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Origins and clinical implications of the brain tumor stem cell hypothesis

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Abstract

With the advent of the cancer stem cell hypothesis, the field of cancer research has experienced a revolution in how we think of and approach cancer. The discovery of “brain tumor stem cells” has offered an explanation for several long-standing conundrums on why brain tumors behave the way they do to treatment. Despite the great amount of research that has been done in order to understand the molecular aspects of malignant gliomas, the prognosis of brain tumors remains dismal. The slow progress in extending the survival of patients with malignant CNS neoplasms is very likely due to poor understanding of the cell of origin in these tumors. This review article discusses the progress in our understanding of brain tumor stem cells as the cell of origin in brain cancers. We review the different proposed mechanisms of how brain tumor stem cells may originate, the intracellular pathways disrupted in the pathogenesis of BTSCs, the molecular markers used to identify BTSCs, the molecular mechanisms of cancer initiation and progression, and finally the clinical implications of this research.

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References

  1. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988. doi:10.1073/pnas.0530291100

    PubMed  CAS  Google Scholar 

  2. Esposito I, Kleeff J, Bischoff SC, Fischer L, Collecchi P, Iorio M, Bevilacqua G, Buchler MW, Friess H (2002) The stem cell factor-c-kit system and mast cells in human pancreatic cancer. Lab Invest 82:1481–1492

    PubMed  CAS  Google Scholar 

  3. Dahlstrand J, Collins VP, Lendahl U (1992) Expression of the class VI intermediate filament nestin in human central nervous system tumors. Cancer Res 52:5334–5341

    PubMed  CAS  Google Scholar 

  4. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104:973–978. doi:10.1073/pnas.0610117104

    PubMed  CAS  Google Scholar 

  5. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115. doi:10.1038/nature05384

    PubMed  CAS  Google Scholar 

  6. Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA (2002) Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39:193–206. doi:10.1002/glia.10094

    PubMed  Google Scholar 

  7. Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183. doi:10.1073/pnas.2036535100

    PubMed  CAS  Google Scholar 

  8. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021. doi:10.1158/0008-5472.CAN-04-1364

    PubMed  CAS  Google Scholar 

  9. Tu SM, Lin SH, Logothetis CJ (2002) Stem-cell origin of metastasis and heterogeneity in solid tumours. Lancet Oncol 3:508–513. doi:10.1016/S1470-2045(02)00820-3

    PubMed  CAS  Google Scholar 

  10. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760. doi:10.1038/nature05236

    PubMed  CAS  Google Scholar 

  11. Xie Z, Chin LS (2008) Molecular and cell biology of brain tumor stem cells: lessons from neural progenitor/stem cells. Neurosurg Focus 24:E25. doi:10.3171/FOC/2008/24/3-4/E24

    PubMed  Google Scholar 

  12. Sakariassen PO, Immervoll H, Chekenya M (2007) Cancer stem cells as mediators of treatment resistance in brain tumors: status and controversies. Neoplasia 9:882–892. doi:10.1593/neo.07658

    PubMed  CAS  Google Scholar 

  13. Dandy W (1928) Removal of right cerebral hemispheres for certain tumors with hemiplegia: preliminary report. JAMA 90:823–825

    Google Scholar 

  14. Salazar OM, Rubin P (1976) The spread of glioblastoma multiforme as a determining factor in the radiation treated volume. Int J Radiat Oncol Biol Phys 1:627–637

    PubMed  CAS  Google Scholar 

  15. Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F, Vescovi AL (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444:761–765. doi:10.1038/nature05349

    PubMed  CAS  Google Scholar 

  16. Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A, Eberhart CG (2007) Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 25:2524–2533. doi:10.1634/stemcells.2007-0166

    PubMed  CAS  Google Scholar 

  17. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M, Frank A, Bayazitov IT, Zakharenko SS, Gajjar A, Davidoff A, Gilbertson RJ (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82. doi:10.1016/j.ccr.2006.11.020

    PubMed  CAS  Google Scholar 

  18. Ramon y Cajal S (1928) Degeration and regeneration of the nervous system. Oxford University Press, New York

    Google Scholar 

  19. Altman J (1962) Autoradiographic study of degenerative and regenerative proliferation of neuroglia cells with tritiated thymidine. Exp Neurol 5:302–318. doi:10.1016/0014-4886(62)90040-7

    PubMed  CAS  Google Scholar 

  20. Goldman SA, Nottebohm F (1983) Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain. Proc Natl Acad Sci USA 80:2390–2394. doi:10.1073/pnas.80.8.2390

    PubMed  CAS  Google Scholar 

  21. Quinones-Hinojosa A, Chaichana K (2007) The human subventricular zone: a source of new cells and a potential source of brain tumors. Exp Neurol 205:313–324. doi:10.1016/j.expneurol.2007.03.016

    PubMed  Google Scholar 

  22. Kirschenbaum B, Nedergaard M, Preuss A, Barami K, Fraser RA, Goldman SA (1994) In vitro neuronal production and differentiation by precursor cells derived from the adult human forebrain. Cereb Cortex 4:576–589. doi:10.1093/cercor/4.6.576

    PubMed  CAS  Google Scholar 

  23. Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL (2000) Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 97:14720–14725. doi:10.1073/pnas.97.26.14720

    PubMed  CAS  Google Scholar 

  24. Pincus DW, Keyoung HM, Harrison-Restelli C, Goodman RR, Fraser RA, Edgar M, Sakakibara S, Okano H, Nedergaard M, Goldman SA (1998) Fibroblast growth factor-2/brain-derived neurotrophic factor-associated maturation of new neurons generated from adult human subependymal cells. Ann Neurol 43:576–585. doi:10.1002/ana.410430505

    PubMed  CAS  Google Scholar 

  25. Kukekov VG, Laywell ED, Suslov O, Davies K, Scheffler B, Thomas LB, O’Brien TF, Kusakabe M, Steindler DA (1999) Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain. Exp Neurol 156:333–344. doi:10.1006/exnr.1999.7028

    PubMed  CAS  Google Scholar 

  26. Arsenijevic Y, Villemure JG, Brunet JF, Bloch JJ, Deglon N, Kostic C, Zurn A, Aebischer P (2001) Isolation of multipotent neural precursors residing in the cortex of the adult human brain. Exp Neurol 170:48–62. doi:10.1006/exnr.2001.7691

    PubMed  CAS  Google Scholar 

  27. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710. doi:10.1126/science.1553558

    PubMed  CAS  Google Scholar 

  28. Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A (1997) Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci 17:5046–5061

    PubMed  CAS  Google Scholar 

  29. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716. doi:10.1016/S0092-8674(00)80783-7

    PubMed  CAS  Google Scholar 

  30. Mirzadeh Z, Merkle FT, Soriano-Navarro M, Garcia-Verdugo JM, Alvarez-Buylla A (2008) Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell 3:265–278. doi:10.1016/j.stem.2008.07.004

    PubMed  CAS  Google Scholar 

  31. Bittman K, Owens DF, Kriegstein AR, LoTurco JJ (1997) Cell coupling and uncoupling in the ventricular zone of developing neocortex. J Neurosci 17:7037–7044

    PubMed  CAS  Google Scholar 

  32. Nadarajah B, Jones AM, Evans WH, Parnavelas JG (1997) Differential expression of connexins during neocortical development and neuronal circuit formation. J Neurosci 17:3096–3111

    PubMed  CAS  Google Scholar 

  33. Kosodo Y, Roper K, Haubensak W, Marzesco AM, Corbeil D, Huttner WB (2004) Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. EMBO J 23:2314–2324. doi:10.1038/sj.emboj.7600223

    PubMed  CAS  Google Scholar 

  34. Noctor SC, Martinez-Cerdeno V, Kriegstein AR (2007) Neural stem and progenitor cells in cortical development. Novartis Found Symp 288:59–73 (discussion 73-58, 96-58)

    Google Scholar 

  35. Spassky N, Merkle FT, Flames N, Tramontin AD, Garcia-Verdugo JM, Alvarez-Buylla A (2005) Adult ependymal cells are postmitotic and are derived from radial glial cells during embryogenesis. J Neurosci 25:10–18. doi:10.1523/JNEUROSCI.1108-04.2005

    PubMed  CAS  Google Scholar 

  36. Voigt T (1989) Development of glial cells in the cerebral wall of ferrets: direct tracing of their transformation from radial glia into astrocytes. J Comp Neurol 289:74–88. doi:10.1002/cne.902890106

    PubMed  CAS  Google Scholar 

  37. Merkle FT, Tramontin AD, Garcia-Verdugo JM, Alvarez-Buylla A (2004) Radial glia give rise to adult neural stem cells in the subventricular zone. Proc Natl Acad Sci USA 101:17528–17532. doi:10.1073/pnas.0407893101

    PubMed  CAS  Google Scholar 

  38. Lois C, Alvarez-Buylla A (1994) Long-distance neuronal migration in the adult mammalian brain. Science 264:1145–1148. doi:10.1126/science.8178174

    PubMed  CAS  Google Scholar 

  39. Lois C, Garcia-Verdugo JM, Alvarez-Buylla A (1996) Chain migration of neuronal precursors. Science 271:978–981. doi:10.1126/science.271.5251.978

    PubMed  CAS  Google Scholar 

  40. Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B, Garcia-Verdugo JM, Doetsch F (2008) A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3:279–288. doi:10.1016/j.stem.2008.07.025

    PubMed  CAS  Google Scholar 

  41. Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ (1999) Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2:260–265. doi:10.1038/6365

    PubMed  CAS  Google Scholar 

  42. Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372–376. doi:10.1038/35066584

    PubMed  CAS  Google Scholar 

  43. Chaichana KL, McGirt MJ, Frazier J, Attenello F, Guerrero-Cazares H, Quinones-Hinojosa A (2008) Relationship of glioblastoma multiforme to the lateral ventricles predicts survival following tumor resection. J Neurooncol 89:219–224. doi:10.1007/s11060-008-9609-2

    PubMed  Google Scholar 

  44. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401. doi:10.1038/nature03128

    PubMed  CAS  Google Scholar 

  45. Bruce WR, Van Der Gaag H (1963) A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 199:79–80. doi:10.1038/199079a0

    PubMed  CAS  Google Scholar 

  46. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737. doi:10.1038/nm0797-730

    PubMed  CAS  Google Scholar 

  47. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648. doi:10.1038/367645a0

    PubMed  CAS  Google Scholar 

  48. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    PubMed  CAS  Google Scholar 

  49. Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, Lichter P, Unterberg A, Radlwimmer B, Herold-Mende CC (2008) Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14:123–129. doi:10.1158/1078-0432.CCR-07-0932

    PubMed  CAS  Google Scholar 

  50. Zimmerman L, Parr B, Lendahl U, Cunningham M, McKay R, Gavin B, Mann J, Vassileva G, McMahon A (1994) Independent regulatory elements in the nestin gene direct transgene expression to neural stem cells or muscle precursors. Neuron 12:11–24. doi:10.1016/0896-6273(94)90148-1

    PubMed  CAS  Google Scholar 

  51. Strojnik T, Rosland GV, Sakariassen PO, Kavalar R, Lah T (2007) Neural stem cell markers, nestin and musashi proteins, in the progression of human glioma: correlation of nestin with prognosis of patient survival. Surg Neurol 68:133–143. doi:10.1016/j.surneu.2006.10.050 (discussion 143-134)

    PubMed  Google Scholar 

  52. Thon N, Damianoff K, Hegermann J, Grau S, Krebs B, Schnell O, Tonn JC, Goldbrunner R (2008) Presence of pluripotent CD133+ cells correlates with malignancy of gliomas. Mol Cell Neurosci. doi:10.1016/j.mcn.2008.07.022

    PubMed  Google Scholar 

  53. Beier D, Wischhusen J, Dietmaier W, Hau P, Proescholdt M, Brawanski A, Bogdahn U, Beier CP (2008) CD133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors. Brain Pathol 18:370–377. doi:10.1111/j.1750-3639.2008.00130.x

    PubMed  Google Scholar 

  54. Kaneko Y, Sakakibara S, Imai T, Suzuki A, Nakamura Y, Sawamoto K, Ogawa Y, Toyama Y, Miyata T, Okano H (2000) Musashi1: an evolutionally conserved marker for CNS progenitor cells including neural stem cells. Dev Neurosci 22:139–153. doi:10.1159/000017435

    PubMed  CAS  Google Scholar 

  55. Toda M, Iizuka Y, Yu W, Imai T, Ikeda E, Yoshida K, Kawase T, Kawakami Y, Okano H, Uyemura K (2001) Expression of the neural RNA-binding protein Musashi1 in human gliomas. Glia 34:1–7. doi:10.1002/glia.1034

    PubMed  CAS  Google Scholar 

  56. Woodward WA, Sulman EP (2008) Cancer stem cells: markers or biomarkers? Cancer Metastasis Rev 27:459–470. doi:10.1007/s10555-008-9130-2

    PubMed  CAS  Google Scholar 

  57. Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D, Weiss S, van der Kooy D (1994) Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13:1071–1082. doi:10.1016/0896-6273(94)90046-9

    PubMed  CAS  Google Scholar 

  58. Cattaneo E, McKay R (1990) Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature 347:762–765. doi:10.1038/347762a0

    PubMed  CAS  Google Scholar 

  59. Vescovi AL, Reynolds BA, Fraser DD, Weiss S (1993) bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron 11:951–966. doi:10.1016/0896-6273(93)90124-A

    PubMed  CAS  Google Scholar 

  60. Tohyama T, Lee VM, Rorke LB, Marvin M, McKay RD, Trojanowski JQ (1992) Nestin expression in embryonic human neuroepithelium and in human neuroepithelial tumor cells. Lab Invest 66:303–313

    PubMed  CAS  Google Scholar 

  61. Almqvist PM, Mah R, Lendahl U, Jacobsson B, Hendson G (2002) Immunohistochemical detection of nestin in pediatric brain tumors. J Histochem Cytochem 50:147–158

    PubMed  CAS  Google Scholar 

  62. Rutka JT, Ivanchuk S, Mondal S, Taylor M, Sakai K, Dirks P, Jun P, Jung S, Becker LE, Ackerley C (1999) Co-expression of nestin and vimentin intermediate filaments in invasive human astrocytoma cells. Int J Dev Neurosci 17:503–515. doi:10.1016/S0736-5748(99)00049-0

    PubMed  CAS  Google Scholar 

  63. Kania G, Corbeil D, Fuchs J, Tarasov KV, Blyszczuk P, Huttner WB, Boheler KR, Wobus AM (2005) Somatic stem cell marker prominin-1/CD133 is expressed in embryonic stem cell-derived progenitors. Stem Cells 23:791–804. doi:10.1634/stemcells.2004-0232

    PubMed  CAS  Google Scholar 

  64. Weigmann A, Corbeil D, Hellwig A, Huttner WB (1997) Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells. Proc Natl Acad Sci USA 94:12425–12430. doi:10.1073/pnas.94.23.12425

    PubMed  CAS  Google Scholar 

  65. Wang J, Sakariassen PO, Tsinkalovsky O, Immervoll H, Boe SO, Svendsen A, Prestegarden L, Rosland G, Thorsen F, Stuhr L, Molven A, Bjerkvig R, Enger PO (2008) CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer 122:761–768. doi:10.1002/ijc.23130

    PubMed  CAS  Google Scholar 

  66. Sulman E, Aldape K, Colman H (2008) Brain tumor stem cells. Curr Probl Cancer 32:124–142. doi:10.1016/j.currproblcancer.2008.02.004

    PubMed  Google Scholar 

  67. Griguer CE, Oliva CR, Gobin E, Marcorelles P, Benos DJ, Lancaster JR Jr, Gillespie GY (2008) CD133 is a marker of bioenergetic stress in human glioma. PLoS ONE 3:e3655. doi:10.1371/journal.pone.0003655

    PubMed  Google Scholar 

  68. Sakakibara S, Okano H (1997) Expression of neural RNA-binding proteins in the postnatal CNS: implications of their roles in neuronal and glial cell development. J Neurosci 17:8300–8312

    PubMed  CAS  Google Scholar 

  69. Okano H, Imai T, Okabe M (2002) Musashi: a translational regulator of cell fate. J Cell Sci 115:1355–1359

    PubMed  CAS  Google Scholar 

  70. Sakakibara S, Imai T, Hamaguchi K, Okabe M, Aruga J, Nakajima K, Yasutomi D, Nagata T, Kurihara Y, Uesugi S, Miyata T, Ogawa M, Mikoshiba K, Okano H (1996) Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell. Dev Biol 176:230–242. doi:10.1006/dbio.1996.0130

    PubMed  CAS  Google Scholar 

  71. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26:101–106. doi:10.1038/nbt1374

    PubMed  CAS  Google Scholar 

  72. Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448:313–317. doi:10.1038/nature05934

    PubMed  CAS  Google Scholar 

  73. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. doi:10.1016/j.cell.2007.11.019

    PubMed  CAS  Google Scholar 

  74. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448:318–324. doi:10.1038/nature05944

    PubMed  CAS  Google Scholar 

  75. Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, Tang Y, DeFrances J, Stover E, Weissleder R, Rowitch DH, Louis DN, DePinho RA (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. doi:10.1016/S1535-6108(02)00046-6

    PubMed  CAS  Google Scholar 

  76. Ding H, Roncari L, Shannon P, Wu X, Lau N, Karaskova J, Gutmann DH, Squire JA, Nagy A, Guha A (2001) Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res 61:3826–3836

    PubMed  CAS  Google Scholar 

  77. Holland EC, Hively WP, DePinho RA, Varmus HE (1998) A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev 12:3675–3685. doi:10.1101/gad.12.23.3675

    PubMed  CAS  Google Scholar 

  78. Rich JN, Guo C, McLendon RE, Bigner DD, Wang XF, Counter CM (2001) A genetically tractable model of human glioma formation. Cancer Res 61:3556–3560

    PubMed  CAS  Google Scholar 

  79. Sonoda Y, Ozawa T, Aldape KD, Deen DF, Berger MS, Pieper RO (2001) Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res 61:6674–6678

    PubMed  CAS  Google Scholar 

  80. Uhrbom L, Kastemar M, Johansson FK, Westermark B, Holland EC (2005) Cell type-specific tumor suppression by Ink4a and Arf in Kras-induced mouse gliomagenesis. Cancer Res 65:2065–2069. doi:10.1158/0008-5472.CAN-04-3588

    PubMed  CAS  Google Scholar 

  81. Weiss WA, Burns MJ, Hackett C, Aldape K, Hill JR, Kuriyama H, Kuriyama N, Milshteyn N, Roberts T, Wendland MF, DePinho R, Israel MA (2003) Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Res 63:1589–1595

    PubMed  CAS  Google Scholar 

  82. Xiao A, Yin C, Yang C, Di Cristofano A, Pandolfi PP, Van Dyke T (2005) Somatic induction of Pten loss in a preclinical astrocytoma model reveals major roles in disease progression and avenues for target discovery and validation. Cancer Res 65:5172–5180. doi:10.1158/0008-5472.CAN-04-3902

    PubMed  CAS  Google Scholar 

  83. Lassman AB, Dai C, Fuller GN, Vickers AJ, Holland EC (2004) Overexpression of c-MYC promotes an undifferentiated phenotype in cultured astrocytes and allows elevated Ras and Akt signaling to induce gliomas from GFAP-expressing cells in mice. Neuron Glia Biol 1:157–163. doi:10.1017/S1740925X04000249

    PubMed  Google Scholar 

  84. Dai C, Celestino JC, Okada Y, Louis DN, Fuller GN, Holland EC (2001) PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15:1913–1925. doi:10.1101/gad.903001

    PubMed  CAS  Google Scholar 

  85. Kondo T, Raff M (2004) Chromatin remodeling and histone modification in the conversion of oligodendrocyte precursors to neural stem cells. Genes Dev 18:2963–2972. doi:10.1101/gad.309404

    PubMed  CAS  Google Scholar 

  86. Kondo T, Raff M (2000) Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289:1754–1757. doi:10.1126/science.289.5485.1754

    PubMed  CAS  Google Scholar 

  87. Belachew S, Chittajallu R, Aguirre AA, Yuan X, Kirby M, Anderson S, Gallo V (2003) Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons. J Cell Biol 161:169–186. doi:10.1083/jcb.200210110

    PubMed  CAS  Google Scholar 

  88. Liu A, Han YR, Li J, Sun D, Ouyang M, Plummer MR, Casaccia-Bonnefil P (2007) The glial or neuronal fate choice of oligodendrocyte progenitors is modulated by their ability to acquire an epigenetic memory. J Neurosci 27:7339–7343. doi:10.1523/JNEUROSCI.1226-07.2007

    PubMed  CAS  Google Scholar 

  89. Ligon KL, Kesari S, Kitada M, Sun T, Arnett HA, Alberta JA, Anderson DJ, Stiles CD, Rowitch DH (2006) Development of NG2 neural progenitor cells requires Olig gene function. Proc Natl Acad Sci USA 103:7853–7858. doi:10.1073/pnas.0511001103

    PubMed  CAS  Google Scholar 

  90. Baracskay KL, Kidd GJ, Miller RH, Trapp BD (2007) NG2-positive cells generate A2B5-positive oligodendrocyte precursor cells. Glia 55:1001–1010. doi:10.1002/glia.20519

    PubMed  Google Scholar 

  91. Globus J, Kuhlenbeck H (1942) Tumors of the striatothalmaic and related regions: their probable source of origin and more common forms. Arch Pathol (Chic) 24:674–734

    Google Scholar 

  92. Globus J, Kuhlenbeck H (1944) Idem: the subependymal cell plate (matrix) and its relationship to brain tumors of the ependymal type. J Neuropathol Exp Neurol 3:1–5. doi:10.1016/0014-4886(61)90003-6

    Google Scholar 

  93. Lim DA, Cha S, Mayo MC, Chen MH, Keles E, VandenBerg S, Berger MS (2007) Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro-oncology 9:424–429. doi:10.1215/15228517-2007-023

    PubMed  Google Scholar 

  94. Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP, Messing A, Parada LF (2005) Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8:119–130. doi:10.1016/j.ccr.2005.07.004

    PubMed  CAS  Google Scholar 

  95. Hopewell JW, Wright EA (1969) The importance of implantation site in cerebral carcinogenesis in rats. Cancer Res 29:1927–1931

    PubMed  CAS  Google Scholar 

  96. Hopewell JW (1975) The subependymal plate and the genesis of gliomas. J Pathol 117:101–103. doi:10.1002/path.1711170208

    PubMed  CAS  Google Scholar 

  97. Copeland DD, Bigner DD (1977) Influence of age at inoculation on avian oncornavirus-induced brain tumor incidence, tumor morphology, and postinoculation survival in F344 rats. Cancer Res 37:1657–1661

    PubMed  CAS  Google Scholar 

  98. Stecca B, Ruiz i Altaba A (2005) Brain as a paradigm of organ growth: Hedgehog-Gli signaling in neural stem cells and brain tumors. J Neurobiol 64:476–490. doi:10.1002/neu.20160

    PubMed  CAS  Google Scholar 

  99. Ruiz i Altaba A, Sanchez P, Dahmane N (2002) Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2:361–372. doi:10.1038/nrc796

    PubMed  CAS  Google Scholar 

  100. Dahmane N, Sanchez P, Gitton Y, Palma V, Sun T, Beyna M, Weiner H, Ruiz i Altaba A (2001) The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 128:5201–5212

    PubMed  CAS  Google Scholar 

  101. Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, Conlon RA, Mak TW, Bernstein A, van der Kooy D (2002) Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev 16:846–858. doi:10.1101/gad.975202

    PubMed  CAS  Google Scholar 

  102. Hallahan AR, Pritchard JI, Hansen S, Benson M, Stoeck J, Hatton BA, Russell TL, Ellenbogen RG, Bernstein ID, Beachy PA, Olson JM (2004) The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res 64:7794–7800. doi:10.1158/0008-5472.CAN-04-1813

    PubMed  CAS  Google Scholar 

  103. Kesari S, Ramakrishna N, Sauvageot C, Stiles CD, Wen PY (2006) Targeted molecular therapy of malignant gliomas. Curr Oncol Rep 8:58–70. doi:10.1007/s11912-006-0011-y

    PubMed  CAS  Google Scholar 

  104. Guha A, Dashner K, Black PM, Wagner JA, Stiles CD (1995) Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int J Cancer 60:168–173. doi:10.1002/ijc.2910600206

    PubMed  CAS  Google Scholar 

  105. Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, Nister M (1992) Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 52:3213–3219

    PubMed  CAS  Google Scholar 

  106. Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA (2002) Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res 62:3729–3735

    PubMed  CAS  Google Scholar 

  107. Weinberg R (2007) The biology of cancer. Garland Science, Taylor & Francis Group, New York

  108. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812. doi:10.1126/science.1164382

    PubMed  CAS  Google Scholar 

  109. Cheng CK, Fan QW, Weiss WA (2009) PI3K signaling in glioma-animal models and therapeutic challenges. Brain Pathol 19:112–120. doi:10.1111/j.1750-3639.2008.00233.x

    PubMed  CAS  Google Scholar 

  110. Chakravarti A, Zhai G, Suzuki Y, Sarkesh S, Black PM, Muzikansky A, Loeffler JS (2004) The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J Clin Oncol 22:1926–1933. doi:10.1200/JCO.2004.07.193

    PubMed  CAS  Google Scholar 

  111. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554. doi:10.1126/science.1096502

    PubMed  CAS  Google Scholar 

  112. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425:962–967. doi:10.1038/nature02060

    PubMed  CAS  Google Scholar 

  113. Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 19:1432–1437. doi:10.1101/gad.1299505

    PubMed  CAS  Google Scholar 

  114. Fasano CA, Dimos JT, Ivanova NB, Lowry N, Lemischka IR, Temple S (2007) shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell 1:87–99. doi:10.1016/j.stem.2007.04.001

    PubMed  CAS  Google Scholar 

  115. Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452. doi:10.1038/nature05091

    PubMed  CAS  Google Scholar 

  116. Meletis K, Wirta V, Hede SM, Nister M, Lundeberg J, Frisen J (2006) p53 suppresses the self-renewal of adult neural stem cells. Development 133:363–369. doi:10.1242/dev.02208

    PubMed  CAS  Google Scholar 

  117. Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, Ling EK, Ward RJ, Jamieson LG, Tyers M, Dirks PB (2007) Chemical genetics reveals a complex functional ground state of neural stem cells. Nat Chem Biol 3:268–273. doi:10.1038/nchembio873

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the Maryland Stem Cell Foundation and NIH KO8. Moreover, the Howard Hughes Medical Institute has generously supported the work of Thomas Kosztowski, Hasan Zaidi, and Dr. Alfredo Quinones-Hinojosa. The authors have no other relevant affiliations or financial involvement with any organization or entity with financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Authors and Affiliations

  1. The Johns Hopkins Hospital, Department of Neurosurgery, Johns Hopkins University, CRB II 1550 Orleans Street, Room 247, Baltimore, MD, 21231, USA

    Hasan A. Zaidi, Thomas Kosztowski, Francesco DiMeco & Alfredo Quiñones-Hinojosa

  2. Istituto Nazionale Neurologico “C.Besta”, Milan, Italy

    Francesco DiMeco

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  1. Hasan A. Zaidi
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  2. Thomas Kosztowski
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  3. Francesco DiMeco
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  4. Alfredo Quiñones-Hinojosa
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Correspondence to Alfredo Quiñones-Hinojosa.

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Zaidi, H.A., Kosztowski, T., DiMeco, F. et al. Origins and clinical implications of the brain tumor stem cell hypothesis. J Neurooncol 93, 49–60 (2009). https://doi.org/10.1007/s11060-009-9856-x

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