Skip to main content

Advertisement

SpringerLink
Log in

Overexpression of Metastasis-Associated Protein 1 is Significantly Correlated with Tumor Angiogenesis and Poor Survival in Patients with Early-Stage Non-Small Cell Lung Cancer

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The aims of this work are to detect the expression levels of metastasis-associated protein 1 (MTA1) in patients with early-stage non-small cell lung cancer (NSCLC), and to investigate the relationship of MTA1 protein with clinicopathologic factors, tumor angiogenesis, and prognosis.

Methods

One hundred and two patients with pathologic stage I NSCLC who successfully underwent curative surgical resection were enrolled in this study. Immunohistochemical staining for MTA1 and CD34 was performed using the streptavidin–peroxidase method, and intratumoral microvessel density (MVD) was recorded by counting CD34-positive immunostained endothelial cells. All statistical analyses were performed with SPSS statistical software to determine the effects of MTA1 protein on clinicopathologic factors, tumor angiogenesis, and prognosis.

Results

MTA1 protein overexpression was detected in 41 cases and was significantly associated with MVD (P = 0.008). MTA1 protein overexpression and high MVD were significantly associated with tumor relapse (P = 0.004 and 0.007) and poor 5-year disease-free survival (P = 0.001 and 0.004). Patients with MTA1 protein overexpression and high MVD had significantly poor overall survival (P = 0.005 and 0.043) and disease-specific survival (P = 0.006 and 0.031) at 5 years after operation. Multivariate analysis demonstrated that MTA1 protein overexpression was an independent prognosticator for unfavorable disease-free, overall, and disease-specific survival (P = 0.011, 0.024, and 0.046).

Conclusions

MTA1 protein overexpression is common in early-stage NSCLC and is significantly associated with tumor angiogenesis and poor survival. These findings suggest that MTA1 may have clinical potential as a promising predictor to identify individuals with poor prognostic potential and as a possible novel target molecule of antiangiogenic therapy for patients with early-stage NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hoffman PC, Mauer AM, Vokes EE. Lung cancer. Lancet. 2000;355:479–85.

    PubMed  CAS  Google Scholar 

  2. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24:2137–50.

    Article  PubMed  Google Scholar 

  3. Brognard J, Clark AS, Ni Y, Dennis PA. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res. 2001;61:3986–97.

    PubMed  CAS  Google Scholar 

  4. Ren H, Tang X, Lee JJ, et al. Expression of hepatoma-derived growth factor is a strong prognostic predictor for patients with early-stage non-small-cell lung cancer. J Clin Oncol. 2004;22:3230–7.

    Article  PubMed  CAS  Google Scholar 

  5. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2:533–43.

    Article  PubMed  CAS  Google Scholar 

  6. Fry WA, Philips JL, Menck HR. Ten-year survey of lung cancer treatment and survival in hospitals in the United States: a national cancer data base report. Cancer. 1999;86:1867–76.

    Article  PubMed  CAS  Google Scholar 

  7. Kim JH, Bogner PN, Ramnath N, Park Y, Yu J, Park YM. Elevated peroxiredoxin 1, but not NF-E2-related factor 2, is an independent prognostic factor for disease recurrence and reduced survival in stage I non-small cell lung cancer. Clin Cancer Res. 2007;13:3875–82.

    Article  PubMed  CAS  Google Scholar 

  8. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non- small-cell lung cancer. N Engl J Med. 2004;350:351–60.

    Article  PubMed  Google Scholar 

  9. Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al., on behalf of the LACE Collaborative Group. Lung Adjuvant Cisplatin Evaluation (LACE): a pooled analysis of five randomized clinical trials including 4,584 patients. J Clin Oncol. 2006;24(18 suppl):366s (abstract 7008).

    Google Scholar 

  10. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005;352:2589–97.

    Article  PubMed  CAS  Google Scholar 

  11. Dango S, Sienel W, Schreiber M, Stremmel C, Kirschbaum A, Pantel K, et al. Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) is associated with increased angiogenic potential in non-small-cell lung cancer. Lung Cancer. 2008;60:426–33.

    Article  PubMed  Google Scholar 

  12. Raz DJ, Ray MR, Kim JY, et al. A multigene assay is prognostic of survival in patients with early-stage lung adenocarcinoma. Clin Cancer Res. 2008;14:5565–70.

    Article  PubMed  CAS  Google Scholar 

  13. Sidransky D. Emerging molecular markers of cancer. Nat Rev Cancer. 2002;2:210–9.

    Article  PubMed  CAS  Google Scholar 

  14. Toh Y, Nicolson GL. The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications. Clin Exp Metastasis. 2009;26:215–27.

    Article  PubMed  CAS  Google Scholar 

  15. Nicolson GL, Nawa A, Toh Y, Taniguchi S, Nishimori K, Moustafa A. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clin Exp Metastasis. 2003;20:19–24.

    Article  PubMed  CAS  Google Scholar 

  16. Kumar R, Wang RA, Bagheri-Yarmand R. Emerging roles of MTA family members in human cancers. Semin Oncol. 2003;30:30–7.

    Article  PubMed  CAS  Google Scholar 

  17. Mazumdar A, Wang RA, Mishra SK, et al. Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat Cell Biol. 2001;3:30–7.

    Article  PubMed  CAS  Google Scholar 

  18. Yan C, Wang H, Toh Y, Boyd DD. Repression of 92-kDa type IV collagenase expression by MTA1 is mediated through direct interactions with the promoter via a mechanism, which is both dependent on and independent of histone deacetylation. J Biol Chem. 2003;278:2309–16.

    Article  PubMed  CAS  Google Scholar 

  19. Jang KS, Paik SS, Chung H, Oh YH, Kong G. MTA1 overexpression correlates significantly with tumor grade and angiogenesis in human breast cancers. Cancer Sci. 2006;97:374–9.

    Article  PubMed  CAS  Google Scholar 

  20. Martin MD, Hilsenbeck SG, Mohsin SK, et al. Breast tumors that overexpress nuclear metastasis-associated 1 (MTA1) protein have high recurrence risks but enhanced responses to systemic therapies. Breast Cancer Res Treat. 2006;95:7–12.

    Article  PubMed  CAS  Google Scholar 

  21. Hofer MD, Kuefer R, Varambally S, et al. The role of metastasis-associated protein 1 in prostate cancer progression. Cancer Res. 2004;64:825–9.

    Article  PubMed  CAS  Google Scholar 

  22. Balasenthil S, Broaddus RR, Kumar R. Expression of metastasis-associate protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas. Hum Pathol. 2006;37:656–61.

    Article  PubMed  CAS  Google Scholar 

  23. Ryu SH, Chung YH, Lee H, et al. Metastatic tumor antigen 1 is closely associated with frequent postoperative recurrence and poor survival in patients with hepatocellular carcinoma. Hepatology. 2008;47:929–36.

    Article  PubMed  Google Scholar 

  24. Mahoney MG, Simpson A, Jost M, et al. Metastasis-associated protein (MTA) 1 enhances migration, invasion and anchorage-independent survival of immortalized human keratinocytes. Oncogene. 2002;21:2161–70.

    Article  PubMed  CAS  Google Scholar 

  25. Hofer MD, Menke A, Genze F, Gierschik P, Giehl K. Expression of MTA1 promotes motility and invasiveness of PANC-1 pancreatic carcinoma cells. Br J Cancer. 2004;90:455–62.

    Article  PubMed  CAS  Google Scholar 

  26. Toh Y, Ohga T, Endo K, et al. Expression of the metastasis-associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cell carcinomas. Int J Cancer. 2004;110:362–7.

    Article  PubMed  CAS  Google Scholar 

  27. Eskens FA. Angiogenesis inhibitors in clinical development; where are we now and where are we going? Br J Cancer. 2004;90:1–7.

    Article  PubMed  CAS  Google Scholar 

  28. Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 2006;12:895–904.

    Article  PubMed  CAS  Google Scholar 

  29. Bremnes RM, Camps C, Sirera R. Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood. Lung Cancer. 2006;51:143–58.

    Article  PubMed  Google Scholar 

  30. Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002;2:727–39.

    Article  PubMed  CAS  Google Scholar 

  31. Moon HE, Cheon H, Chun KH, et al. Metastasis-associated protein 1 enhances angiogenesis by stabilization of HIF-1alpha. Oncol Rep. 2006;16:929–35.

    PubMed  CAS  Google Scholar 

  32. Naruke T, Suematu K, Ishikawa S. Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg. 1978;76:832–9.

    PubMed  CAS  Google Scholar 

  33. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004.

    Google Scholar 

  34. Mountain CF. Revision in the international system for staging lung cancer. Chest. 1997;111:1710–7.

    Article  PubMed  CAS  Google Scholar 

  35. Yuan A, Yu CJ, Shun CT, Luh KT, Kuo SH, Lee YC, et al. Total cyclooxygenase-2 mRNA levels correlate with vascular endothelial growth factor mRNA levels, tumor angiogenesis and prognosis in non-small cell lung cancer patients. Int J Cancer. 2005;115:545–55.

    Article  PubMed  CAS  Google Scholar 

  36. Li SH, Wang Z, Liu XY. Metastasis-associated protein 1 (MTA1) overexpression is closely associated with shorter disease-free interval after complete resection of histologically node-negative esophageal cancer. World J Surg. 2009;33:1876–81.

    Article  PubMed  Google Scholar 

  37. Vermeulen PB, Gasparini G, Fox SB, et al. Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours. Eur J Cancer. 2002;38:1564–79.

    Article  PubMed  CAS  Google Scholar 

  38. Yuan A, Yu CJ, Chen WJ, Lin FY, Kuo SH, Luh KT, et al. Correlation of total VEGF mRNA and protein expression with histologic type, tumor angiogenesis, patient survival and timing of relapse in non-small-cell lung cancer. Int J Cancer. 2000;89:475–83.

    Article  PubMed  CAS  Google Scholar 

  39. Masuya D, Huang C, Liu D, et al. The intratumoral expression of vascular endothelial growth factor and interleukin-8 associated with angiogenesis in nonsmall cell lung carcinoma patients. Cancer. 2001;92:2628–38.

    Article  PubMed  CAS  Google Scholar 

  40. Huang C, Liu D, Masuya D, et al. Clinical application of biological markers for treatments of resectable non-small-cell lung cancers. Br J Cancer. 2005;92:1231–9.

    Article  PubMed  CAS  Google Scholar 

  41. Kadota K, Huang CL, Liu D, Ueno M, Kushida Y, Haba R, et al. The clinical significance of lymphangiogenesis and angiogenesis in non-small cell lung cancer patients. Eur J Cancer. 2008;44:1057–67.

    Article  PubMed  CAS  Google Scholar 

  42. Guo NL, Wan YW, Tosun K, et al. Confirmation of gene expression-based prediction of survival in non-small cell lung cancer. Clin Cancer Res. 2008;14:8213–20.

    Article  PubMed  CAS  Google Scholar 

  43. D’Amico TA. Angiogenesis in non-small cell lung cancer. Semin Thorac Cardiovasc Surg. 2004;16:13–8.

    Article  PubMed  Google Scholar 

  44. Kim HS, Youm HR, Lee JS, Min KW, Chung JH, Park CS. Correlation between cyclooxygenase-2 and tumor angiogenesis in non-small cell lung cancer. Lung Cancer. 2003;42:163–70.

    Article  PubMed  Google Scholar 

  45. Chen HY, Yu SL, Chen CH, et al. A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med. 2007;356:11–20.

    Article  PubMed  CAS  Google Scholar 

  46. Sasaki H, Moriyama S, Nakashima Y, et al. Expression of the MTA1 mRNA in advanced lung cancer. Lung Cancer. 2002;35:149–54.

    Article  PubMed  Google Scholar 

  47. Li D, Qian J, Hong Z. Expression and clinical significance of MTA1 in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi. 2008;11:775–9.

    PubMed  CAS  Google Scholar 

  48. Zhu XX, Guo Y, Chen LH, Ding YQ. Expressions of metastatic tumor antigen 1 and hypoxia-inducible-factor l alpha in lung cancer and their clinical significance. Nan Fang Yi Ke Da Xue Xue Bao. 2009;29:642–4.

    PubMed  CAS  Google Scholar 

  49. Zhu X, Guo Y, Li X, Ding Y, Chen L. Metastasis-associated protein 1 nuclear expression is associated with tumor progression and clinical outcome in patients with non-small cell lung cancer. J Thorac Oncol. 2010;5:1159–66.

    Article  PubMed  Google Scholar 

  50. Shijubo N, Kojima H, Nagata M, Ohchi T, Suzuki A, Abe S, et al. Tumor angiogenesis of non-small cell lung cancer. Microsc Res Tech. 2003;60:186–98.

    Article  PubMed  CAS  Google Scholar 

  51. Meert AP, Paesmans M, Martin B, et al. The role of microvessel density on the survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer. 2002;87:694–701.

    Article  PubMed  Google Scholar 

  52. Marrogi AJ, Travis WD, Welsh JA, et al. Nitric oxide synthase, cyclooxygenase 2, and vascular endothelial growth factor in the angiogenesis of non-small cell lung carcinoma. Clin Cancer Res. 2000;6:4739–44.

    PubMed  CAS  Google Scholar 

  53. Han H, Silverman JF, Santucci TS, et al. Vascular endothelial growth factor expression in stage I non-small cell lung cancer correlates with neoangiogenesis and a poor prognosis. Ann Surg Oncol. 2001;8:72–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Thoracic Surgery, Qi Lu Hospital, Shandong University, Jinan, Shandong Province, China

    Shu-hai Li MD, Hui Tian MD, Wei-ming Yue MD, Lin Li MD, Wen-jun Li MD, Wen-si Hu MD, Ying-chao Zhu MMed & Lei Qi MMed

  2. Department of Thoracic Surgery, Jinan Central Hospital Affiliated to Shandong University, Shandong University, Jinan, Shandong Province, China

    Zhi-tao Chen MD

Authors
  1. Shu-hai Li MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui Tian MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei-ming Yue MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lin Li MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen-jun Li MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhi-tao Chen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wen-si Hu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ying-chao Zhu MMed
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lei Qi MMed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hui Tian MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Sh., Tian, H., Yue, Wm. et al. Overexpression of Metastasis-Associated Protein 1 is Significantly Correlated with Tumor Angiogenesis and Poor Survival in Patients with Early-Stage Non-Small Cell Lung Cancer. Ann Surg Oncol 18, 2048–2056 (2011). https://doi.org/10.1245/s10434-010-1510-5

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-010-1510-5

Keywords

Search

Navigation