Tuberc Respir Dis.  2007 Jan;62(1):43-50. 10.4046/trd.2007.62.1.43.

Immunohistochemical Study of C-erbB-2 and VEGF Expression in Non-Small Cell Lung Cancer

• Shin JW
• Ha KW
• Choi JC
• Kim JY
• Park IW
• Choi BW
• Yoo JH

• KMID: 1518488
• DOI: http://doi.org/10.4046/trd.2007.62.1.43

Abstract

BACKGROUND: Mutated or deregulated expression of C-erbB-2 causes this gene to function as a potent oncogene. Vascular endothelial growth factor (VEGF) is a crucial angiogenic molecule in lung cancer. Both C-erbB-2 and VEGF can promote growth, proliferation and metastasis in non-small cell lung cancer (NSCLC). The purpose of this study was to investigate evaluate the relationship between the expressions of the C-erbB-2 and VEGF genes using immunohistochemistry.
MATERIALS AND METHODS
Ninety-five patients with NSCLC were involved (60 squamous cell carcinoma and 35 adenocarcinoma). The formalin-fixed paraffin embedded specimens were immunohistochemically stained for C-erbB-2 and VEGF using the avidin-biotin complex method.
RESULTS
Positive C-erbB-2 expression was observed more often in adenocarcinomas than squamous cell carcinomas (p<0.05). Although the immunohistochemical expressions of C-erbB-2 and VEGF in non-small-cell lung cancer showed increased tendencies at an advanced stage, the correlation between early and advanced cancers was insignificant. In adenocarcinomas, the expressions of VEGF and C-erbB-2 were significantly (p<0.05).
CONCLUSION
The overexpression fo C-erbB-2 was significantly higher in adenocarcinomas than squamous cell carcinomas, and correlated with the expression of VEGF in adenocarcinomas of the lungs.

Keyword

C-erbB-2; VEGF; Non-small-cell lung cancer

MeSH Terms

Adenocarcinoma
Carcinoma, Non-Small-Cell Lung*
Carcinoma, Squamous Cell
Humans
Immunohistochemistry
Lung
Lung Neoplasms
Neoplasm Metastasis
Oncogenes
Paraffin
Vascular Endothelial Growth Factor A*
Paraffin
Vascular Endothelial Growth Factor A

Figure

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  Figure 1 Immunohistochemical staining for C-erbB-2 in squamous cell carcinoma(1-a) and adenocarcinoma(1-b) of lung shows intracytoplasmic and membranous positive reaction(Avidin-Biotin Complex, ×400).

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  Figure 2 Immunohistochemical staining for VEGF in squamous cell carcinoma(2-a) and adenocarcinoma(2-b) of lung shows diffuse granular positive reaction(Avidin-Biotin Complex, ×400)

Reference

1. Beenken SW, Gizzle WE, Crowe DR, Conner MG, Weiss HL, Sellers MT, et al. Molecular biomarkers for breast cancer prognosis: coexpression of C-erbB-2 of p53. Ann Surg. 2001. 233:630–638.

2. Jacobs TW, Gown AM, Yaziji H, Barnes MJ, Schnitt SJ. Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol. 1999. 17:1974–1982.

3. Hsieh CC, Chow KC, Fahn HJ, Tsai CM, Liu WY, Huang MH, et al. Prognostic significance of HER-2/ neu overexpression in stage I adenocarcinoma of lung. Ann Thorac Surg. 1998. 66:1159–1164.

4. Henengstler JG, Lange J, Kett A, Dornhofer N, Meinert R, Arand M, et al. Contribution of c-erbB-2 and topoisomerase II alpha to chemoresistance in ovarian cancer. Cancer Res. 1999. 59:3206–3214.

5. David L, Serruca R, Nesland JM, Soares P, Sansonetty F, Holm R, et al. C-erb-B2 expression in primary gastric carcinoma and their metastases. Mod Pathol. 1992. 5:384–390.

6. Wester K, Sjostrom A, Torre M, Carlsson J, Malmstrom PU. HER-2: a possible target for therapy of metastatic urinary bladder carcinoma. Acta Oncol. 2002. 41:282–288.

7. Ross JS, Fletcher JA. HER-2/neu(c-erbB-2) gene and protein in breast cancer. Am J Clin Pathol. 1999. 112:Suppl 1. S53–S67.

8. Hirsch FR, Varcella-Garcia M, Franklin WA, Veve R, Cehn L, Helfrich B, et al. Evaluation of HER-2/neu gene amplification and protein expression in non-small-cell lung carcinomas. Br J Cancer. 2002. 86:1449–1456.

9. Brabernder J, Danenberg KD, Metzger R, Schneider PM, Park J, Salinga D, et al. Epidermal growth factor receptor and HER-2-neu mRNA expression in non-small-cell lung cancer is correlated with survival. Clin Cancer Res. 2001. 7:1850–1855.

10. Bunn PA Jr, Helfrich B, Soriano A, Franklin WA, Varella-Garcia M, Hirsch F, et al. Expression of HER-2/neu in human lung cancer cell lines by immunohistochemistry and fluorescence in situ hybridization and relationship to in vitro cytotoxicity by trastuzumab and cytotherapeutic. Clin Cancer Res. 2001. 7:3239–3250.

11. Weidman N, Folkman J. Tumoral vascularity as a prognostic factor in cancer. Drug Dev Res. 1996. 25:249–265.

12. Yano T, Tanikawa S, Fujie T, Masutani M, Horie T. Vascular endothelial growth factor expression and neovascularization in non-small cell lung cancer. Eur J Cancer. 2000. 36:601–609.

13. Brattstrom D, Wester K, Bergqvist M, Hesselius P, Malmstrom PU, Nordgren H, et al. HER-2, EGFR, COX-2 expression status correlated to microvessel density and survival in resected non-small cell lung cancer. Acta Oncol. 2004. 43:80–86.

14. Izumi Y, Xu L, Tomaso E, Fukumura D, Jain RK. Tumour biology Herceptin® acts as an anti-angiogenetic cocktail. Nature. 2002. 416:279–280.

15. Jacobs TW, Gown AM, Yaziji H, Barnes MJ, Shinitt SJ. Specificity of Hercep Test in determining HER-2/neu status of breast cancers using the United States Food and Drug Administration-approved scoring system. J Clin Oncol. 1999. 17:1983–1987.

16. Lohrisch C, Piccart M. An overview of HER-2. Semin Oncol. 2001. 28(6):Suppl. 3–11.

17. Hansen HH. An update on management for lung cancer: Acta Oncologica Lecture-Vasteras 21 March 2002. Acta Oncol. 2002. 41:500–506.

18. Itakura Y, Sasano H, Shiaga C, Furukawa Y, Shiga K, Mori S, et al. Epidermal growth factor receptor overexpression in esophageal carcinoma: an immunohistochemical study correlated with clinicopathologic findings and DNA amplification. Cancer. 1994. 74:795–804.

19. Newby JC, A'Hern RP, Leek RD, Smith IX, Harris AL, Dowsett M. Immunohistochemical assay for epidermal growth factor receptor on paraffin-embedded sections: validation against ligand-bindingand clinical relevance in breast cancer. Br J Cancer. 1995. 71:1237–1242.

20. Riou G, Mathieu MC, Barrois M, Le Bihan ML, Ahomadegbe JC, Benard J, et al. C-erbB-2(HER-2/neu) gene amplification is a better indicator of poor prognosis than protein over-expression in operable breast-cancer patients. Int J Cancer. 2001. 95:266–270.

21. Allred DC, Swanson PE. Testing for erbB-2 by immunohistochemistry in breast cancer. Am J Clin Pathol. 2000. 113:171–175.

22. Solbach C, Roller M, Budischewski K, Loibl S, Nicoletti M, Stegmueller M, et al. EGFR and Her2/neu overexpressing tumors: independent collectives for treatment of breast cancer by specific monoclonal antibody-therapy. J Cancer Res Clin Oncol. 2003. 129:250–251.

23. Shak S. Overview of the trastuzumab(Herceptin®) anti HER-2 monoclonal antibody clinical program in HER-2 overexpressing metastatic breast cancer. Semin Oncol. 1999. 26:71–77.

24. Nahta R, Trent S, Yang C, Schmidt EV. Epidermal growth factor receptor expression is a candidate target of the synergistic combination of trastuzumab and flavopiridol in breast cancer. Cancer Res. 2003. 63:3626–3631.

25. Brabender J, Danenberg KD, Metzger R, Schneider PM, Park J, Salonga D, et al. Epidermal growth factor receptor andmRNA expression in non small cell lung cancer is correlated with survival. Clin Cancer Res. 2001. 7:1850–1855.

26. Korrapati V, Gaffney M, Larsson LG, Nunno LD, Riggs M, Beissner RS, et al. Effects of HER-2/neu expression on survival in non small cell lung cancer. Clin Lung Cancer. 2001. 2:216–219.

27. Folkman J, Watson K, Ingiber D, Hanahan D. Induction of angiogenesis during the transitionfrom hyperplasia to neoplasia. Nature. 1989. 339:58–61.

28. Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and this receptor, KDR, correlates with vascularity, metastasis and proliferation of humancancer. Cancer Res. 1995. 55:3964–3968.

29. Kerbel RS, Klement G, Prichard KI, Kamen B. Continuous low-dose anti-angiogenic/metronomic chemotherapy: from the research laboratory into the oncology clinic. Ann Oncol. 2002. 13:12–15.