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Brain tumour stem cells

Key Points

  • Adult somatic stem cells are a rare population of long-lived cells that have significant proliferative capacity, show extensive self-renewal and have a wide differentiation potential.

  • Cells that have the cardinal properties of stem cells have been identified in restricted regions of the CNS, where they are arranged in specific lineage hierarchies.

  • Similar to other adult stem cells, neural stem cells or their immediate progeny, which are called transiently dividing progenitors, can be considered a credible target for malignant transformation. This concept is supported by the finding that many of the molecular determinants that regulate normal neurogenesis seem also to be involved in tumorigenesis.

  • Brain tumour stem cells have been identified and isolated from different types of brain tumour: in particular, glioblastoma multiforme and medulloblastoma.

  • Brain tumour stem cells show all the features of stem cells, including the ability to generate new tumours that faithfully reproduce the phenotype of the human disease.

  • The availability of brain tumour stem-cell lines provides a model system for the identification of specific antigenic and molecular markers that might target the tumour-initiating cell.

  • The development of agents that selectively target and inhibit the tumour-initiating and propagation potential of brain tumour stem cells might reduce or eliminate primary tumour establishment, growth and recurrence.

Abstract

The dogma that the genesis of new cells is a negligible event in the adult mammalian brain has long influenced our perception and understanding of the origin and development of CNS tumours. The discovery that new neurons and glia are produced throughout life from neural stem cells provides new possibilities for the candidate cells of origin of CNS neoplasias. The emerging hypothesis is that alterations in the cellular and genetic mechanisms that control adult neurogenesis might contribute to brain tumorigenesis, thereby allowing the identification of new therapeutic strategies.

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Figure 1: The anatomy and functioning of the subventricular zone and subgranular zone in rodents and humans.
Figure 2: Hierarchical organization of the functional compartments in renewing tissues.
Figure 3: Isolation and perpetuation of brain tumour stem cells in culture.
Figure 4: Neurogenetic compartments as developmental 'beltways'.

References

  1. 1

    Behin, A., Hoang-Xuan, K., Carpentier, A. F. & Delattre, J. Y. Primary brain tumours in adults. Lancet 361, 323–331 (2003).

    PubMed  Google Scholar 

  2. 2

    Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).

    CAS  PubMed  Google Scholar 

  3. 3

    Holland, E. C. Glioblastoma multiforme: the terminator. Proc. Natl Acad. Sci. USA 97, 6242–6244 (2000).

    CAS  PubMed  Google Scholar 

  4. 4

    Ellison, D. Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathol. Appl. Neurobiol. 28, 257–282 (2002).

    CAS  PubMed  Google Scholar 

  5. 5

    Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730–737 (1997). Describes for the first time the identification of stem-like cells in haematopoietic malignancies.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Hope, K. J., Jin, L. & Dick, J. E. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nature Immunol. 5, 738–743 (2004).

    CAS  Google Scholar 

  9. 9

    Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Altman, J. & Das, G. D. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. 124, 319–335 (1965).

    CAS  Google Scholar 

  11. 11

    Altman, J. Proliferation and migration of undifferentiated precursor cells in the rat during postnatal gliogenesis. Exp. Neurol. 16, 263–278 (1966).

    CAS  PubMed  Google Scholar 

  12. 12

    Dacey, M. L. & Wallace, R. B. Postnatal neurogenesis in the feline cerebellum: a structural-functional investigation. Acta Neurobiol. Exp. (Wars.) 34, 253–263 (1974).

    CAS  Google Scholar 

  13. 13

    Sell, S. Stem cell origin of cancer and differentiation therapy. Crit. Rev. Oncol. Hematol. 51, 1–28 (2004).

    PubMed  Google Scholar 

  14. 14

    Nottebohm, F. The road we travelled: discovery, choreography, and significance of brain replaceable neurons. Ann. N. Y. Acad. Sci. 1016, 628–658 (2004).

    PubMed  Google Scholar 

  15. 15

    Reynolds, B. A. & Weiss, S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707–1710 (1992). Reports the initial evidence that multipotent neural stem cells that reside in the adult rodent brain can be identified and isolated in vitro following mitogen stimulation.

    CAS  PubMed  Google Scholar 

  16. 16

    Gould, E., McEwen, B. S., Tanapat, P., Galea, L. A. & Fuchs, E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 2492–2498 (1997).

    CAS  Google Scholar 

  17. 17

    Gould, E., Tanapat, P., McEwen, B. S., Flugge, G. & Fuchs, E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc. Natl Acad. Sci. USA 95, 3168–3171 (1998).

    CAS  Google Scholar 

  18. 18

    Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nature Med. 4, 1313–1317 (1998).

    CAS  Google Scholar 

  19. 19

    Lie, D. C., Song, H., Colamarino, S. A., Ming, G. L. & Gage, F. H. Neurogenesis in the adult brain: new strategies for central nervous system diseases. Annu. Rev. Pharmacol. Toxicol. 44, 399–421 (2004).

    CAS  Google Scholar 

  20. 20

    Ming, G. L. & Song, H. Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 28, 223–250 (2005).

    CAS  PubMed  Google Scholar 

  21. 21

    Loeffler M. and Potten, C. in Stem Cells and Cellular Pedigrees — A Conceptual Introduction. (ed. Potten, C.) Ch. 1 (Academic Press, London, 1997).

    Google Scholar 

  22. 22

    Passegue E. J. C., Ailles L. E. & Weissman I. L. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc. Natl Acad. Sci. USA. 100, 11842–11849 (2003).

    CAS  PubMed  Google Scholar 

  23. 23

    Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999). Results in this paper show that the bona fide subventricular-zone stem cell is the type B cell, which shows features of a differentiated astrocyte.

    CAS  Google Scholar 

  24. 24

    Morshead, C. M. et al. Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13, 1071–1082 (1994).

    CAS  Google Scholar 

  25. 25

    Sanai, N. et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427, 740–744 (2004). Provides the first evidence of the existence of neural stem cells in the subventricular zone of the adult human brain, and highlights the differences from the same compartment in rodents and the implications for the origin of brain tumours.

    CAS  PubMed  Google Scholar 

  26. 26

    Sanai, N., Alvarez-Buylla, A. & Berger, M. S. Neural stem cells and the origin of gliomas. N. Engl. J. Med. 353, 811–822 (2005).

    CAS  PubMed  Google Scholar 

  27. 27

    Quinones-Hinojosa, A. et al. Cellular composition and cytoarchitecture of the adult human subventricular zone: A niche of neural stem cells. J. Comp. Neurol. 494, 415–434 (2006).

    PubMed  Google Scholar 

  28. 28

    Seri, B., Garcia-Verdugo, J. M., McEwen, B. S. & Alvarez-Buylla, A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J. Neurosci. 21, 7153–7160 (2001).

    CAS  PubMed  Google Scholar 

  29. 29

    Seri, B., Garcia-Verdugo, J. M., Collado-Morente, L., McEwen, B. S. & Alvarez-Buylla, A. Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. J. Comp. Neurol. 478, 359–378 (2004).

    PubMed  Google Scholar 

  30. 30

    Roy, N. S. et al. In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nature Med. 6, 271–277 (2000).

    CAS  Google Scholar 

  31. 31

    Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36, 1021–1034 (2002).

    CAS  Google Scholar 

  32. 32

    Gritti, A. et al. Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J. Neurosci. 16, 1091–1100 (1996).

    CAS  PubMed  Google Scholar 

  33. 33

    Gritti, A. et al. Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain. J. Neurosci. 19, 3287–3297 (1999).

    CAS  PubMed  Google Scholar 

  34. 34

    Reynolds, B. A. & Rietze, R. L. Neural stem cells and neurospheres — re-evaluating the relationship. Nature Methods 2, 333–336 (2005).

    CAS  PubMed  Google Scholar 

  35. 35

    Reynolds, B. A. & Weiss, S. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev. Biol. 175, 1–13 (1996).

    CAS  PubMed  Google Scholar 

  36. 36

    Vescovi, A. L. et al. Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cell lines by epigenetic stimulation. Exp. Neurol. 156, 71–83 (1999).

    CAS  PubMed  Google Scholar 

  37. 37

    Galli, R. et al. Emx2 regulates the proliferation of stem cells of the adult mammalian central nervous system. Development 129, 1633–1644 (2002).

    CAS  PubMed  Google Scholar 

  38. 38

    Parras, C. M. et al. Mash1 specifies neurons and oligodendrocytes in the postnatal brain. EMBO J. 23, 4495–4505 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Soria, J. M. et al. Defective postnatal neurogenesis and disorganization of the rostral migratory stream in absence of the Vax1 homeobox gene. J. Neurosci. 24, 11171–11181 (2004).

    CAS  PubMed  Google Scholar 

  40. 40

    Weiss, S. et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J. Neurosci. 16, 7599–7609 (1996).

    CAS  PubMed  Google Scholar 

  41. 41

    Gritti, A. et al. Multipotent neural stem cells reside into the rostral extension and olfactory bulb of adult rodents. J. Neurosci. 22, 437–445 (2002).

    CAS  PubMed  Google Scholar 

  42. 42

    Svendsen, C. N., Caldwell, M. A. & Ostenfeld, T. Human neural stem cells: isolation, expansion and transplantation. Brain Pathol. 9, 499–513 (1999).

    CAS  Google Scholar 

  43. 43

    Uchida, N. et al. Direct isolation of human central nervous system stem cells. Proc. Natl Acad. Sci. USA 97, 14720–14725 (2000).

    CAS  PubMed  Google Scholar 

  44. 44

    Palmer, T. D., Markakis, E. A., Willhoite, A. R., Safar, F. & Gage, F. H. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J. Neurosci. 19, 8487–8497 (1999).

    CAS  Google Scholar 

  45. 45

    Zhao, M. et al. Evidence for neurogenesis in the adult mammalian substantia nigra. Proc. Natl Acad. Sci. USA 100, 7925–7930 (2003).

    CAS  PubMed  Google Scholar 

  46. 46

    Zhang, X., Klueber, K. M., Guo, Z., Lu, C. & Roisen, F. J. Adult human olfactory neural progenitors cultured in defined medium. Exp. Neurol. 186, 112–123 (2004).

    PubMed  Google Scholar 

  47. 47

    Consiglio, A. et al. Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors. Proc. Natl Acad. Sci. USA 101, 14835–14840 (2004).

    CAS  Google Scholar 

  48. 48

    Markakis, E. A., Palmer, T. D., Randolph-Moore, L., Rakic, P. & Gage, F. H. Novel neuronal phenotypes from neural progenitor cells. J. Neurosci. 24, 2886–2897 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Toma, J. G., McKenzie, I. A., Bagli, D. & Miller, F. D. Isolation and characterization of multipotent skin-derived precursors from human skin. Stem Cells 23, 727–737 (2005).

    CAS  PubMed  Google Scholar 

  50. 50

    Messina, E. et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ. Res. 95, 911–921 (2004).

    CAS  PubMed  Google Scholar 

  51. 51

    Dontu, G. et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17, 1253–1270 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Rietze, R. L. et al. Purification of a pluripotent neural stem cell from the adult mouse brain. Nature 412, 736–739 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Capela, A. & Temple, S. LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 35, 865–875 (2002).

    PubMed  Google Scholar 

  54. 54

    Kim, M. & Morshead, C. M. Distinct populations of forebrain neural stem and progenitor cells can be isolated using side-population analysis. J. Neurosci. 23, 10703–10709 (2003).

    CAS  PubMed  Google Scholar 

  55. 55

    Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004). Shows that only CD133+ human brain tumour cells are endowed with tumour-initiating capacity in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Ignatova, T. N. et al. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39, 193–206 (2002).

    PubMed  Google Scholar 

  57. 57

    Singh S. K. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821–5828 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Hemmati, H. D. et al. Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl Acad. Sci. USA 100, 15178–15183 (2003).

    CAS  PubMed  Google Scholar 

  59. 59

    Corbeil, D., Roper, K., Weigmann, A. & Huttner, W. B. AC133 hematopoietic stem cell antigen: human homologue of mouse kidney prominin or distinct member of a novel protein family? Blood 91, 2625–2626 (1998).

    CAS  PubMed  Google Scholar 

  60. 60

    Tamaki, S. et al. Engraftment of sorted/expanded human central nervous system stem cells from fetal brain. J. Neurosci. Res. 69, 976–986 (2002).

    CAS  PubMed  Google Scholar 

  61. 61

    Galli, R. et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64, 7011–7021 (2004).

    CAS  PubMed  Google Scholar 

  62. 62

    Tunici, P. et al. Genetic alterations and in vivo tumorigenicity of neurospheres derived from an adult glioblastoma. Mol. Cancer 3, 25 (2004).

    PubMed  PubMed Central  Google Scholar 

  63. 63

    Yuan, X. et al. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23, 9392–9400 (2004).

    CAS  PubMed  Google Scholar 

  64. 64

    Taylor, M. D. et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8, 323–335 (2005).

    CAS  PubMed  Google Scholar 

  65. 65

    Merkle, F. T., Tramontin, A. D., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Radial glia give rise to adult neural stem cells in the subventricular zone. Proc. Natl Acad. Sci. USA 101, 17528–17532 (2004).

    CAS  PubMed  Google Scholar 

  66. 66

    Wechsler-Reya, R. & Scott, M. P. The developmental biology of brain tumors. Annu. Rev. Neurosci. 24, 385–428 (2001).

    CAS  PubMed  Google Scholar 

  67. 67

    Hopewell, J. W. & Wright, E. A. The importance of implantation site in cerebral carcinogenesis in rats. Cancer Res. 29, 1927–1931 (1969).

    CAS  PubMed  Google Scholar 

  68. 68

    Vick, N. A., Lin, M. J. & Bigner, D. D. The role of the subependymal plate in glial tumorigenesis. Acta Neuropathol. 40, 63–71 (1977).

    CAS  PubMed  Google Scholar 

  69. 69

    Zhu, Y. et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8, 119–130 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Holland, E. C. et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genet. 25, 55–57 (2000). Shows that cell-specific deregulation of oncogenic pathways leads to the development of glial tumours that arise from nestin-positive progenitors but not from differentiated astrocytes.

    CAS  PubMed  Google Scholar 

  71. 71

    Holland, E. C., Hively, W. P., Gallo, V. & Varmus, H. E. Modeling mutations in the G1 arrest pathway in human gliomas: overexpression of CDK4 but not loss of INK4a-ARF induces hyperploidy in cultured mouse astrocytes. Genes Dev. 12, 3644–3649 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Dai, C. et al. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev. 15, 1913–1925 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Bachoo, R. M. et al. 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 (2002).

    CAS  Google Scholar 

  74. 74

    Berger, F., Gay, E., Pelletier, L., Tropel, P. & Wion, D. Development of gliomas: potential role of asymmetrical cell division of neural stem cells. Lancet Oncol. 5, 511–514 (2004).

    CAS  PubMed  Google Scholar 

  75. 75

    Seaberg, R. M. & van der Kooy, D. Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J. Neurosci. 22, 1784–1793 (2002).

    CAS  PubMed  Google Scholar 

  76. 76

    Bull, N. D. & Bartlett, P. F. The adult mouse hippocampal progenitor is neurogenic but not a stem cell. J. Neurosci. 25, 10815–10821 (2005).

    CAS  PubMed  Google Scholar 

  77. 77

    Frank, S. A. & Nowak, M. A. Cell biology: Developmental predisposition to cancer. Nature 422, 494 (2003).

    CAS  PubMed  Google Scholar 

  78. 78

    Huntly, B. J. & Gilliland, D. G. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nature Rev. Cancer 5, 311–321 (2005).

    CAS  Google Scholar 

  79. 79

    Mellinghoff, I. K. et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. 353, 2012–2024 (2005).

    CAS  PubMed  Google Scholar 

  80. 80

    Kuhn, H. G., Winkler, J., Kempermann, G., Thal, L. J. & Gage, F. H. Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J. Neurosci. 17, 5820–5829 (1997).

    CAS  PubMed  Google Scholar 

  81. 81

    Craig, C. G. et al. In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J. Neurosci. 16, 2649–2658 (1996).

    CAS  PubMed  Google Scholar 

  82. 82

    Potten, C. S., Booth, C. & Hargreaves, D. The small intestine as a model for evaluating adult tissue stem cell drug targets. Cell Prolif. 36, 115–129 (2003).

    CAS  PubMed  Google Scholar 

  83. 83

    Potten, C. S. & Loeffler, M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110, 1001–1020 (1990). Provides a fundamental introduction to the general concept of stem cells by describing the properties of the stem-cell compartment that is localized within the intestinal crypt.

    CAS  Google Scholar 

  84. 84

    Ross, E. A., Anderson, N. & Micklem, H. S. Serial depletion and regeneration of the murine hematopoietic system. Implications for hematopoietic organization and the study of cellular aging. J. Exp. Med. 155, 432–444 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Hock, H. et al. Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431, 1002–1007 (2004).

    CAS  PubMed  Google Scholar 

  86. 86

    Cairns, J. Mutation selection and the natural history of cancer. Nature 255, 197–200 (1975).

    CAS  PubMed  Google Scholar 

  87. 87

    Potten, C. S., Owen, G. & Booth, D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J. Cell Sci. 115, 2381–2388 (2002).

    CAS  PubMed  Google Scholar 

  88. 88

    Karpowicz, P. et al. Support for the immortal strand hypothesis: neural stem cells partition DNA asymmetrically in vitro. J. Cell Biol. 170, 721–732 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Louis, D. N., Holland, E. C. & Cairncross, J. G. Glioma classification: a molecular reappraisal. Am. J. Pathol. 159, 779–786 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Vescovi, A. L., Reynolds, B. A., Fraser, D. D. & Weiss, S. bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron 11, 951–966 (1993).

    CAS  PubMed  Google Scholar 

  91. 91

    Joy, A. et al. Nuclear accumulation of FGF-2 is associated with proliferation of human astrocytes and glioma cells. Oncogene 14, 171–183 (1997).

    CAS  PubMed  Google Scholar 

  92. 92

    Auguste, P. et al. Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependent and-independent mechanisms. Cancer Res. 61, 1717–1726 (2001).

    CAS  PubMed  Google Scholar 

  93. 93

    Purow, B. W. et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 65, 2353–2363 (2005).

    CAS  PubMed  Google Scholar 

  94. 94

    Hitoshi, S. et al. Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev. 16, 846–858 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Shen, Q. et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004).

    CAS  PubMed  Google Scholar 

  96. 96

    Molofsky, A. V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Bruggeman, S. W. et al. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev. 19, 1438–1443 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Leung, C. et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428, 337–341 (2004).

    CAS  PubMed  Google Scholar 

  99. 99

    Palma, V. et al. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development 132, 335–344 (2005).

    CAS  PubMed  Google Scholar 

  100. 100

    Goodrich, L. V., Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Pomeroy, S. L. et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415, 436–442 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Baker, S. J. & McKinnon, P. J. Tumour-suppressor function in the nervous system. Nature Rev. Cancer 4, 184–196 (2004).

    CAS  Google Scholar 

  103. 103

    Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005).

    CAS  Google Scholar 

  104. 104

    Groszer, M. et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186–2189 (2001).

    CAS  PubMed  Google Scholar 

  105. 105

    Li, L. et al. PTEN in neural precursor cells: regulation of migration, apoptosis, and proliferation. Mol. Cell. Neurosci. 20, 21–29 (2002).

    CAS  PubMed  Google Scholar 

  106. 106

    Rasheed, B. K., Wiltshire, R. N., Bigner, S. H. & Bigner, D. D. Molecular pathogenesis of malignant gliomas. Curr. Opin. Oncol. 11, 162–167 (1999).

    CAS  PubMed  Google Scholar 

  107. 107

    Chenn, A. & Walsh, C. A. Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in β-catenin overexpressing transgenic mice. Cereb. Cortex 13, 599–606 (2003).

    PubMed  Google Scholar 

  108. 108

    Lie, D. C. et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370–1375 (2005).

    CAS  Google Scholar 

  109. 109

    Marino, S. Medulloblastoma: developmental mechanisms out of control. Trends Mol. Med. 11, 17–22 (2005).

    CAS  PubMed  Google Scholar 

  110. 110

    Roth, W. et al. Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells. Oncogene 19, 4210–4220 (2000).

    CAS  PubMed  Google Scholar 

  111. 111

    Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nature Rev. Cancer 5, 275–284 (2005).

    CAS  Google Scholar 

  112. 112

    Shah, K. et al. Glioma therapy and real-time imaging of neural precursor cell migration and tumor regression. Ann. Neurol. 57, 34–41 (2005).

    CAS  PubMed  Google Scholar 

  113. 113

    Glass, R. et al. Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J. Neurosci. 25, 2637–2646 (2005).

    CAS  PubMed  Google Scholar 

  114. 114

    Benedetti, S. et al. Gene therapy of experimental brain tumors using neural progenitor cells. Nature Med. 6, 447–450 (2000). Shows that implantation in established glial tumours of neural stem/progenitor cells that have been engineered to secrete IL-4 elicits a strong anti-tumour effect.

    CAS  PubMed  Google Scholar 

  115. 115

    Ehtesham, M. et al. The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res. 62, 5657–5663 (2002).

    CAS  PubMed  Google Scholar 

  116. 116

    Kim, S. K. et al. PEX-producing human neural stem cells inhibit tumor growth in a mouse glioma model. Clin. Cancer Res. 11, 5965–5970 (2005).

    CAS  PubMed  Google Scholar 

  117. 117

    Aboody, K. S. et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc. Natl Acad. Sci. USA 97, 12846–12851 (2000). The first demonstration that distally implanted somatic neural stem cells can migrate considerable distances and target previously established tumours, including tumour cells that have infiltrated surrounding tissue.

    CAS  PubMed  Google Scholar 

  118. 118

    Zhang, Z. G. et al. Magnetic resonance imaging and neurosphere therapy of stroke in rat. Ann. Neurol. 53, 259–263 (2003).

    PubMed  Google Scholar 

  119. 119

    Tang, Y. et al. In vivo tracking of neural progenitor cell migration to glioblastomas. Hum. Gene Ther. 14, 1247–1254 (2003).

    CAS  PubMed  Google Scholar 

  120. 120

    Schmidt, N. O. et al. Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor. Neoplasia 7, 623–629 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Ehtesham, M. et al. Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 6, 287–293 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to S. Piccirillo for valuable help with the preparation of this manuscript and to R. Rietze and M. De Palma for their useful suggestions and comments.

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Correspondence to Angelo L. Vescovi.

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A.L.V. is the director of research and owns shares in StemGen, a biotechnology company that is based in Milan, Italy.

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DATABASES

National Cancer Institute

brain tumours

FURTHER INFORMATION

International Society for Stem Cell Research

Glossary

Abnormal ionic flux

Alterations in the transit of ions through specific channels (NMDA receptors) that is generated by the massive release of glutamate from damaged cells and which leads to excito-toxicity.

Reperfusion

CNS injury that is produced by tumour-induced transient ischaemia followed by blood re-oxygenation, which induces neural damage through the generation of reactive oxygen species.

Resting embryonic-like tissue

Remnants of cells that maintain the features of embryonic cells but are located in a semi-quiescent mature tissue.

Nestin-expressing cells

Undifferentiated neural precursors that express the neuroepithelial intermediate filament nestin.

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Vescovi, A., Galli, R. & Reynolds, B. Brain tumour stem cells. Nat Rev Cancer 6, 425–436 (2006). https://doi.org/10.1038/nrc1889

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