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Thymidylate synthase expression is closely associated with outcome in patients with pulmonary adenocarcinoma

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Abstract

The aim of this study is to elucidate the prognostic significance of thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) in completely resected non-small cell lung cancer (NSCLC). One hundred and sixty patients with NSCLC were included in this study. Tumor sections were stained by immunohistochemistry for TS, OPRT, DPD, glucose transporter 1 (Glut1), hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), microvessel density (MVD) determinated by CD34, epidermal growth factor receptor (EGFR), phosph-Akt, phosph-mammalian target of rapamycin (mTOR) and p53. TS, OPRT and DPD were positively expressed in 46, 71 and 54%, respectively. The expression of TS and OPRT was significantly higher in patients with non-adenocarcinoma (non-AC) (n = 53) than adenocarcinoma (AC) (n = 107), and DPD expression was higher in adenocarcinoma as compared with non-adenocarcinoma. A positive TS expression was an independent prognostic factor for predicting a poor outcome in patients with AC, but not in those with non-AC. In AC patients, TS expression was significantly associated with advanced stage, lymph node metastases, vascular invasion, Glut1, HIF-1α, angiogenesis, EGFR signaling pathway and p53. In patients with non-AC, TS expression was not closely correlated with outcome and these biomarkers. A positive TS expression was a powerful prognostic factor to predict a poor outcome in completely resected AC patients.

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References

  1. Brundage MD, Davies D, Mackillop WJ. Prognostic factors in non-small cell lung cancer: a decade of prognosis. Chest. 2002;122:1037–57.

    Article  PubMed  Google Scholar 

  2. Danenberg PV. Thymidylate synthase: a target enzyme in cancer chemotherapy. Biochim Biophys Acta. 1997;473:73–92.

    Google Scholar 

  3. Wada H, Hitomi S, Teramatsu T. Adjuvant chemotherapy after complete resection in non-small cell lung cancer. West Japan Study Group for Lung Cancer Surgery. J Clin Oncol. 1996;14:1048–54.

    PubMed  CAS  Google Scholar 

  4. Nakano J, et al. Evaluation of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT. Br J Cancer. 2006;95:607–15.

    Article  PubMed  CAS  Google Scholar 

  5. Nakagawa T, et al. Expression of thymidylate synthase is correlated with proliferative activity in non-small cell lung cancer (NSCLC). Lung Cancer. 2004;43:145–9.

    Article  PubMed  Google Scholar 

  6. Ceppi P, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 2006;107:1589–96.

    Article  PubMed  CAS  Google Scholar 

  7. Hashimoto H, et al. Significance of thymidylate synthase gene expression level in patients with adenocarcinoma of the lung. Cancer. 2006;106:1595–601.

    Article  PubMed  CAS  Google Scholar 

  8. Atkin GK, et al. The impact of surgically induced ischaemia on protein levels in patients undergoing rectal cancer surgery. Br J Cancer. 2006;95:928–33.

    Article  PubMed  CAS  Google Scholar 

  9. Okabe T, et al. Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase. Mol Cancer Ther. 2008;7:599–606.

    Article  PubMed  CAS  Google Scholar 

  10. Mountain CF. Revision in the international system for staging lung cancer. Chest. 1997;11:1710–7.

    Article  Google Scholar 

  11. Kaira K, et al. Biologic correlation of 2-[18F]-fluoro-2-deoxy-d-glucose uptake on positron emission tomography in thymic epithelial tumors. J Clin Oncol. 2010;28:3746–53.

    Article  PubMed  CAS  Google Scholar 

  12. Shirota Y, et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol. 2001;19:4298–304.

    PubMed  CAS  Google Scholar 

  13. Lenz H, et al. Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol. 1995;14:176–82.

    Google Scholar 

  14. Ceppi P, et al. Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors. Clin Cancer Res. 2008;14:1059–64.

    Article  PubMed  CAS  Google Scholar 

  15. Ibe T, et al. High-grade neuroendocrine carcinoma of the lung shows increased thymidylate synthase expression compared to other histotypes. J Surg Oncol. 2010;102:11–7.

    Article  PubMed  Google Scholar 

  16. Griffiths L, et al. The influence of oxygen tension and pH on the expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast tumor cells grown in vitro and in vivo. Cancer Res. 1997;57:570–2.

    PubMed  CAS  Google Scholar 

  17. Vleugel MM, et al. Differential prognostic impact of hypoxia induced and diffuse HIF-1 alpha expression in invasive breast cancer. J Clin Pathol. 2005;58:172–7.

    Article  PubMed  CAS  Google Scholar 

  18. Elson DA, et al. Coordinate up-regulation of hypoxia inducible factor (HIF)-1a and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing 1. Cancer Res. 2000;60:6189–95.

    PubMed  CAS  Google Scholar 

  19. Ryan HE, et al. Hypoxia-inducible factor-1α is a positive factor in solid tumor growth. Cancer Res. 2000;60:4010–5.

    PubMed  CAS  Google Scholar 

  20. Kaira K, et al. Correlation of angiogenesis with 18F-FMT and 18F-FDG uptake in non-small cell lung cancer. Cancer Sci. 2009;100:753–8.

    Article  PubMed  CAS  Google Scholar 

  21. Hamada C, et al. Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer. J Clin Oncol. 2005;23:4999–5007.

    Article  PubMed  CAS  Google Scholar 

  22. Ishihama H, et al. Comparison of 5-fluorouracil-related gene expression levels between adenocarcinomas and squamous cell carcinomas of the lung. Jpn J Clin Oncol. 2009;39:33–6.

    Article  PubMed  Google Scholar 

  23. Harada K, Kawashima Y, Yoshida H, Sato M. Thymidylate synthase expression in oral squamous cell carcinoma predicts response to S-1. Oncol Rep. 2006;15:1417–23.

    PubMed  CAS  Google Scholar 

  24. Lee S, et al. Thymidylate synthase, thymidine phosphorylase, and excision repair-complementation group 1 expression as predictive markers of capecitabine plus cisplatin chemotherapy as first-line treatment for patients with advanced oesophageal squamous cell carcinoma. Br J Cancer. 2010;7:845–51.

    Article  Google Scholar 

  25. Shirasaka T, et al. Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs. 1996;7:548–57.

    Article  PubMed  CAS  Google Scholar 

  26. Kawahara M, et al. Phase II study of S-1, a novel oral fluorouracil, in advanced non-small-cell lung cancer. Br J Cancer. 2001;85:939–43.

    Article  PubMed  CAS  Google Scholar 

  27. Yamamoto N, et al. Pooled analysis of S-1 trials in non-small cell lung cancer according to histological type. Anticancer Res. 2010;30:2985–90.

    PubMed  CAS  Google Scholar 

  28. Fukui Y, Oka T, Nagayama S, Danenberg PV, Danenberg KD, Fukushima M. Thymidylate synthase, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase mRNA and protein expression levels in solid tumors in large scale population analysis. Int J Mol Med. 2008;22:709–16.

    PubMed  CAS  Google Scholar 

  29. Takeda M, Okamoto I, Hirabayashi N, Kitano M, Nakagawa K. Thymidylate synthase and dihydropyrimidine dehydrogenase expression levels are associated with response to S-1 plus carboplatin in advanced non-small cell lung cancer. Lung Cancer. 2011;73:103–9.

    Google Scholar 

  30. Sun JM, Han J, Ahn JS, Park K, Ahn MJ. Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy. J Thorac Oncol. 2011;6:1392–9.

    Google Scholar 

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Acknowledgments

This work was supported in part by Grant 21790793 (K. K) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and National Hospital Organization Policy Based Medical Services. We thank all staffs of pathology department in Shizuoka Cancer Center for their technical assistance of immunohistochemical analysis.

Conflict of interest

We, all authors, have no financial or personal relationships with other people or organizations that could inappropriately influence our work.

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Authors and Affiliations

  1. Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan

    Kyoichi Kaira, Haruyasu Murakami, Toshiaki Takahashi & Nobuyuki Yamamoto

  2. Division of Thoracic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan

    Yasuhisa Ohde, Kazuo Nakagawa, Takehiro Okumura & Haruhiko Kondo

  3. Division of Pathology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan

    Takashi Nakajima

  4. Division of Diagnostic Radiology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan

    Masahiro Endo

Authors
  1. Kyoichi Kaira
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  2. Yasuhisa Ohde
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  3. Kazuo Nakagawa
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  4. Takehiro Okumura
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  5. Haruyasu Murakami
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  6. Toshiaki Takahashi
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  7. Haruhiko Kondo
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  8. Takashi Nakajima
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  9. Masahiro Endo
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  10. Nobuyuki Yamamoto
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Correspondence to Kyoichi Kaira.

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Kaira, K., Ohde, Y., Nakagawa, K. et al. Thymidylate synthase expression is closely associated with outcome in patients with pulmonary adenocarcinoma. Med Oncol 29, 1663–1672 (2012). https://doi.org/10.1007/s12032-011-0069-8

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  • DOI: https://doi.org/10.1007/s12032-011-0069-8

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