Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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The Relationship between Expression of EGFR, MMP-9, and C-erbB-2 and Survival Time in Resected Non-Small Cell Lung Cancer

수술을 시행한 비소세포 폐암 환자에서 EGFR, MMP-9 및 C-erbB-2의 발현과 환자 생존율과의 관계

  • Lee, Seung Heon (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Jung, Jin Yong (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Lee, Kyoung Ju (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Lee, Seung Hyeun (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Kim, Se Joong (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Ha, Eun Sil (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Kim, Jeong-Ha (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Lee, Eun Joo (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Hur, Gyu Young (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Jung, Ki Hwan (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Jung, Hye Cheol (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Lee, Sung Yong (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Lee, Sang Yeub (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Kim, Je Hyeong (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Shin, Chol (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Shim, Jae Jeong (Department of Internal Medicine, College of Medicine, Korea University) ;
  • In, Kwang Ho (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Kang, Kyung Ho (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Yoo, Se Hwa (Department of Internal Medicine, College of Medicine, Korea University) ;
  • Kim, Chul Hwan (Department of Pathology, College of Medicine, Korea University)
  • 이승헌 (고려대학교 의과대학 내과학교실) ;
  • 정진용 (고려대학교 의과대학 내과학교실) ;
  • 이경주 (고려대학교 의과대학 내과학교실) ;
  • 이승현 (고려대학교 의과대학 내과학교실) ;
  • 김세중 (고려대학교 의과대학 내과학교실) ;
  • 하은실 (고려대학교 의과대학 내과학교실) ;
  • 김정하 (고려대학교 의과대학 내과학교실) ;
  • 이은주 (고려대학교 의과대학 내과학교실) ;
  • 허규영 (고려대학교 의과대학 내과학교실) ;
  • 정기환 (고려대학교 의과대학 내과학교실) ;
  • 정혜철 (고려대학교 의과대학 내과학교실) ;
  • 이승룡 (고려대학교 의과대학 내과학교실) ;
  • 이상엽 (고려대학교 의과대학 내과학교실) ;
  • 김제형 (고려대학교 의과대학 내과학교실) ;
  • 신철 (고려대학교 의과대학 내과학교실) ;
  • 심재정 (고려대학교 의과대학 내과학교실) ;
  • 인광호 (고려대학교 의과대학 내과학교실) ;
  • 강경호 (고려대학교 의과대학 내과학교실) ;
  • 유세화 (고려대학교 의과대학 내과학교실) ;
  • 김철환 (고려대학교 의과대학 병리학교실)
  • Received : 2004.12.09
  • Accepted : 2005.08.25
  • Published : 2005.09.30
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Abstract

Background : Non-small cell lung cancer (NSCLC) is a common cause of cancer-related death in North America and Korea, with an overall 5-year survival rate of between 4 and 14%. The TNM staging system is the best prognostic index for operable NSCLC . However, epidermal growth factor receptor (EGFR), matrix metalloproteinase-9(MMP-9), and C-erbB-2 have all been implicated in the pathogenesis of NSCLC and might provide prognostic information. Methods : Immunohistochemical staining of 81 specimens from a resected primary non-small cell lung cancer was evaluated in order to determine the role of the biological markers on NSCLC . Immunohistochemical staining for EGFR, MMP-9, and C-erbB-2 was performed on paraffin-embedded tissue sections to observe the expression pattern according to the pathologic type and surgical staging. The correlations between the expression of each biological marker and the survival time was determined. Results : When positive immunohistochemical staining was defined as the extent area>20%(more than Grade 2), the positive rates for EGFR, MMP-9, and C-erbB-2 staining were 71.6%, 44.3%, and 24.1% of the 81 patients, respectively. The positive rates of EGFR and MMP-9 stain for NSCLC according to the surgical stages I, II, and IIIa were 75.0% and 41.7%, 66.7% and 47.6%, and 76.9% and 46.2%, respectively. The median survival time of the EGFR(-) group, 71.8 months, was significantly longer than that of the EGFR(+) group, 33.5 months.(p=0.018, Kaplan-Meier Method, log-rank test).. The MMP-9(+) group had a shorter median survival time than the MMP-9(-) group, 35.0 and 65.3 months, respectively (p=0.2). The co-expression of EGFR and MMP-9 was associated with a worse prognosis with a median survival time of 26.9 months, when compared with the 77 months for both negative-expression groups (p=0.0023). There were no significant differences between the C-erbB-2(+) and C-erbB-2 (-) groups. Conclusion : In NSCLC, the expression of EGFR might be a prognostic factor, and the co-expression of EGFR and MMP-9 was found to be associated with a poor prognosis. However, C-erbB-2 expression had no prognostic significance.

서 론 : 비소세포 폐암은 악성 종양 관련 사망의 중요한 원인 질환으로, 주요 병태생리 기전에 관여하는 EGFR, MMP-9 및 C-erbB-2의 발현 양상을 관찰 하는 것이 환자의 예후와 향후 치료 방향을 결정하는데 도움이 될 수 있다. 방 법 : 1995년 부터 2001년 까지 고려 대학교 의료원에 내원 후 원발성 비소세포 폐암 확진 후 외과절제술을 받은 81명 환자의 조직에 EGFR, MMP-9 및 C-erbB-2 면역 조직 화학 염색 및 정량화 후, 환자들의 특성 및 생존 기간과 함께, 조직 및 수술 병기에 따른 생물학적 표지자의 발현 양상을 후향적 고찰 하였다. 결 과 : 각 종양 조직 부위의 20%이상 염색되는 Grade 2 이상의 염색 양성률은, 편평상피세포암과 선암에서 EGFR은 75.0%와 63.4%, MMP-9은 43.3%와 43.9%, C-erbB-2는 23.3%와 22.0%를 보였다. 수술 병기가 I, II, IIIa 일때 EGFR 염색 양성률은 각각 75.0%, 66.7%, 76.9%, MMP-9은 41.7%, 47.6%, 46.2%, 그리고 C-erbB-2는 19.4%, 40.0%, 30.8%를 보였다. EGFR 양성군은 중앙 생존기간이 33.5개월로 EGFR 음성군의 71.8개월보다 유의한 불량한 예후를 나타냈다.(p<0.05). 그리고 MMP-9 양성군은 중앙 생존기간 35개월로 MMP-9 음성군의 65.3개월보다 불량한 생존 곡선의 양상을 보였으나 통계적 유의성은 없었다. 또한 C-erbB-2 양성군은 중앙 생존기간이 44.2개월, C-erbB-2 음성군은 58.4개월을 나타냈으나 통계적 유의한 차이는 없었다. EGFR과 MMP-9 동시 양성군은 전체 환자의 34.2%로서 중앙 생존기간이 26.9개월로 EGFR과 MMP-9 동시 음성군의 77.0개월보다 유의한 불량한 예후를 나타냈다(p<0.05) 결 론 : 비소세포 폐암 에서 EGFR의 양성군에서 음성군 보다 환자의 생존기간이 불량하였고, EGFR과 MMP-9의 동시 양성군에서 동시 음성군보다 생존기간이 불량하였다. C-erbB-2는 다른 생물학적 표지자에 비해서 낮은 염색 양성률을 나타냈으며 특이한 상관관계는 보이지 않았다.

Keywords

References

  1. Osann KE, Ernster VL, Mustacchi P. Chapter 45. Epidemiology of lung cancer. In: Murray JF, Nadel JA, editors. Textbook of respiratory medicine. 3rd ed. Philadelphia: W.B. Sanuders, company; 2001. p. 1395- 407
  2. Perez-Soler R. HER1/EGFR targeting: refining the strategy. Oncologist 2004;9:58-67 https://doi.org/10.1634/theoncologist.9-1-58
  3. Cox G, Jones JL, Andi A, Walker DA, O'Byrne KJ. A biological staging model for operable non-small cell lung cancer. Thorax 2001;56:561-6 https://doi.org/10.1136/thorax.56.7.561
  4. Westermarck J, Kahari VM. Regulation of matrix meꠀ talloproteinase expression in tumor invasion. FASEB J 1999;13:781-92
  5. Pinto CA, Carvalho PE, Antonangelo L, Garripo A, da Silva AG, Soares F, et al. Morphometric evaluation of tumor matrix metalloproteinase 9 predicts survival after surgical resection of adeno-carcinoma of the lung. Clin Cancer Res 2003;9:3098-104
  6. Tsai CM, Chang KT, Perng RP, Mitsudomi T, Chen MH, Kadoyama C, et al. Correlation of intrinsic chemoresistance of non-small cell lung cancer cell lines with HER-2/neu gene expression but not with ras gene mutations. J Natl Cancer Inst 1993;85:897-901 https://doi.org/10.1093/jnci/85.11.897
  7. Akita K, Inagaki H, Sato S, Niimi T, Maeda H, Ninomiya S, et al. $P185^{HER}-^{2/neu}$ and $P21^{CIP1/WAF1$ expression in primary tumors and lymph node metastases in Non-small lung cance. Jpn J Cancer Res 2002;93:1007-11
  8. Pfeiffer P, Calussen PP, Andersen K, Rose C. Lack of prognostic significance of epidermal growth factor receptor and the oncoprotein p185 HER-2 patients with systematically untreated non-small cell lung cancer: an immunohistochemical study on cryosections. Br J Cancer 1996;74;86-91
  9. Kern JA, Schwarts DA, Nordberg JE, Weiner DB, Greene MI, Torney L, et al. P185neu expression in human lung adenocarcinomas predicts shortened survival. Cancer Res 1990;50:5184-7
  10. Diez M, Pollan M, Maestro M, Torres A, Ortega D, Gomez A, et al. Prediction of recurrence by quantification of p 185neu protein in non-small cell lung cancer tissue. Br J Cancer 1997;75:684-9
  11. Ciardiello F, Caputo R, Bianco R, Damiano V, Fontaꠀ nini G, Cuccato S, et al. Inhibition of growth factor production and angiogenesis in human cander cells by ZD1839(Irresa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 2001;7:1459-65
  12. Curran S, Murray GI. Matrix metalloproteinases: moꠀ lecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer 2000;36:1621-30 https://doi.org/10.1016/S0959-8049(00)00156-8
  13. Schneider PM, Praeuer HW, Stoeltzing O, Boehm J, Manning J, Metzger R, et al. Multiple molecular marker testing(p-53, C-ki-ras, C-erbB-2) improves estimation of prognosis in potentially curative resected non-small cell lung cancer. Br J Cancer 2000;83: 473-9 https://doi.org/10.1054/bjoc.2000.1287
  14. Brown PD, Bloxidge RE, Stuart NS, Gatter KC, Camichael J. Association between expression of 72-kilodalton gelatinase and tumour spread in non-small cell lung cancer. J Natl Cancer Inst 1993; 85:574-8 https://doi.org/10.1093/jnci/85.7.574
  15. Rosenthal EL, Johnson TM, Allen ED, Apel IJ, Punturieri A, Weiss SJ. Role of the plasminogen activator and matrix metalloproteinase systems in epidermal growth factor and scatter factor stimulated invasion of carcinoma cells. Cancer Res 1998;58: 5221-30
  16. O-charoenrat P, Rhys-Evens P, Modjtahedi H, Court W, Box G, Eccles S. Overexpression of epidermal growth factor receptor in human head and neck squamous carcinoma cell lines correlates with matrix metalloproteinase-9 expression and in vitro invsion. Int J Cancer 2000;86:307-17 https://doi.org/10.1002/(SICI)1097-0215(20000501)86:3<307::AID-IJC2>3.0.CO;2-I
  17. Cox G, Jones JL, O'Byrne KJ. MMP-9 and the epidermal growth factor receptor signal pathway in operable non-small cell lung cancer. Clin Cancer Res 2000;6:2349-55
  18. Llorens A, Rodrigo I, Lopez-Barcons L, Gonzalez-Gaꠀ rrigues M, Lozano E, Vinyals A, et al. Down regulation of E-cadherin in mouse skin carcinoma cells enhance a migratory and invasive phenotype linked to matrix metalloproteinase-9 gelatinase expression. Lab Invest 1998;78:1131-42
  19. Kim HR, Jeong ET. Expression of EGFR in non-small cell lung cancer and effects on survival. Tuberc Respir Dis 1997;44:1285-95
  20. Selvaggi G, Novello S, Torri V, Leonardo E, de Giuli P, Borasio P, et al. Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer. Ann Oncol 2004;15;28-32 https://doi.org/10.1093/annonc/mdh011
  21. Sienel W, Hellers J, Morresi-Hauf A, Lichtinghagen R, Mutschler W, Jochum M, et al. Prognostic impact of matrix metalloproteinase-9 in operable non-small cell lung cancer. Int J Cancer 2003;103:647-51 https://doi.org/10.1002/ijc.10841
  22. O'Byrne KJ, Cox G, Swinson D, Richardson D, Edwards JG, Lolljee J, et al. Towards a biological staging model for operable non-small cell lung cancer. Lung Cancer 2001;34:S83-9 https://doi.org/10.1016/S0169-5002(01)00216-1
  23. Pastorino U, Andreola S, Tagliabue E, Pezzella F, Incarbone M, Sozzi G, et al. Immunocytochemical markers in stage I lung cancer: relevance to prognosis. J Clin Oncol 1997;15:2858-65