Molecules and Cells

, Volume 28, Issue 1, pp 7–12

Biology of glioma cancer stem cells

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Abstract

Gliomas, much like other cancers, are composed of a heterogeneous mix of neoplastic and non-neoplastic cells that include both native and recruited cells. There is extensive diversity among the tumor cells, with differing capacity for in vitro and in vivo growth, a property intimately linked to the cell’s differentiation status. Those cells that are undifferentiated, self-renewing, with the capacity for developing tumors (tumorigenic) cells are designated by some as cancer stem cells, because of the stem-like properties. These cells may be a critical therapeutic target. However the exact identity and cell(s) of origin of the so-called glioma cancer stem cell remain elusive. Here we review the current understanding of glioma cancer stem cell biology.

Keywords

brain tumor cancer stem cell glioma glioblastoma 

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References

  1. Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J., and Clarke, M.F. (2003). Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100, 3983–3988.PubMedCrossRefGoogle Scholar
  2. Amariglio, N., Hirshberg, A., Scheithauer, B.W., Cohen, Y., Loewenthal, R., Trakhtenbrot, L., Paz, N., Koren-Michowitz, M., Waldman, D., Leider-Trejo, L., et al. (2009). Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 6, e1000029.PubMedCrossRefGoogle Scholar
  3. Androutsellis-Theotokis, A., Leker, R.R., Soldner, F., Hoeppner, D.J., Ravin, R., Poser, S.W., Rueger, M.A., Bae, S.K., Kittappa, R., and McKay, R.D. (2006). Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442, 823–826.PubMedCrossRefGoogle Scholar
  4. Bachoo, R.M., Maher, E.A., Ligon, K.L., Sharpless, N.E., Chan, S.S., You, M.J., Tang, Y., DeFrances, J., Stover, E., Weissleder, R., et al. (2002). Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1, 269–277.PubMedCrossRefGoogle Scholar
  5. Bajenaru, M.L., Zhu, Y., Hedrick, N.M., Donahoe, J., Parada, L.F., and Gutmann, D.H. (2002). Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. Mol. Cell. Biol. 22, 5100–5113.PubMedCrossRefGoogle Scholar
  6. Bao, S., Wu, Q., McLendon, R.E., Hao, Y., Shi, Q., Hjelmeland, A.B., Dewhirst, M.W., Bigner, D.D., and Rich, J.N. (2006a). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760.PubMedCrossRefGoogle Scholar
  7. Bao, S., Wu, Q., Sathornsumetee, S., Hao, Y., Li, Z., Hjelmeland, A.B., Shi, Q., McLendon, R.E., Bigner, D.D., and Rich, J.N. (2006b). Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 66, 7843–7848.PubMedCrossRefGoogle Scholar
  8. Bao, S., Wu, Q., Li, Z., Sathornsumetee, S., Wang, H., McLendon, R.E., Hjelmeland, A.B., and Rich, J.N. (2008). Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res. 68, 6043–6048.PubMedCrossRefGoogle Scholar
  9. Bar, E.E., Chaudhry, A., Lin, A., Fan, X., Schreck, K., Matsui, W., Piccirillo, S., Vescovi, A.L., DiMeco, F., Olivi, A., et al. (2007). Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 25, 2524–2533.PubMedCrossRefGoogle Scholar
  10. Beier, D., Hau, P., Proescholdt, M., Lohmeier, A., Wischhusen, J., Oefner, P.J., Aigner, L., Brawanski, A., Bogdahn, U., and Beier, C.P. (2007). CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 67, 4010–4015.PubMedCrossRefGoogle Scholar
  11. Beier, D., Rohrl, S., Pillai, D.R., Schwarz, S., Kunz-Schughart, L.A., Leukel, P., Proescholdt, M., Brawanski, A., Bogdahn, U., Trampe-Kieslich, A., et al. (2008). Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Res. 68, 5706–5715.PubMedCrossRefGoogle Scholar
  12. Ben-Porath, I., Thomson, M.W., Carey, V.J., Ge, R., Bell, G.W., Regev, A., and Weinberg, R.A. (2008). An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 40, 499–507.PubMedCrossRefGoogle Scholar
  13. Bonnet, D., and Dick, J.E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730–737.PubMedCrossRefGoogle Scholar
  14. Carstensen, H., Juhler, M., Bogeskov, L., and Laursen, H. (2006). A report of nine newborns with congenital brain tumours. Childs Nerv. Syst. 22, 1427–1431.PubMedCrossRefGoogle Scholar
  15. Clarke, M.F., Dick, J.E., Dirks, P.B., Eaves, C.J., Jamieson, C.H., Jones, D.L., Visvader, J., Weissman, I.L., and Wahl, G.M. (2006). Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66, 9339–9344.PubMedCrossRefGoogle Scholar
  16. Collins, A.T., Berry, P.A., Hyde, C., Stower, M.J., and Maitland, N.J. (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65, 10946–10951.PubMedCrossRefGoogle Scholar
  17. Conheim, V. (1875). Congenitales, quergestreiftes muskelsarkom der nieren. Virchows Arch. Pathol. Anat. Physiol. Klin. Med. 65, 64–69.CrossRefGoogle Scholar
  18. Dahlstrand, J., Collins, V.P., and Lendahl, U. (1992). Expression of the class VI intermediate filament nestin in human central nervous system tumors. Cancer Res. 52, 5334–5341.PubMedGoogle Scholar
  19. Dalerba, P., Cho, R.W., and Clarke, M.F. (2007). Cancer stem cells: models and concepts. Ann. Rev. Med. 58, 267–284.PubMedCrossRefGoogle Scholar
  20. Dietrich, J., Imitola, J., and Kesari, S. (2008). Mechanisms of Disease: the role of stem cells in the biology and treatment of gliomas. Nat. Clin. Pract. 5, 393–404.Google Scholar
  21. Eyler, C.E., Foo, W.C., LaFiura, K.M., McLendon, R.E., Hjelmeland, A.B., and Rich, J.N. (2008). Brain cancer stem cells display preferential sensitivity to Akt inhibition. Stem Cells 26, 3027–3036.PubMedCrossRefGoogle Scholar
  22. Fidler, I.J., and Kripke, M.L. (1977). Metastasis results from preexisting variant cells within a malignant tumor. Science 197, 893–895.PubMedCrossRefGoogle Scholar
  23. Galli, R., Binda, E., Orfanelli, U., Cipelletti, B., Gritti, A., De Vitis, S., Fiocco, R., Foroni, C., Dimeco, F., and Vescovi, A. (2004). Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64, 7011–7021.PubMedCrossRefGoogle Scholar
  24. Gilbertson, R.J., and Rich, J.N. (2007). Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat. Rev. 7, 733–736.Google Scholar
  25. Hanahan, D., and Weinberg, R.A. (2000). The hallmarks of cancer. Cell 100, 57–70.PubMedCrossRefGoogle Scholar
  26. Harris, H. (2004). Tumour suppression: putting on the brakes. Nature 427, 201.PubMedCrossRefGoogle Scholar
  27. Harris, H. (2005). A long view of fashions in cancer research. Bioessays 27, 833–838.PubMedCrossRefGoogle Scholar
  28. Hemmati, H.D., Nakano, I., Lazareff, J.A., Masterman-Smith, M., Geschwind, D.H., Bronner-Fraser, M., and Kornblum, H.I. (2003). Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl. Acad. Sci. USA 100, 15178–15183.PubMedCrossRefGoogle Scholar
  29. Holland, E.C., Celestino, J., Dai, C., Schaefer, L., Sawaya, R.E., and Fuller, G.N. (2000). Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat. Genet. 25, 55–57.PubMedCrossRefGoogle Scholar
  30. Horbinski, C., Mintz, A., Engh, J., Lieberman, F., Hamilton, R.L., and Park, D.M. (2009). Post-therapeutic changes in the molecular profile of glioblastomas. J. Clin. Oncol. 27, No 15S, 93.Google Scholar
  31. Ignatova, T.N., Kukekov, V.G., Laywell, E.D., Suslov, O.N., Vrionis, F.D., and Steindler, D.A. (2002). Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39, 193–206.PubMedCrossRefGoogle Scholar
  32. Jackson, E.L., Garcia-Verdugo, J.M., Gil-Perotin, S., Roy, M., Quinones-Hinojosa, A., VandenBerg, S., and Alvarez-Buylla, A. (2006). PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron 51, 187–199.PubMedCrossRefGoogle Scholar
  33. Joo, K.M., Kim, S.Y., Jin, X., Song, S.Y., Kong, D.S., Lee, J.I., Jeon, J.W., Kim, M.H., Kang, B.G., Jung, Y., et al. (2008). Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas. Lab. Invest. 88, 808–815.PubMedCrossRefGoogle Scholar
  34. Kim, C.F., Jackson, E.L., Woolfenden, A.E., Lawrence, S., Babar, I., Vogel, S., Crowley, D., Bronson, R.T., and Jacks, T. (2005). Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835.PubMedCrossRefGoogle Scholar
  35. Kreisl, T.N., Kim, L., Moore, K., Duic, P., Royce, C., Stroud, I., Garren, N., Mackey, M., Butman, J.A., Camphausen, K., et al. (2009). Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J. Clin. Oncol. 27, 740–745.PubMedCrossRefGoogle Scholar
  36. Kripke, M.L., Gruys, E., and Fidler, I.J. (1978). Metastatic heterogeneity of cells from an ultraviolet light-induced murine fibrosarcoma of recent origin. Cancer Res. 38, 2962–2967.PubMedGoogle Scholar
  37. Lagasse, E. (2008). Cancer stem cells with genetic instability: the best vehicle with the best engine for cancer. Gene Ther. 15, 136–142.PubMedCrossRefGoogle Scholar
  38. Lapidot, T., Sirard, C., Vormoor, J., Murdoch, B., Hoang, T., Caceres-Cortes, J., Minden, M., Paterson, B., Caligiuri, M.A., and Dick, J.E. (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648.PubMedCrossRefGoogle Scholar
  39. Louis, D.N., Ohgaki, H., Wiestler, O.D., and Cavenee, W.K. (2007). WHO Classification of Tumours of the Central Nervous System; in World Health Organization Classification of Tumours, International Agency for Research on Cancer (IARC), Lyon.Google Scholar
  40. Marchuk, D.A., Saulino, A.M., Tavakkol, R., Swaroop, M., Wallace, M.R., Andersen, L.B., Mitchell, A.L., Gutmann, D.H., Boguski, M., and Collins, F.S. (1991). cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 11, 931–940.PubMedCrossRefGoogle Scholar
  41. Miele, L., Golde, T., and Osborne, B. (2006). Notch signaling in cancer. Curr. Mol. Med. 6, 905–918.PubMedCrossRefGoogle Scholar
  42. O’Brien, C.A., Pollett, A., Gallinger, S., and Dick, J.E. (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110.PubMedCrossRefGoogle Scholar
  43. Odoux, C., Fohrer, H., Hoppo, T., Guzik, L., Stolz, D.B., Lewis, D.W., Gollin, S.M., Gamblin, T.C., Geller, D.A., and Lagasse, E. (2008). A stochastic model for cancer stem cell origin in metastatic colon cancer. Cancer Res. 68, 6932–6941.PubMedCrossRefGoogle Scholar
  44. Ogden, A.T., Waziri, A.E., Lochhead, R.A., Fusco, D., Lopez, K., Ellis, J.A., Kang, J., Assanah, M., McKhann, G.M., Sisti, M.B., et al. (2008). Identification of A2B5+CD133- tumor-initiating cells in adult human gliomas. Neurosurgery 62, 505–514; discussion 514–515.PubMedCrossRefGoogle Scholar
  45. Osawa, M., Hanada, K., Hamada, H., and Nakauchi, H. (1996). Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245.PubMedCrossRefGoogle Scholar
  46. Palmer, T.D., Willhoite, A.R., and Gage, F.H. (2000). Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494.PubMedCrossRefGoogle Scholar
  47. Park, D.M., Li, J., Okamoto, H., Akeju, O., Kim, S.H., Lubensky, I., Vortmeyer, A., Dambrosia, J., Weil, R.J., Oldfield, E.H., et al. (2007). N-CoR pathway targeting induces glioblastoma derived cancer stem cell differentiation. Cell Cycle 6, 467–470.PubMedGoogle Scholar
  48. Park, D.M., Hoeppner, D.J., Ravin, R., Androutsellis-Theotokis, A., Miller, J., Park, M.J., Soeda, A., and McKay, R.D. (2008). SSEA-1 is expressed by glioblastoma-derived cancer stem cells and identifies the highly proliferative fraction. Society for Neuroscience 2008 Annual Meeting Abstract 654.21/DD2.Google Scholar
  49. Peiffer, J., and Kleihues, P. (1999). Hans-Joachim Scherer (1906–1945), pioneer in glioma research. Brain Pathol. 9, 241–245.PubMedCrossRefGoogle Scholar
  50. Quinones-Hinojosa, A., Sanai, N., Soriano-Navarro, M., Gonzalez-Perez, O., Mirzadeh, Z., Gil-Perotin, S., Romero-Rodriguez, R., Berger, M.S., Garcia-Verdugo, J.M., and Alvarez-Buylla, A. (2006). Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. J. Comp. Neurol. 494, 415–434.PubMedCrossRefGoogle Scholar
  51. Quintana, E., Shackleton, M., Sabel, M.S., Fullen, D.R., Johnson, T.M., and Morrison, S.J. (2008). Efficient tumour formation by single human melanoma cells. Nature 456, 593–598.PubMedCrossRefGoogle Scholar
  52. Ravin, R., Hoeppner, D.J., Munno, D.M., Carmel, L., Sullivan, J., Levitt, D.L., Miller, J.L., Athaide, C., Panchision, D.M., and McKay, R.D. (2008). Potency and fate specification in CNS stem cell populations in vitro. Cell Stem Cell 3, 670–680.PubMedCrossRefGoogle Scholar
  53. Reya, T., Morrison, S.J., Clarke, M.F., and Weissman, I.L. (2001). Stem cells, cancer, and cancer stem cells. Nature 414, 105–111.PubMedCrossRefGoogle Scholar
  54. Rich, J.N., and Eyler, C.E. (2008). Cancer stem cells in brain tumor biology. Cold Spring Harbor symposia on quantitative biology 73, 411–420.PubMedGoogle Scholar
  55. Rizzo, P., Osipo, C., Foreman, K., Golde, T., Osborne, B., and Miele, L. (2008). Rational targeting of Notch signaling in cancer. Oncogene 27, 5124–5131.PubMedCrossRefGoogle Scholar
  56. Rosen, J.M., and Jordan, C.T. (2009). The increasing complexity of the cancer stem cell paradigm. Science 324, 1670–1673.PubMedCrossRefGoogle Scholar
  57. Samuelsen, S.O., Bakketeig, L.S., Tretli, S., Johannesen, T.B., and Magnus, P. (2006). Head circumference at birth and risk of brain cancer in childhood: a population-based study. Lancet Oncol. 7, 39–42.PubMedCrossRefGoogle Scholar
  58. Schulenburg, A., Ulrich-Pur, H., Thurnher, D., Erovic, B., Florian, S., Sperr, W.R., Kalhs, P., Marian, B., Wrba, F., Zielinski, C.C., et al. (2006). Neoplastic stem cells: a novel therapeutic target in clinical oncology. Cancer 107, 2512–2520.PubMedCrossRefGoogle Scholar
  59. Shen, Q., Goderie, S.K., Jin, L., Karanth, N., Sun, Y., Abramova, N., Vincent, P., Pumiglia, K., and Temple, S. (2004). Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340.PubMedCrossRefGoogle Scholar
  60. Singh, S.K., Clarke, I.D., Terasaki, M., Bonn, V.E., Hawkins, C., Squire, J., and Dirks, P.B. (2003). Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821–5828.PubMedGoogle Scholar
  61. Singh, S.K., Hawkins, C., Clarke, I.D., Squire, J.A., Bayani, J., Hide, T., Henkelman, R.M., Cusimano, M.D., and Dirks, P.B. (2004). Identification of human brain tumour initiating cells. Nature 432, 396–401.PubMedCrossRefGoogle Scholar
  62. Spangrude, G.J., Heimfeld, S., and Weissman, I.L. (1988). Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62.PubMedCrossRefGoogle Scholar
  63. Stupp, R., Mason, W.P., van den Bent, M.J., Weller, M., Fisher, B., Taphoorn, M.J., Belanger, K., Brandes, A.A., Marosi, C., Bogdahn, U., et al. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996.PubMedCrossRefGoogle Scholar
  64. Taipale, J., and Beachy, P.A. (2001). The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349–354.PubMedCrossRefGoogle Scholar
  65. Tohyama, T., Lee, V.M., Rorke, L.B., Marvin, M., McKay, R.D., and Trojanowski, J.Q. (1992). Nestin expression in embryonic human neuroepithelium and in human neuroepithelial tumor cells. Lab. Invest. 66, 303–313.PubMedGoogle Scholar
  66. Uchida, N., Buck, D.W., He, D., Reitsma, M.J., Masek, M., Phan, T.V., Tsukamoto, A.S., Gage, F.H., and Weissman, I.L. (2000). Direct isolation of human central nervous system stem cells. Proc. Natl. Acad. Sci. USA 97, 14720–14725.PubMedCrossRefGoogle Scholar
  67. Uhrbom, L., Dai, C., Celestino, J.C., Rosenblum, M.K., Fuller, G.N., and Holland, E.C. (2002). Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res. 62, 5551–5558.PubMedGoogle Scholar
  68. Valtz, N.L., Hayes, T.E., Norregaard, T., Liu, S.M., and McKay, R.D. (1991). An embryonic origin for medulloblastoma. New Biol. 3, 364–371.PubMedGoogle Scholar
  69. Virchow, R. (1858). Cellular Pathology, Berlin.Google Scholar
  70. Vredenburgh, J.J., Desjardins, A., Herndon, J.E., 2nd, Marcello, J., Reardon, D.A., Quinn, J.A., Rich, J.N., Sathornsumetee, S., Gururangan, S., Sampson, J., et al. (2007). Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol. 25, 4722–4729.PubMedCrossRefGoogle Scholar
  71. Wang, J., Sakariassen, P.O., Tsinkalovsky, O., Immervoll, H., Boe, S.O., Svendsen, A., Prestegarden, L., Rosland, G., Thorsen, F., Stuhr, L., et al. (2008). CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int. J. Cancer 122, 761–768.PubMedCrossRefGoogle Scholar
  72. Yuan, X., Curtin, J., Xiong, Y., Liu, G., Waschsmann-Hogiu, S., Farkas, D.L., Black, K.L., and Yu, J.S. (2004). Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23, 9392–9400.PubMedCrossRefGoogle Scholar
  73. Zhu, Y., Romero, M.I., Ghosh, P., Ye, Z., Charnay, P., Rushing, E.J., Marth, J.D., and Parada, L.F. (2001). Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes. Dev. 15, 859–876.PubMedCrossRefGoogle Scholar
  74. Zhu, Y., Guignard, F., Zhao, D., Liu, L., Burns, D.K., Mason, R.P., Messing, A., and Parada, L.F. (2005a). Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8, 119–130.PubMedCrossRefGoogle Scholar
  75. Zhu, Y., Harada, T., Liu, L., Lush, M.E., Guignard, F., Harada, C., Burns, D.K., Bajenaru, M.L., Gutmann, D.H., and Parada, L.F. (2005b). Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development 132, 5577–5588.PubMedCrossRefGoogle Scholar

Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2009

Authors and Affiliations

  1. 1.University of Pittsburgh Cancer InstitutePittsburghUSA
  2. 2.Department of Neurological SurgeryUniversity of PittsburghPittsburghUSA
  3. 3.Department of Pharmacology and Chemical BiologyUniversity of PittsburghPittsburghUSA
  4. 4.Department of Stem Cell Biology and Regenerative MedicineCleveland ClinicClevelandUSA

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