Annals of Coloproctology

The Korean Society of Coloproctology (대한대장항문학회)
권호 표지
DOI QR코드

DOI QR Code

Invasiveness of and Drug Sensitivity to Various Anti-cancer Regimens in Five Colorectal Cancer Cell Lines

대장암 세포주의 개별 항암화학요법에 대한 침습성과 약제감수성

  • Lee, Yoo-Mi (Department of Surgery and Institute of Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Yoon, Yong-Sik (Department of Surgery and Institute of Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Roh, Seon-Ae (Department of Surgery and Institute of Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Cho, Dong-Hyung (Department of Surgery and Institute of Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Jin-Cheon (Department of Surgery and Institute of Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine)
  • 이유미 (울산대학교 의과대학 외과학교실.서울아산병원 혁신형 암 연구중심병원) ;
  • 윤용식 (울산대학교 의과대학 외과학교실.서울아산병원 혁신형 암 연구중심병원) ;
  • 노선애 (울산대학교 의과대학 외과학교실.서울아산병원 혁신형 암 연구중심병원) ;
  • 조동형 (울산대학교 의과대학 외과학교실.서울아산병원 혁신형 암 연구중심병원) ;
  • 김진천 (울산대학교 의과대학 외과학교실.서울아산병원 혁신형 암 연구중심병원)
  • Received : 2009.09.15
  • Accepted : 2009.12.17
  • Published : 2010.04.30
⟨ Previous Next ⟩

Abstract

Purpose: Colorectal cancer (CRC) is one of the leading causes of cancer death in South Korea. Angiogenesis has been associated with invasion and metastasis of tumors and with the secretion of various growth factors. Bevacizumab is a humanized monoclonal antibody that recognizes and blocks vascular endothelial growth factor (VEGF) and that targets integrin ${\alpha}V{\beta}3$ and matrix metalloproteinases (MMPs) as angiogensis inhibitors. The aims of this study were identification of the mechanism of target molecules related to angiogenesis and demonstration of identifiable invasion by using chemotherapeutic regimens in vitro. Methods: The five colorectal cancer cell lines were treated with bevacizumab using standard or combined regimens. The expression of integrin ${\alpha}V{\beta}3$ was detected and the investigation of apoptosis was done by using flow cytometry. The activations of MMP-2 and MMP-9 were measured by using gelatin zymography. Results: The apoptotic cell death was significantly increased for the combined regimens, especially for FOLFOX (5-FU, leucovorin, and oxaliplatin) with bevacizumab. Bevacizumab inhibited the expression of integrin ${\alpha}V{\beta}3$ in the HT29 (59%), LoVo (67%), and SW480 (17%) cell lines, but did not in the AMC5 and the RKO cell lines. The activations of MMP-2 and MMP-9 were significantly reduced by treatment with bevacizumab in the HT29 and the LoVo cell lines. In the HT29 and the LoVo cell lines, thus, bevacizumab inhibited invasion and metastasis activity through down-regulation of integrin ${\alpha}V{\beta}3$ and MMPs. Conclusion: Our results provide biological evidence of potent angiogenic activity and indicate that angiogenesis is a complex process that involves multiple factors, including VEGF, integrin ${\alpha}V{\beta}3$, and MMPs.

Keywords

Acknowledgement

Supported by : 아산생명과학연구소

References

  1. Headquarter of Korea Central Cancer Registry. Cancer registry system in Korea [updated 2009 May 27; cited 2009 Jan 15]. Available from: http://www.ncc.re.kr.
  2. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10-30. https://doi.org/10.3322/canjclin.55.1.10
  3. Pallis AG, Mouzas IA. Adjuvant chemotherapy for colon cancer. Anticancer Res 2006;26:4809-15.
  4. Koopman M, Venderbosch S, Nagtegaal ID, van Krieken JH, Punt CJ. A review on the use of molecular markers of cytotoxic therapy for colorectal cancer, what have we learned? Eur J Cancer 2009;45:1935-49. https://doi.org/10.1016/j.ejca.2009.04.023
  5. Motl S. Bevacizumab in combination chemotherapy for colorectal and other cancers. Am J Health Syst Pharm 2005;62:1021-32.
  6. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of antitumour activity. Nat Rev Cancer 2008;8:579-91. https://doi.org/10.1038/nrc2403
  7. Prat A, Casado E, Cortes J. New approaches in angiogenic targeting for colorectal cancer. World J Gastroenterol 2007;13:5857-66. https://doi.org/10.3748/wjg.v13.i44.5857
  8. Ma J, Waxman DJ. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Mol Cancer Ther 2008;7:3670-84. https://doi.org/10.1158/1535-7163.MCT-08-0715
  9. Kim JC, Koo KH, Kim BS, Park KC, Bicknell DC, Bodmer WF. Carcino- embryonic antigen may function as a chemo-attractant in colorectalcarcinoma cell lines. Int J Cancer 1999;82:880-5. https://doi.org/10.1002/(SICI)1097-0215(19990909)82:6<880::AID-IJC18>3.0.CO;2-S
  10. Guo HY, Colangelo D, Li L, Connors KM, Kubota T, Hoffman RM. In vitro histoculture of human tumors with fluorescent dye end-points measured by confocal microscopy: high correlation of in vitro and in vivo chemosensitivity. Anticancer Res 1992;12:1055-61.
  11. Ohie S, Udagawa Y, Kozu A, Komuro Y, Aoki D, Nozawa S, et al. Cisplatin sensitivity of ovarian cancer in the histoculture drug response cisplatin, doxorubicin and cyclophosphamide. Anticancer Res 2000; 20:2049-54.
  12. Ghosh S, Maity P. Vascular endothelial growth factor immunoneutralization in combination with cisplatin reduces EAC tumor growth. Int Immunopharmacol 2006;6:1550-9. https://doi.org/10.1016/j.intimp.2006.05.005
  13. Danese S, Sans M, de la Motte C, Graziani C, West G, Phillips MH, et al. Angiogenesis as a novel component of inflammatory bowel disease pathogenesis. Gastroenterology 2006;130:2060-73. https://doi.org/10.1053/j.gastro.2006.03.054
  14. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249-57. https://doi.org/10.1038/35025220
  15. Pandya NM, Dhalla NS, Santani DD. Angiogenesis--a new target for future therapy. Vascul Pharmacol 2006;44:265-74. https://doi.org/10.1016/j.vph.2006.01.005
  16. Brooks SA, Lomax-Browne HJ, Carter TM, Kinch CE, Hall DM. Molecular interactions in cancer cell metastasis. Acta Histochem 2010;112: 3-25. https://doi.org/10.1016/j.acthis.2008.11.022
  17. Jia J, Zhu F, Ma X, Cao Z, Li Y, Chen YZ. Mechanisms of drug combinations: interaction and network perspectives. Nat Rev Drug Discov 2009;8:111-28. https://doi.org/10.1038/nrd2683
  18. Karran P, Hampson R. Genomic instability and tolerance to alkylating agents. Cancer Surv 1996;28:69-85.
  19. Hagedorn M, Bikfalvi A. Target molecules for anti-angiogenic therapy: from basic research to clinical trials. Crit Rev Oncol Hematol 2000;34: 89-110. https://doi.org/10.1016/S1040-8428(00)00056-1
  20. Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 2008;8:604-17. https://doi.org/10.1038/nrc2353
  21. Zucker S, Vacirca J. Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev 2004;23:101-17. https://doi.org/10.1023/A:1025867130437
  22. Rundhaug JE. Matrix metalloproteinases and angiogenesis. J Cell Mol Med 2005;9:267-85. https://doi.org/10.1111/j.1582-4934.2005.tb00355.x
  23. Ahn EJ, Chung SS, Lee RA, Kim KH. The expression and clinical correlations of matrix metalloproteinase-2, -7, -9 and -12 in colorectal cancer. J Korean Soc Coloproctol 2009;25:26-33. https://doi.org/10.3393/jksc.2009.25.1.26
  24. Aznavoorian S, Liotta LA, Kupchik HZ. Characteristics of invasive and noninvasive human colorectal adenocarcinoma cells. J Natl Cancer Inst 1990;82:1485-92. https://doi.org/10.1093/jnci/82.18.1485
  25. Hoffman RM. Three-dimensional histoculture: origins and applications in cancer research. Cancer Cells 1991;3:86-92.
  26. Furukawa T, Kubota T, Hoffman RM. Clinical applications of the histoculture drug response assay. Clin Cancer Res 1995;1:305-11.