비소세포 폐암에서 C-erbB-2와 VEGF 발현에 대한 면역조직화학적 연구

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

  • 신종욱 (중앙대학교 의과대학 내과학교실) ;
  • 하경원 (중앙대학교 의과대학 병리학교실) ;
  • 최재철 (중앙대학교 의과대학 내과학교실) ;
  • 김재열 (중앙대학교 의과대학 내과학교실) ;
  • 박인원 (중앙대학교 의과대학 내과학교실) ;
  • 최병휘 (중앙대학교 의과대학 내과학교실) ;
  • 유재형 (중앙대학교 의과대학 병리학교실)
  • Shin, Jong Wook (Department of Internal Medicine, College of Medicine, Chung-Ang University) ;
  • Ha, Kyung Won (Department of Pathology, College of Medicine, Chung-Ang University) ;
  • Choi, Jae Cheol (Department of Internal Medicine, College of Medicine, Chung-Ang University) ;
  • Kim, Jae Yeol (Department of Internal Medicine, College of Medicine, Chung-Ang University) ;
  • Park, In Whon (Department of Internal Medicine, College of Medicine, Chung-Ang University) ;
  • Choi, Byoung Whui (Department of Internal Medicine, College of Medicine, Chung-Ang University) ;
  • Yoo, Jae Hyung (Department of Pathology, College of Medicine, Chung-Ang University)
  • 투고 : 2006.09.29
  • 심사 : 2006.12.28
  • 발행 : 2007.01.30

초록

배경 및 목적: 인체암에서 C-erbB-2의 과발현에 대한 광범위한 연구가 시행되고 있지만, 임상적 의의에 대해서는 논란의 대상이 되고 있다. 악성종양에서 신생혈관형성은 암의 진행에 필수적인 요소이다. 본 연구에서는 비소세포 폐암에서 C-erbB-2의 과발현의 의미, 암조직의 신생혈관형성에 중요한 역할을 하는 VEGF의 발현 및 두 표지자의 연관성을 연구하였다. 방 법: 파라핀 포매된 95예의 비소세포 폐암조직을 이용하여 avidin-biotin complex 법에 의한 면역조직화학적 염색을 시행하였으며, 연구재료는 원발성 편평세포암종 60예 그리고 원발성 선암종 35예를 대상으로 하였다. 결 과: 비소세포 폐암에서 선암종의 C-erbB-2의 과발현은 편평세포암종보다 의미 있게 높게 나타났다. 임상병기에 따른 C-erbB-2와 VEGF의 과발현은 진행암에서 증가하는 경향을 나타내었으나, 초기암과의 유의한 차이는 없었다. 선암종에서 C-erbB-2와 VEGF의 발현은 유의하게 상관성을 나타내었다. 결 론: 비소세포 폐암에서 C-erbB-2의 과발현은 암의 유형에 따라 다르다는 것을 알 수 있었으며, C-erbB-2의 과발현이 높게 나타나는 선암종에서는 이 성적과 암세포의 VEGF의 발현이 상관성을 나타낸다는 것을 알 수 있었다.

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.

키워드

참고문헌

  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 2001233:630-8 https://doi.org/10.1097/00000658-200105000-00006
  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 199917: 1974-82 https://doi.org/10.1200/JCO.1999.17.7.1974
  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;66:1159-64 https://doi.org/10.1016/S0003-4975(98)00792-9
  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;59:3206-14
  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;5:384-90
  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;41:282-8 https://doi.org/10.1080/02841860260088836
  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):S53-67
  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 nonsmall- cell lung carcinomas. Br J Cancer 2002;86: 1449-56 https://doi.org/10.1038/sj.bjc.6600286
  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;7:1850-5
  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;7:3239-50
  11. Weidman N, Folkman J. Tumoral vascularity as a prognostic factor in cancer. Drug Dev Res 1996;25: 249-65
  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;36:601-9 https://doi.org/10.1016/S0959-8049(99)00327-5
  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;43:80-6 https://doi.org/10.1080/02841860310017441
  14. Izumi Y, Xu L, Tomaso E, Fukumura D, Jain RK. Tumour biology Herceptin${\circledR}$ acts as an anti-angiogenetic cocktail. Nature 2002;416:279-80
  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;17:1983-7 https://doi.org/10.1200/JCO.1999.17.7.1983
  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;41:500-6 https://doi.org/10.1080/02841860214961
  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 https://doi.org/10.1002/1097-0142(19940801)74:3<795::AID-CNCR2820740303>3.0.CO;2-I
  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: 1237-42 https://doi.org/10.1038/bjc.1995.239
  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;95:266-70 https://doi.org/10.1002/1097-0215(20010720)95:4<266::AID-IJC1045>3.0.CO;2-E
  21. Allred DC, Swanson PE. Testing for erbB-2 by immunohistochemistry in breast cancer. Am J Clin Pathol 2000;113:171-5 https://doi.org/10.1309/9X6X-1EL6-5QB1-YLD2
  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: 250-1
  23. Shak S. Overview of the trastuzumab(Herceptin$^{\circledR}$) anti HER-2 monoclonal antibody clinical program in HER-2 overexpressing metastatic breast cancer. Semin Oncol 1999;26:71-7
  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; 63:3626-31
  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;7:1850-5
  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;2:216-9 https://doi.org/10.3816/CLC.2001.n.006
  27. Folkman J, Watson K,Ingiber D, Hanahan D. Induction of angiogenesis during the transitionfrom hyperplasia to neoplasia.1989;339:58-61 https://doi.org/10.1038/339058a0
  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;55:3964-8
  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;13:12-5 https://doi.org/10.1093/annonc/mdf093