생명과학회지 (Journal of Life Science)

한국생명과학회 (Korean Society of Life Science)
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다형성 교모세포종의 항생제 내성 종양 줄기세포

Chemotherapeutic Drug Resistant Cancer Stem-like Cells of Glioma

  • Kang, Mi-Kyung (Department of Physiology, College of Medicine, Pusan National University) ;
  • Kang, Soo-Kyung (Department of Physiology, College of Medicine, Pusan National University)
  • 발행 : 2007.08.30
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초록

다형성 교모세포종은 뇌종양 가운데 가장 빈번하게 발병하는 악성종양이다. 다형성 교모세포종에 종양 줄기세포가 존재한다는 보고가 있음에도 불구하고, 항암제 내성과 종양 줄기세포 사이의 상호 연관성에 관한 연구는 아직 미비한 실정이다. 본 연구에서 다형성 교모세포종 세포주 A172 및 뇌종양 환자로부터 확립한 GBM2에 1,3-bis(2 -chloroethyl)-1-nitrosourea (BiCNU)를 처리시 극소량의 세포군만이 생존하며, 이들 생존 세포군은 BiCNU 재처리에 내성을 나타내는 것으로 조사되었다. 또한 이 다형성 교모세포종 유래 BiCNU-내성세포군의 Erk 및 Akt 인산화 활성이 증가되었으며, CD133 줄기세포 표지인자를 발현하는 세포가 다량 존재하였다. 이와 아울러, 다형성 교모세포종 유래 BiCNU-내성세포를 severe combined immuno-deficient (SCID) mouse brain에 이식하였을 때 암이 형성되는 것을 관찰할 수 있었다. 이와 같은 결과는 다형성 교모세포종 유래 BiCNU-내성세포가 종양줄기세포의 능력을 가지는 것으로 생각된다. 따라서 이상의 결과는 다형성 교모세포종에 존재하는 종양줄기세포가 항암제 내성에 관여 한다는 중요한 단서를 제공해줄 수 있을 것으로 사료된다.

Glioblastoma multiforme (GBM) is the most frequently occurring brain cancer. Although the existence of cancer stem cells (CSCs) in GBM has been established, there is little evidence to explain the link between CSCs and chemoresistance. In this study, we investigated that only a few cells of A172 and established GBM2 survived after 1,3-bis(2chloroethyl)-1-nitrosourea (BiCNU) exposures and these sur-vived cells resist the subsequent BiCNU treatment. In addition, these BiCNU-resistant small pop-ulations derived from GBM cells increased the phosphorylations of Erk and Akt and highly expressed CD133 stem cell surface marker. Furthermore, we observed that the BiCNU-resistant cancer cells de-rived from GBM have grown tumors when transplanted into severe combined immuno-deficient (SCID) mouse brain. These results demonstrate that BiCNU-resistant subpopulation cells derived from GBM have cancer stem-like cell properties. Therefore, it may provide provide further evidence that CSCs in GBM have chemotherapeutic drug resistance.

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참고문헌

  1. Al-Hajj, M., M. S. Wicha, A. Benito-Hernandez, S. J. Morrison and M. F. Clarke. 2003. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100, 3983-3988. https://doi.org/10.1073/pnas.0530291100
  2. Ali-Osman, F., D. E. Stein and A. Renwick. 1990. Glutathione content and glutathione-S-transferase expression in l,3-bis(2-chloroethyl)-1-nitrosourea-resistant human malignant astrocytoma cell lines. Cancer Res. 50, 6976-6980.
  3. Bonnet, D. and J. E. Dick. 1997. Acute myeloid leukemia is organized as a hierarch that originates from a primitive hematopoietic cell. Nature Med. 3, 730-737. https://doi.org/10.1038/nm0797-730
  4. Gottesman, M. M., T. Fojo and S. E. Bates. 2002. Muitidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer 2, 48-58. https://doi.org/10.1038/nrc706
  5. Green, S. B., D. P. Byar, M. D. Walker, D. A. Pistenmaa, E. J. Alexander, U. Batzdorf W. H. Brooks, W. E. Hunt, J. J. Mealey, G. L. Odom, P. Paoletti, J. D. Ransohoff, J. T. Robertson, G. R. Selker, W. R. Shapiro, K. R. J. Smith, C. B. Wilson and T. A. Strike, 1983. Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treat Rep. 67, 121-132.
  6. Hemmaiti, H. D., I. Nakano, J. A. Lazareff, M. Masterman-Smith, D. H. Geschwind, M. Bronner-Fraser and H. I. Kornblum. 2003. Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl. Acad. Sci. USA 100, 15178-15183.
  7. Ignatova, T. N., V. G. Kukekov, F. D. Vrionis and D. A. Steindler. 2003. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia. 39, 139-206.
  8. Kang, S. K., J. B. Park and S. H. Chao 2006. Muitipotent, Dedifferentiated Cancer Stem-like Cells from Brain Gliomas. Stem Cell Develop. 15, 423 - 435. https://doi.org/10.1089/scd.2006.15.423
  9. Kondo, T., T. Setoguchi and T. Taga. 2004. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc. Natl. Acad. Sci. USA 101, 781-786. https://doi.org/10.1073/pnas.0307618100
  10. Marx, J. 2003. Mutant stem cells may seed cancer. Science 301, 1308-1310. https://doi.org/10.1126/science.301.5638.1308
  11. Massengale, M., A. J. Wagers, H. Vogel and I. L. Weissman. 2005. Hematopoietic cells maintain hematopoietic fates upon entering the brain. J. Exp. Med. 201, 1579-1589. https://doi.org/10.1084/jem.20050030
  12. Nutt, C. L., M. Noble, A. F. Chambers and J. G. Cairncross. 2000. Differential expression of drug resistance genes and chemosensitivity in glial cell lineages correlate with differential response of oligodendrogliomas and astrocytomas to chemotherapy. Cancer Res. 60, 4812-4818.
  13. Paoletti, P. 1984. Therapeutic strategy for central nervous system tumors: present status, criticism and potential. J. Neurosurg. Sci. 28, 51-60.
  14. Park, C. H., D. E. Bergsugel and E. A. McCulloch. 1997. Mouse myeloma tumor stem cells: a primary cell culture assay. J. Natl. Cancer Inst. 46, 411-422.
  15. Peichev, M., A. J. Maiyer, D. Pereira, Z. Zhu, W. J. Land, M. Eillians, M. C. Oz, D. J. Hicklin, L. Witte and M. A. Moore. 2000. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identified a population of functional endothelial precursors. Blood 95, 952-958.
  16. Ponti, D., A. Costa, N. Zaffaroni, G. Pratesi, G. Petrangolini, D. Coradini, S. Pilotti, M. Pierotii and M. G. Diadone. 2005. Isolation and in vitro propagation of tumorigenic breast cancer cell with stem/progenitor cell properties. Cancer Res. 65, 5506-5511. https://doi.org/10.1158/0008-5472.CAN-05-0626
  17. Reya, T., S. J. Morrison, M. F. Clarke and I. L. Weissman. 2001. Stem cells, cancer, and cancer stem cells. Nature 414, 105-111. https://doi.org/10.1038/35102167
  18. Richardson, G. D., C. N. Robson, S. H. Lang, D. E. Neal and N. J. Maitland. 2004. CD133, a novel marker for human prostatic epithelial stem cells. J. Cell Sci. 117, 3539-3545. https://doi.org/10.1242/jcs.01222
  19. Rolhion, C., F. Penault-Llorca, J. L. Kemeny, F. Kwiatkowski, J. J. Lemaire, P. Chollet, F. Finat-Duclos and P. O. Verrelle. 1999. O(6)-methylguanine-DNA methyltransferase gene (MGMT) expression in human glioblastomas in relation to patient characteristics and p53 accumulation. Int. J. Cancer 84, 416-420. https://doi.org/10.1002/(SICI)1097-0215(19990820)84:4<416::AID-IJC15>3.0.CO;2-A
  20. Singh, S. K., I. D. Clarke, M. Terasaki, V. E. Bonn, C. Hawkins, J. A. Squire and P. B. Dirks. 2003. Identification of cancer stem cell in human brain tumors. Cancer Res. 63, 5821-5828.
  21. Singh, S. K., C. Hawkins, I. D. Clarke, J. A. Squire, J. Bayani, T. Hide, R. M. Henkelman, M. D. Cusimano and P. B. Dirks. 2004. Identification of human brain tumor initiating cells. Nature 432, 396-401. https://doi.org/10.1038/nature03128
  22. Shapiro, J. R. and W. R. Shapiro. 1985. The subpoulations and isolated cell types of freshly resected high grade human gliomas: their influence on the tumor's evolution in vivo and behavior and therapy in vitro. Cancer Meta. Rev. 4, 107-124. https://doi.org/10.1007/BF00050691
  23. Wechsler-Reya, R. J. and M. P. Scott. 2001. The developmental biology of brain tumors. Annu. Rev. Neurasci. 24, 385-428. https://doi.org/10.1146/annurev.neuro.24.1.385
  24. Wheeler, G. P., B. J. Bowdon, J. A. Grimsley and H. H. Lloyd. 1993. Interrelationships of some hemical, physicochemical, and biological activities of several 1-(2haloethyl)-1-nitrosoureas. Cancer Res. 34, 194-200.
  25. Zhou, S., J. D. Schuetz, K. D. Bunting, A. M. Colapietro, J. Sampath, J. J. Morris, I. Lagutina, G. C. Grosveld, M. Osawa, H. Nakauchi and B. P. Sorrentino. 2001. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nature Med. 7, 1028-1034. https://doi.org/10.1038/nm0901-1028
  26. van Meter, T. E., W. C. Broaddus, D. Cash and H. Fillmore. 2006. Cotreatment with a novel phosphoinositide analogue inhibitor and carmustine enhances chemotherapeutic efficacy by attenuating AKT activity in gliomas. Cancer 107, 2446-2454. https://doi.org/10.1002/cncr.22248
  27. Vescovi, A. L., E. A. Parati, A. Gritti, P. Poulin, M. Ferrario, E. Wanke, P. Frolichsthal-Schoeller, L. Cava, M. Crcellana-Panlilio, A. Colombo and R. Galli. 1998. Isolation and cloning of nultipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cells lines by epigenetic stimulation. Exp. Neural. 156, 71-83.