome in oesophageal cancer. Eur J Cancer. 2008;44:54–60.

    Article  CAS  PubMed  Google Scholar 

  34. Hamer DH. Metallothionein. Annu Rev Biochem. 1986;55:913–51.

    Article  CAS  PubMed  Google Scholar 

  35. Kondo Y, Rusnak JM, Hoyt DG, Settineri CE, Pitt BR, Lazo JS. Enhanced apoptosis in metallothionein null cells. Mol Pharmacol. 1997;52:195–201.

    CAS  PubMed  Google Scholar 

  36. Backer MV, Hamby CV, Backer JM. Inhibition of vascular endothelial growth factor receptor signaling in angiogeneic tumor vasculature. Adv Genet. 2009;67:1–27.

    Article  CAS  PubMed  Google Scholar 

  37. Kulke MH, Odze RD, Mueller JD, Wang H, Redston M, Bertagnolli MM. Prognostic significance of vascular endothelial growth factor and cyclooxygenase 2 expression in patients receiving preoperative chemoradiation for esophageal cancer. J Thorac Cardiovasc Surg. 2004;127:1579–86.

    Article  CAS  PubMed  Google Scholar 

  38. Furukawa T, Yoshimura A, Sumizawa T, Haraguchi M, Akiyama S, Fukui K, et al. Angiogenic factor. Nature. 1992;356:668.

    Article  CAS  PubMed  Google Scholar 

  39. Subbaramaiah K, Telang N, Ramonetti JT, Araki R, DeVito B, Weksler BB, et al. Transcription of cyclooxygenase-2 is enhanced in transformed mammary epithelial cells. Cancer Res. 1996;56:4424–9.

    CAS  PubMed  Google Scholar 

  40. Williams CS, Tsujii M, Reese J, Dey SK, DuBois RN. Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest. 2000;105:1589–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Takatori H, Natsugoe S, Okumura H, Matsumoto M, Ishigami S, Owaki T, et al. Predictive value of COX-2 for the effect of chemoradiotherapy on esophageal squamous cell carcinoma. Oncol Rep. 2005;13:697–701.

    CAS  PubMed  Google Scholar 

  42. Youssef EM, Matsuda T, Takada N, Osugi H, Higashino M, Kinoshita H, et al. Prognostic significance of the MIB-1 proliferative index for patients with squamous cell carcinoma of the esophagus. Cancer. 1995;76:358–66.

    Article  CAS  PubMed  Google Scholar 

  43. Lam KY, Law SYK, So MKP, Fok M, Ma LT, Wong J. Prognostic implication of proliferative markers MIB-1 and PC10 in esophageal squamous cell carcinoma. Cancer. 1996;77:7–13.

    Article  CAS  PubMed  Google Scholar 

  44. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15:3059–87.

    Article  CAS  PubMed  Google Scholar 

  45. van den Brink GR, Hardwick JC, Tytgat GN, Brink MA, Ten Kate FJ, Van Deventer SJ, et al. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology. 2001;121:317–28.

    Article  PubMed  Google Scholar 

  46. Yoshikawa R, Nakano Y, Tao L, Koishi K, Matsumoto T, Sasako M, et al. Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy. Br J Cancer. 2008;98:1670–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Zhu W, You Z, Li T, Yu C, Tao G, Hu M, et al. Correlation of hedgehog signal activation with chemoradiotherapy sensitivity and survival in esophageal squamous cell carcinomas. Jpn J Clin Oncol. 2011;41:386–93.

    Article  PubMed  Google Scholar 

  48. Kim MK, Cho KJ, Kwon GY, Park SI, Kim YH, Kim JH, et al. Patients with ERCC1-negative locally advanced esophageal cancers may benefit from preoperative chemoradiotherapy. Clin Cancer Res. 2008;14:4225–31.

    Article  CAS  PubMed  Google Scholar 

  49. Okumura H, Natsugoe S, Yokomakura N, Kita Y, Matsumoto M, Uchikado Y, et al. Expression of p53R2 is related to prognosis in patients with esophageal squamous cell carcinoma. Clin Cancer Res. 2006;12:3740–5.

    Article  CAS  PubMed  Google Scholar 

  50. Hironaka S, Hasebe T, Kamijo T, Ohtsu A, Boku N, Yoshida S, et al. Biopsy specimen microvessel density is a useful prognostic marker in patients with T(2–4)M(0) esophageal cancer treated with chemoradiotherapy. Clin Cancer Res. 2002;8:124–30.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan

    Hiroshi Okumura, Yasuto Uchikado, Tetsuro Setoyama, Masataka Matsumoto, Tetsuhiro Owaki, Sumiya Ishigami & Shoji Natsugoe

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  1. Hiroshi Okumura
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  2. Yasuto Uchikado
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  3. Tetsuro Setoyama
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  4. Masataka Matsumoto
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  7. Shoji Natsugoe
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Correspondence to Hiroshi Okumura.

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Okumura, H., Uchikado, Y., Setoyama, T. et al. Biomarkers for predicting the response of esophageal squamous cell carcinoma to neoadjuvant chemoradiation therapy. Surg Today 44, 421–428 (2014). https://doi.org/10.1007/s00595-013-0580-y

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  • DOI: https://doi.org/10.1007/s00595-013-0580-y

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