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High thymidine kinase 1 (TK1) expression is a predictor of poor survival in patients with pT1 of lung adenocarcinoma

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Tumor Biology

Abstract

In this study, we explore the association of thymidine kinase 1 (TK1) expression in tumour tissues with clinical pathological parameters and prognosis in patients with pathological T1 (pT1) lung adenocarcinoma. The expression of TK1 was studied by immunohistochemistry techniques in 80 patients with surgically resected pT1 lung adenocarcinoma, retrospectively and at >10-year follow-up. Compared to patients with low TK1 expression [labelling index (LI) <25.0%], patients with high TK1 expression (LI ≥25.0%) showed significantly increased lymphatic/vascular permeation and lymph node involvement and higher stromal invasion grade and pathological stage, and a greater number of patients had a tumour size of 2.1 to 3.0 cm. The 5-year survival and the mortality during follow-up for patients with high TK1 expression were significantly worse than that of patients with low TK1 expression. The prognoses of the cases with grade 0, grade 1 and grade 2 stromal invasions were similar and were better than those of cases with grade 3. In patients with stromal invasion grade 3, the 5-year survival and the mortality during follow-up were significantly worse for patients with high TK1 compared to patients with low TK1 expression. Univariate analyses showed that stromal invasion and TK1 expression were significant prognostic factors, while in the multivariate analysis, TK1 expression and tumour stage were found to be independent prognostic factors, but not stromal invasion. This is the first study showing that TK1 expression in combination with stromal invasion is a more reliable prognostic factor than stromal invasion classification itself in patients with pT1 lung adenocarcinoma. TK1 expression enables a further classification of the patients and opens opportunities for improved treatment outcome.

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References

  1. Kaneko M, Eguchi K, Ohmatsu H, Kakinuma R, Naruke T, Suemasu K, et al. Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography. Radiology. 1996;201:798–802.

    PubMed  CAS  Google Scholar 

  2. Sone S, Takashima S, Li F, Yang Z, Honda T, Maruyama Y, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet. 1998;351:1242–5.

    Article  PubMed  CAS  Google Scholar 

  3. Kawakami T, Nabeshima K, Makimoto Y, Hamasaki M, Iwasaki A, Shirakusa T, et al. Micropapillary pattern and grade of stromal invasion in pT1 adenocarcinoma of the lung: usefulness as prognostic factors. Mod Pathol. 2007;20:514–21.

    Article  PubMed  Google Scholar 

  4. Suzuki K, Yokose T, Yoshida J, Nishimura M, Takahashi K, Nagai K, et al. Prognostic significance of the size of central fibrosis in peripheral adenocarcinoma of the lung. Ann Thorac Surg. 2000;69:893–7.

    Article  PubMed  CAS  Google Scholar 

  5. Yokose T, Suzuki K, Nagai K, Nishiwaki Y, Sasaki S, Ochiai A. Favorable and unfavorable morphological prognosis factors in peripheral adenocarcinoma of the lung 3 cm or less in diameter. Lung Cancer. 2000;29:179–88.

    Article  PubMed  CAS  Google Scholar 

  6. Maeshima AM, Niki T, Maeshima A, Yamada T, Kondo H, Matsuno Y. Modified scar grade: a prognostic indicator in small peripheral lung adenocarcinoma. Cancer. 2002;95:2546–54.

    Article  PubMed  Google Scholar 

  7. He Q, Fornander T, Johansson H, Johansson U, Hu GZ, Rutqvist LE, et al. Thymidine kinase 1 in serum predicts increased risk of distant or loco-regional recurrence following surgery in patients with early breast cancer. Anticancer Res. 2006;26:4753–9.

    PubMed  CAS  Google Scholar 

  8. Nisman B, Allweis T, Kaduri L, Maly B, Gronowitz S, Hamburger T, et al. Cancer biomark. Serum thymidine kinase 1 activity in breast cancer. Cancer Biomark. 2010;7:65–72.

    PubMed  CAS  Google Scholar 

  9. He E, Xu XH, Guan H, Chen Y, Chen ZH, Pan ZL, et al. Thymidine kinase 1 is a potential marker for prognosis and monitoring the response to treatment of patients with breast, lung, and esophageal cancer and non-Hodgkin’s lymphoma. Nucleos Nucleot Nucleic Acids. 2010;29:352–8.

    Article  CAS  Google Scholar 

  10. Li HX, Zhang S, Lei DS, Wang XQ, Skog S, He Q. Serum thymidine 1 is a prognostic and monitoring factor in patients with non-small cell lung cancer. Oncol Rep. 2005;13:145–9.

    PubMed  CAS  Google Scholar 

  11. Nisman B, Yutkin V, Nechushtan H, Gofrit ON, Peretz T, Gronowitz S, et al. Circulating tumor M2 pyruvate kinase and thymidine kinase 1 are potential predictors for disease recurrence in renal cell carcinoma after nephrectomy. Urology. 2010;76:513–6.

    Article  PubMed  Google Scholar 

  12. Li Z, Wang Y, He J, Ma J, Zhao L, Chen H, et al. Serological thymidine kinase 1 is a prognostic factor in oesophageal, cardial and lung carcinomas. Eur J Cancer Prev. 2010;19:313–8.

    Article  PubMed  CAS  Google Scholar 

  13. Chen Y, Ying M, Chen Y, Hu M, Lin Y, Chen D, et al. Serum thymidine kinase 1 correlates to clinical stages and clinical reactions and monitors the outcome of therapy of 1,247 cancer patients in routine clinical settings. Int J Clin Oncol. 2010;15:359–68.

    Article  PubMed  CAS  Google Scholar 

  14. Pan ZL, Ji XY, Shi YM, Zhou J, He E, Skog S. Serum thymidine kinase 1 concentration as a prognostic factor of chemotherapy-treated non-Hodgkin’s lymphoma patients. J Cancer Res Clin Oncol. 2010;136:1193–9.

    Article  PubMed  CAS  Google Scholar 

  15. Konoplev SN, Fritsche HA, O’Brien S, Wierda WG, Keating MJ, Gornet TG, et al. High serum thymidine kinase 1 level predicts poorer survival in patients with chronic lymphocytic leukemia. Am J Clin Pathol. 2010;134:472–7.

    Article  PubMed  Google Scholar 

  16. Xu W, Cao X, Miao KR, Qiao C, Wu YJ, Liu Q, et al. Serum thymidine kinase 1 concentration in Chinese patients with chronic lymphocytic leukemia and its correlation with other prognostic factors. Int J Hematol. 2009;90:205–11.

    Article  PubMed  CAS  Google Scholar 

  17. Holdenrieder S, Von Pawel J, Duell T, Feldmann K, Raith H, Schollen A, et al. Clinical relevance of thymidine kinase for the diagnosis, therapy monitoring and prognosis of non-operable lung cancer. Anticancer Res. 2010;30:1855–62.

    PubMed  CAS  Google Scholar 

  18. Broet P, Romain S, Daver A, Ricolleau G, Quillen V, Rallet A, et al. Thymidine kinase as a proliferative marker: clinical relevance in 1,692 primary breast cancer patients. J Clin Oncol. 2001;19:2778–87.

    PubMed  CAS  Google Scholar 

  19. Guan H, Sun Y, Zan Q, Xu M, Li Y, Zhou J, et al. Thymidine kinase 1 expression is significantly different in breast benign (UDH), and in pre-malignant (ADH), primary tumour in situ (DCIS) and invasive ductal (IDC) of breast carcinoma. Mol Med Report. 2009;2:923–9.

    PubMed  CAS  Google Scholar 

  20. Sakurai H, Maeshima A, Watanabe S, Suzuki K, Tsuchiya R, Maeshima AM, et al. Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis. Am J Surg Pathol. 2004;28:198–206.

    Article  PubMed  Google Scholar 

  21. Sakao Y, Miyamoto H, Sakuraba M, Oh T, Shiomi K, Sonobe S, et al. Prognostic significance of a histologic subtype in small adenocarcinoma of the lung: the impact of nonbronchioloalveolar carcinoma components. Ann Thorac Surg. 2007;83:209–83214.

    Article  PubMed  Google Scholar 

  22. Sakao Y, Sakuragi T, Natsuaki M, Itoh T. Clinicopathological analysis of prognostic factors in clinical IA peripheral adenocarcinoma of the lung. Ann Thorac Surg. 2003;75:1113–7.

    Article  PubMed  Google Scholar 

  23. Yamashiro K, Yasuda S, Nagase A, Hirata T, Nojima T, Nagashima K. Prognostic significance of an interface pattern of central fibrosis and tumor cells in peripheral adenocarcinoma of the lung. Hum Pathol. 1995;26:67–73.

    Article  PubMed  CAS  Google Scholar 

  24. Terasaki H, Niki T, Matsuno Y, Yamada T, Maeshima A, Asamura H, et al. Lung adenocarcinoma with mixed bronchioloalveolar and invasive components: clinicopathological features, subclassification by extent of invasive foci, and immunohistochemical characterization. Am J Surg Pathol. 2003;27:937–51.

    Article  PubMed  Google Scholar 

  25. Yim J, Zhu LC, Chiriboga L, Watson HN, Goldberg JD, Moreira AL. Histologic features are important prognostic indicators in early stages lung adenocarcinomas. Mod Pathol. 2007;20:233–41.

    Article  PubMed  CAS  Google Scholar 

  26. Xu Y, Zhou XJ, Ma HH, Lu ZF, He Y. Prognostic significance of stromal invasion grade and micropapillary pattern in early-stage adenocarcinoma of the lung. J Clin Exp Pathol. 2009;25:498–502.

    Google Scholar 

  27. Sobin LH, Gospodarowicz MK, Wittekind CH, International Union Against Cancer (UICC). TNM classification of malignant tumours. 7th ed. New York: Wiley-Liss; 2009. p. 138–46.

    Google Scholar 

  28. Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC. World Health Organization Classification of tumours. Pathology and genetics: tumours of lung, pleura, thymus and heart. Lyon: IARC; 2004. p. 68–77.

    Google Scholar 

  29. Brockenbrough JS, Morihara JK, Hawes SE, Stern JE, Rasey JS, Wiens LW, et al. Thymidine kinase 1 and thymidine phosphorylase expression in non-small-cell lung carcinoma in relation to angiogenesis and proliferation. J Histochem Cytochem. 2009;57:1087–97.

    Article  PubMed  CAS  Google Scholar 

  30. Chen YL, Eriksson S, Chang ZF. Regulation and functional contribution of thymidine kinase 1 in repair of DNA damage. J Biol Chem. 2010;28:27327–35.

    Article  Google Scholar 

  31. Topolcan O, Lubos Holubec L. The role of thymidine kinase in cancer diseases. Expert Opin Med Diagn. 2008;2:129–40.

    Article  CAS  Google Scholar 

  32. Mao Y, Wu J, Wang N, He L, Wu C, He Q, et al. A comparative study: immunohistochemical detection of cytosolic thymidine kinase and proliferating cell nuclear antigen in breast cancer. Cancer Invest. 2002;20:922–31.

    Article  PubMed  CAS  Google Scholar 

  33. He Q, Mao Y, Wu J, Decker C, Merza M, Wang N, et al. Cytosolic thymidine kinase is a specific histopathologic tumour marker for breast carcinomas. Int J Oncol. 2004;25:945–53.

    PubMed  CAS  Google Scholar 

  34. Wu J, Mao Y, He L, Wang N, Wu C, He Q, et al. A new cell proliferating marker: cytosolic thymidine kinase as compared to proliferating cell nuclear antigen in patients with colorectal carcinoma. Anticancer Res. 2000;20:4815–20.

    PubMed  CAS  Google Scholar 

  35. Mao Y, Wu J, Skog S, Eriksson S, Zhao Y, Zhou J, et al. Expression of cell proliferating genes in patients with non-small cell lung cancer by immunohistochemistry and cDNA profiling. Oncol Rep. 2005;13:837–46.

    PubMed  CAS  Google Scholar 

  36. Gakis G, Hennenlotter J, Scharpf M, Hevler J, Schilling D, Kuehs U, et al. (2011) XPA-210: a new proliferation marker to characterize tumor biology and progression of renal cell carcinoma. World J Urol (in press).

  37. Zhao H, Albino AP, Jorgensen E, Traganos F, Darzynkiewicz Z. DNA damage response induced by tobacco smoke in normal human bronchial epithelial and A549 pulmonary adenocarcinoma cells assessed by laser scanning cytometry. Cytometry A. 2009;75:840–7.

    PubMed  Google Scholar 

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Acknowledgements

This study was made possible by the support of Nanjing Jinling Hospital, Nanjing University Medical School, China; the Cancer Society of Stockholm; Faculty of Karolinska Institute, Clinical Research Center, Karolinska University Hospital; Swedish International Development Cooperation Agency, Stockholm, Sweden; and by a grant to S.E. from the Swedish Research Council. The anti-TK1 monoclonal ab was supplied by SSTK Ltd., Shenzhen, China.

Conflicts of interest

Yan Xu, Qun-Li Shi, Henghui Ma, Hangbo Zhou, Zhenfeng Lu, Bo Yu, Xiaojun Zhou and Staffan Eriksson declare no conflict of interest. Ellen He and Sven Skog are consultants to SSTK Ltd., Shenzhen, China.

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Authors and Affiliations

  1. Department of Pathology, Nanjing Jinling Hospital, Nanjing University Medical School, 305 Zhongshangdong Road, Nanjing, 210002, Jiangsu Province, China

    Yan Xu, Qun-Li Shi, Henghui Ma, Hangbo Zhou, Zhenfeng Lu, Bo Yu & Xiaojun Zhou

  2. Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, BMC, Uppsala, Sweden

    Staffan Eriksson

  3. Sino-Swed Molecular Bio-Medicine Research Institute, Shenzhen, People’s Republic of China

    Ellen He & Sven Skog

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  1. Yan Xu
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Correspondence to Qun-Li Shi.

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Xu, Y., Shi, QL., Ma, H. et al. High thymidine kinase 1 (TK1) expression is a predictor of poor survival in patients with pT1 of lung adenocarcinoma. Tumor Biol. 33, 475–483 (2012). https://doi.org/10.1007/s13277-011-0276-0

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