Abstract
Despite continued advances in surgical and medical therapies, the outcomes for patients diagnosed with glioblastoma multiforme remain dismal. Recent data suggest that progression of these brain tumors is driven by a small subpopulation of tumor cells, which are termed cancer stem cells (CSCs) because of their capability to self-renew, proliferate and give rise to progeny of multiple neuroepithelial lineages. According to the CSC hypothesis, current therapies that are extremely cytotoxic to the bulk of highly proliferative tumor cells fail to obliterate the relatively quiescent and resistant CSC compartment, thereby allowing these cells to survive and drive tumor recurrence. This Review summarizes current knowledge regarding neural stem cells in the normal adult brain and CSCs in glial tumors and discusses the implications of the CSC hypothesis for the development of future therapies for brain tumors.
Key Points
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Despite continued advances in surgical and medical therapies, outcomes for patients diagnosed with glioblastoma multiforme (GBM) remain dismal
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GBM progression is driven by a small subpopulation of tumor cells, termed cancer stem cells because of their capability to self-renew, proliferate and give rise to multiple neuroepithelial lineages
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Neurogenesis continues throughout life in two germinal regions: the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus
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The cell of origin for GBM remains unclear, though there is evidence to support both NSC transformation and dedifferentiation of mature astrocytes in the genesis of gliomas
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Brain tumor stem cells (BTSCs) are relatively resistant to current cytotoxic therapies; conventional therapies for high-grade gliomas might be more effective if combined with agents that increase the sensitivity of BTSCs to chemotherapy and radiation therapy
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Novel therapies targeting BTSC differentiation are likely to be directed by our understanding of signaling pathways involved in normal NSC biology
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References
National Cancer Institute: Brain Tumor Home Page [http://www.nci.nih.gov/cancertopics/types/brain]
Stupp R et al. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352: 987–996
Jordan CT et al. (2006) Cancer stem cells. N Engl J Med 355: 1253–1261
Gross CG (2000) Neurogenesis in the adult brain: death of a dogma. Nat Rev Neurosci 1: 67–73
Ayuso-Sacido A et al. (2008) Long-term expansion of adult human brain subventricular zone precursors. Neurosurgery 62: 223–229
Curtis MA et al. (2007) Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315: 1243–1249
Roy NS et al. (2000) Promoter-targeted selection and isolation of neural progenitor cells from the adult human ventricular zone. J Neurosci Res 59: 321–331
Sanai N et al. (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427: 740–744
Roy NS et al. (2000) In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med 6: 271–277
Alvarez-Buylla A and Lim DA (2004) For the long run: maintaining germinal niches in the adult brain. Neuron 41: 683–686
Ninkovic J et al. (2007) Distinct modes of neuron addition in adult mouse neurogenesis. J Neurosci 27: 10906–10911
Drapeau E et al. (2007) Learning-induced survival of new neurons depends on the cognitive status of aged rats. J Neurosci 27: 6037–6044
Tashiro A et al. (2007) Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J Neurosci 27: 3252–3259
Pereira AC et al. (2007) An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci USA 104: 5638–5643
Saxe MD et al. (2006) Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci USA 103: 17501–17506
Aimone JB et al. (2006) Potential role for adult neurogenesis in the encoding of time in new memories. Nat Neurosci 9: 723–727
Quiñones-Hinojosa A et al. (2007) The human brain subventricular zone: stem cells in this niche and its organization. Neurosurg Clin N Am 18: 15–20
Lim DA and Alvarez-Buylla A (1999) Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis. Proc Natl Acad Sci USA 96: 7526–7531
Lim DA et al. (2000) Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28: 713–726
Zhang RL et al. (2007) Stroke induces ependymal cell transformation into radial glia in the subventricular zone of the adult rodent brain. J Cereb Blood Flow Metab 27: 1201–1212
Leker RR et al. (2007) Long-lasting regeneration after ischemia in the cerebral cortex. Stroke 38: 153–161
Zhao LR et al. (2007) Brain repair by hematopoietic growth factors in a rat model of stroke. Stroke 38: 2584–2591
Zhang RL et al. (2006) Reduction of the cell cycle length by decreasing G1 phase and cell cycle reentry expand neuronal progenitor cells in the subventricular zone of adult rat after stroke. J Cereb Blood Flow Metab 26: 857–863
Thored P et al. (2006) Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells 24: 739–747
Komitova M et al. (2005) Enriched environment increases neural stem/progenitor cell proliferation and neurogenesis in the subventricular zone of stroke-lesioned adult rats. Stroke 36: 1278–1282
Hoglinger GU et al. (2004) Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci 7: 726–735
Liu Z and Martin LJ (2006) The adult neural stem and progenitor cell niche is altered in amyotrophic lateral sclerosis mouse brain. J Comp Neurol 497: 468–488
Mazurova Y et al. (2006) Proliferation and differentiation of adult endogenous neural stem cells in response to neurodegenerative process within the striatum. Neurodegener Dis 3: 12–18
Joyner AL and Zervas M (2006) Genetic inducible fate mapping in mouse: establishing genetic lineages and defining genetic neuroanatomy in the nervous system. Dev Dyn 235: 2376–2385
Zhao C et al. (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132: 645–660
Breunig JJ et al. (2007) Everything that glitters isn't gold: a critical review of postnatal neural precursor analyses. Cell Stem Cell 1: 612–627
Eriksson PS et al. (1998) Neurogenesis in the adult human hippocampus. Nat Med 4: 1313–1317
Lendahl U et al. (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60: 585–595
Sakakibara S et al. (1996) Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell. Dev Biol 176: 230–242
Doetsch F et al. (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97: 703–716
Doetsch F et al. (2002) EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36: 1021–1034
Jackson EL et al. (2006) PDGFRα-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
Hack MA et al. (2005) Neuronal fate determinants of adult olfactory bulb neurogenesis. Nat Neurosci 8: 865–872
Gleeson JG et al. (1999) Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23: 257–271
Zhou Q et al. (2000) Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors. Neuron 25: 331–343
Reynolds BA et al. (1992) A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 12: 4565–4574
Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57–70
Lapidot T et al. (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367: 645–648
Bonnet D and Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3: 730–737
Castor A et al. (2005) Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 11: 630–637
Cobaleda C et al. (2000) A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. Blood 95: 1007–1013
Cox CV et al. (2004) Characterization of acute lymphoblastic leukemia progenitor cells. Blood 104: 2919–2925
Holyoake TL et al. (2002) Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia. Leukemia 16: 549–558
Al-Hajj M et al. (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100: 3983–3988
O'Brien CA et al. (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445: 106–110
Ricci-Vitiani L et al. (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445: 111–115
Eramo A et al. (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15: 504–514
Fang D et al. (2005) A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 65: 9328–9337
Galli R et al. (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64: 7011–7021
Singh SK et al. (2004) Identification of human brain tumour initiating cells. Nature 432: 396–401
Taylor MD et al. (2005) Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8: 323–335
Singh SK et al. (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63: 5821–5828
Yi L et al. (2007) Isolation and characterization of stem cell-like precursor cells from primary human anaplastic oligoastrocytoma. Mod Pathol 20: 1061–1068
Dirks PB (2008) Brain tumour stem cells: the undercurrents of human brain cancer and their relationship to neural stem cells. Philos Trans R Soc Lond B Biol Sci 363: 139–152
Vescovi AL et al. (2006) Brain tumour stem cells. Nat Rev Cancer 6: 425–436
Beier D et al. (2007) CD133+ and CD133− glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67: 4010–4015
Ogden AT et al. (2008) Identification of A2B5+CD133− tumor-initiating cells in adult human gliomas. Neurosurgery 62: 505–514
Wang J 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
Kelly PN et al. (2007) Tumor growth need not be driven by rare cancer stem cells. Science 317: 337
Cushing H and Bailey PA (1926) Classification of the Tumors of the Glioma Group on a Histogenetic Basis with a Correlated Study of Prognosis. Philadelphia: JB Lippincott
Cairncross JG (1987) The biology of astrocytoma: lessons learned from chronic myelogenous leukemia—hypothesis. J Neurooncol 5: 99–104
Copeland DD and Bigner DD (1977) The role of the subependymal plate in avian sarcoma virus brain tumor induction: comparison of incipient tumors in neonatal and adult rats. Acta Neuropathol 38: 1–6
Globus JH and Kuhlenbeck H (1944) The subependymal cell plate (matrix) and its relationship to brain tumors of the ependymal type. J Neuropathol Exp Neurol 3: 1–35
Vick NA et al. (1977) The role of the subependymal plate in glial tumorigenesis. Acta Neuropathol 40: 63–71
Holland EC et al. (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25: 55–57
Bachoo RM 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
Sneddon JB et al. (2006) Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc Natl Acad Sci USA 103: 14842–14847
De Toni F et al. (2006) A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemia. Oncogene 25: 3113–3122
Kaplan RN et al. (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438: 820–827
Calabrese C et al. (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11: 69–82
Giannini C et al. (2005) Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. Neuro Oncol 7: 164–176
Bao S et al. (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66: 7843–7848
Zhao C et al. (2007) Loss of β-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12: 528–541
Liu G et al. (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5: 67
Eramo A et al. (2006) Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ 13: 1238–1241
Kang MK and Kang SK (2007) Tumorigenesis of chemotherapeutic drug-resistant cancer stem-like cells in brain glioma. Stem Cells Dev 16: 837–847
Dean M et al. (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5: 275–284
Hirschmann-Jax C et al. (2004) A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 101: 14228–14233
Salmaggi A et al. (2006) Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. Glia 54: 850–860
Bao S et al. (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444: 756–760
Stupp R and Hegi ME (2007) Targeting brain-tumor stem cells. Nat Biotechnol 25: 193–194
Wang ZG et al. (1998) Role of PML in cell growth and the retinoic acid pathway. Science 279: 1547–1551
Clark PA et al. (2007) Developmental signaling pathways in brain tumor-derived stem-like cells. Dev Dyn 236: 3297–3308
Schmierer B and Hill CS (2007) TGFβ–SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8: 970–982
Piccirillo SG et al. (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444: 761–765
Lee J et al. (2008) Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13: 69–80
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Das, S., Srikanth, M. & Kessler, J. Cancer stem cells and glioma. Nat Rev Neurol 4, 427–435 (2008). https://doi.org/10.1038/ncpneuro0862
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DOI: https://doi.org/10.1038/ncpneuro0862
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