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Transforming growth factor-β1 and α-smooth muscle actin in stromal fibroblasts are associated with a poor prognosis in patients with clinical stage I–IIIA nonsmall cell lung cancer after curative resection

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Tumor Biology

Abstract

The aims of this study were to investigate the expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in surgical resection specimens from nonsmall cell lung cancer (NSCLC) and to evaluate the prognostic significance of this gene expression in stromal fibroblasts for patients with clinical stage I–IIIA NSCLC. The immunohistochemical expression of TGF-β1 and α-SMA was evaluated in 78 formalin-fixed paraffin-embedded tumor specimens from clinical stage I–IIIA NSCLC. Correlations between this gene expression and the clinicopathologic characteristics were determined by chi-square test. The prognostic impact of this gene expression in stromal fibroblasts with regard to overall survival (OS) was determined by Kaplan-Meier and Cox hazard proportional model. The percentages of high TGF-β1 expression in stromal fibroblasts and cancer cells were 19.2 % (15/78) and 35.9 % (28/78), respectively. There were 28.2 % (22/78) of patients with high α-SMA expression in stromal fibroblasts. The analysis revealed a significant positive association between TGF-β1 expression in stromal fibroblasts and in cancer cells (χ 2 = 4.86, p = 0.03). No significant association was found between TGF-β1 in cancer cells and α-SMA expression in stromal fibroblasts (χ 2 = 0.978, p = 0.326). The 3-year OS rates with low and high TGF-β1 expression in stromal fibroblasts were 52.4 and 26.7 %, respectively (χ 2 = 5.42, p = 0.019). The 3-year OS rates with low and high α-SMA expression in stromal fibroblasts were 53.9 and 31.0 %, respectively (χ 2 = 5.01, p = 0.025). The multivariate analysis revealed that clinical stage and TGF-β1 and α-SMA expression levels in stromal fibroblasts were identified as independent predictive factors of OS. The results suggest that the expression level of TGF-β1 and α-SMA in stromal fibroblasts may have prognostic significance in patients with clinical stage I–IIIA NSCLC after curative resection.

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References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  2. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.

    Article  CAS  PubMed  Google Scholar 

  3. Haithcock BE, Stinchcombe TE, Socinski MA. Treatment of surgically resectable non-small-cell lung cancer in elderly patients. Clin Lung Cancer. 2009;10:405–9.

    Article  CAS  PubMed  Google Scholar 

  4. Williams BA, Sugimura H, Endo C, et al. Predicting postrecurrence survival among completely resected non small cell lung cancer patients. Ann Thorac Surg. 2006;81:1021–7.

    Article  PubMed  Google Scholar 

  5. Kim MP, Chen Y, Bekele BN, et al. Activating enhancer-binding protein-2β nucleolar localization predicts poor survival after stage I non-small cell lung cancer resection. Ann Thorac Surg. 2011;92:1044–50.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Konopa K. Do we have markers to select patients for adjuvant therapies of non-small-cell lung cancer? Ann Oncol. 2010;7:199–202.

    Google Scholar 

  7. Cirri P, Chiarugi P. Cancer-associated-fibroblasts and tumor cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev. 2012;31:195–208.

    Article  PubMed  Google Scholar 

  8. Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and their microenvironment. Trends Genet. 2009;25:30–8.

    Article  CAS  PubMed  Google Scholar 

  9. Tomasek JJ, Gabbiani G, Hinz B, et al. Myofibroblasts and mechano-regulation of connective tissue remodeling. Nat Rev Mol Cell Biol. 2002;3:349–63.

    Article  CAS  PubMed  Google Scholar 

  10. Cirri P, Chiarugi P. Cancer associated fibroblasts: the dark side of coin. Am J Cancer Res. 2011;1:482–97.

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Mantoni TS, Lunardi SL, AI-Assar O, et al. Pancreatic stellate cells radioprotect pancreatic cancer cells through β1-integrin signaling. Cancer Res. 2011;71:3453–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Xu Z, Wang S, Wu M, et al. TGF-β1 and HGF protein secretion by esophageal squamous epithelial cells and stromal fibroblasts in oesophageal carcinogenesis. Oncol Lett. 2013;6:401–6.

    PubMed Central  PubMed  Google Scholar 

  13. Desmouliere A, Geinoz A, Gabbiani F, et al. Transforming growth factor-β1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993;122:103–11.

    Article  CAS  PubMed  Google Scholar 

  14. Hazelbag S, Gorter A, Kenter GG, et al. Transforming growth factor-β1 induces tumor stroma and reduces tumor infiltrate in cervical cancer. Hum Pathol. 2002;33:1193–9.

    Article  CAS  PubMed  Google Scholar 

  15. Hawinkels LJAC, Paauwe M, Verspage HW, et al. Interaction with colon cancer cells hyperactivates TGF-β signaling in cancer-associated fibroblasts. Oncogene. 2012. doi:10.1038/onc.2012.536.

    PubMed  Google Scholar 

  16. Peng Y, Li Z, Li Z. GRP78 secreted by tumor cells stimulates differentiation of bone marrow mesenchymal stem cells to cancer-associated fibroblasts. Biochem Biophys Res Commun. 2013;440:558–63.

    Article  CAS  PubMed  Google Scholar 

  17. Liu C, Wu JF. Expression of TGF-β1, HIF-1α, VEGF and their clinical significance of gastric cancer. J Clin Exp Pathol. 2013;29:733–6.

    CAS  Google Scholar 

  18. Fuyuhiro Y, Yashiro M, Noda S, et al. Myofibroblasts are associated with the progression of scirrhous gastric carcinoma. Exp Ther Med. 2010;1:547–51.

    PubMed Central  PubMed  Google Scholar 

  19. Zhi K, Shen X, Zhang H, et al. Cancer-associated fibroblasts are positively correlated with metastasis potential of human gastric cancers. J Exp Clin Cancer Res. 2010;29:66–74.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Yamashita M, Ogawa T, Zhang X, et al. Role of stromal myofibroblasts in invasive breast cancer: stromal expression of alpha-smooth muscle actin correlates with worse clinical outcome. Breast Cancer. 2012;19:170–6.

    Article  PubMed  Google Scholar 

  21. Valach J, Fik Z, Strnad H, et al. Smooth muscle actin-expressing stromal fibroblasts in head and neck squamous cell carcinoma: Increased expression of galectin-1 and induction of poor prognosis factors. Int J Cancer. 2012;131:2499–508.

    Article  CAS  PubMed  Google Scholar 

  22. Tsamandas AC, Kardamakis D, Ravazoula P, et al. The potential role of TGFbeta1, TGFbeta2 and TGFbeta3 protein expression in colorectal carcinomas. Correlation with classic histopathologic factors and patient survival. Strahlenther Onkol. 2004;180:201–8.

    Article  PubMed  Google Scholar 

  23. Vagenas K, Spyropoulos C, Gavala V, et al. TGFbeta1, TGFbeta2, and TGFbeta3 protein expression in gastric carcinomas: correlation with prognostics factors and patient survival. J Surg Res. 2007;139:182–8.

    Article  CAS  PubMed  Google Scholar 

  24. Soufla G, Sifakis S, Porichis F, et al. Prognostic value of tgfb1 protein in endometrioid adenocarcinoma. Eur J Clin Investig. 2013;43:79–90.

    Article  CAS  Google Scholar 

  25. Kojima Y, Acar A, Eaton EN, et al. Autocrine TGF-beta and stromal cell-derived factor (SDF-1) signaling derives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci USA. 2010;107:20009–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Fuyuhiro Y, Yashiro M, Noda S, et al. Upregulation of cancer-associated myofibroblasts by TGF-β from scirrhous gastric carcinoma cells. Br J Cancer. 2011;105:996–1001.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Brenmoehl J, Miller SN, Hofmann C, et al. Transforming growth factor-beta 1 induces intestinal myofibroblast differentiation and modulates their migration. World J Gastroenterol. 2009;15:1431–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Rosenthal E, McCrory A, Talbert M, et al. Elevated expression of TGF-β1 in head and neck cancer-associated fibroblasts. Mol Carcinogen. 2004;40:116–21.

    Article  CAS  Google Scholar 

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Acknowledgments

This study was supported by grants from the Priority Academic Program Development of Jiangsu Higher Education Institutions and Jiangsu Province’s Key Medical Department in 2011.

Conflicts of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Thoracic Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, China

    Yongbing Chen & Wentao Yang

  2. Department of Oncology and Radiotherapy, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu Province, People’s Republic of China

    Li Zou, Yuanyuan Chen, Pengfei Xing, Xiaoqing Ji & Xueguan Lu

  3. Department of Pathology, the Second Affiliated Hospital of Soochow University, Suzhou, China

    Yongsheng Zhang & Feng Li

  4. Department of Radiation Biology, School of Radiation Medicine of Soochow University, Suzhou, China

    Fengjv Liu

Authors
  1. Yongbing Chen
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  2. Li Zou
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  3. Yongsheng Zhang
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  4. Yuanyuan Chen
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  10. Xueguan Lu
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Correspondence to Xueguan Lu.

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Chen, Y., Zou, L., Zhang, Y. et al. Transforming growth factor-β1 and α-smooth muscle actin in stromal fibroblasts are associated with a poor prognosis in patients with clinical stage I–IIIA nonsmall cell lung cancer after curative resection. Tumor Biol. 35, 6707–6713 (2014). https://doi.org/10.1007/s13277-014-1908-y

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  • DOI: https://doi.org/10.1007/s13277-014-1908-y

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