Neurochemical Research

, Volume 33, Issue 12, pp 2407–2415

Stem Cell Markers in Gliomas

Review Article

Abstract

Gliomas are the most common tumours of the central nervous system (CNS) and a frequent cause of mental impairment and death. Treatment of malignant gliomas is often palliative because of their infiltrating nature and high recurrence. Genetic events that lead to brain tumours are mostly unknown. A growing body of evidence suggests that gliomas may rise from cancer stem cells (CSC) sharing with neural stem cells (NSC) the capacity of cell renewal and multipotency. Accordingly, a population of cells called “side population” (SP), which has been isolated from gliomas on the basis of their ability to extrude fluorescent dyes, behaves as stem cells and is resistant to chemotherapeutic treatments. This review will focus on the expression of the stem cell markers nestin and CD133 in glioma cancer stem cells. In addition, the possible role of Platelet Derived Growth Factor receptor type α (PDGFR-α) and Notch signalling in normal development and tumourigenesis of gliomas are also discussed. Future work elucidating the mechanisms that control normal development will help to identify new cancer stem cell-related genes. The identification of important markers and the elucidation of signalling pathways involved in survival, proliferation and differentiation of CSCs appear to be fundamental for developing an effective therapy of brain tumours.

Keywords

Gliomas Stem cell markers CD133 Nestin Notch PDGF 

References

  1. 1.
    Garden AS, Maor MH, Yung WK et al (1991) Outcome and patterns of failure following limited-volume irradiation for malignant astrocytomas. Radiother Oncol 20:99–110PubMedCrossRefGoogle Scholar
  2. 2.
    Gage FH, Ray J, Fisher LJ (1995) Isolation, characterization, and use of stem cells from CNS. Annu Rev Neurosci 18:159–192PubMedCrossRefGoogle Scholar
  3. 3.
    Loeffler M, Potten CS (1997) Stem-like cells and cellular pedigrees, a conceptual introduction. In: Potten CS (ed) Stem cells. London, Academic Press, Inc., pp 1–27CrossRefGoogle Scholar
  4. 4.
    Gritti A, Vescovi AL, Galli R (2002) Adult neural stem cells: plasticity and developmental potential. J Physiol 96:81–90Google Scholar
  5. 5.
    Gould E, Tanapat P, McEwen BS et al (1998) Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci USA 95:3168–3171PubMedCrossRefGoogle Scholar
  6. 6.
    Eriksson PS, Perfilieva E, Björk-Eriksson T et al. (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317Google Scholar
  7. 7.
    Ridet JL, Malhotra SK, Privat A et al (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577PubMedCrossRefGoogle Scholar
  8. 8.
    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(13):5046–5061PubMedGoogle Scholar
  9. 9.
    Jackson EL, Garcia-Verdugo JM, Gil-Perotin S 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 signalling. Neuron 51:187–199PubMedCrossRefGoogle Scholar
  10. 10.
    Doetsch F, Caille I, Lim DA et al (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:1–20CrossRefGoogle Scholar
  11. 11.
    Lim DA, Alvarez-Buylla A (2001) Glial characteristics of adult subventricular zone stem cells. In: Rao MS (ed) Stem cells in CNS development. Humana Press, Towton, NJ, pp 71–92CrossRefGoogle Scholar
  12. 12.
    Parras CM, Galli R, Britz O et al (2004) Mash1 specifies neurons and oligodendrocytes in the postnatal brain. EMBO J 23:4495–4505PubMedCrossRefGoogle Scholar
  13. 13.
    Coskum V, Wu H, Blanchi B et al (2008) CD133 neural stem cells in the ependymal of mammalian postnatal forebrain. Proc Natl Acad Sci USA 105(3):1026–1031CrossRefGoogle Scholar
  14. 14.
    Sanai N, Tramontin AD, Quinones-Hinojosa A et al (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427:740–744PubMedCrossRefGoogle Scholar
  15. 15.
    Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111PubMedCrossRefGoogle Scholar
  16. 16.
    Tu SM, Lin SH, Logothetis CJ (2002) Stem-cell origin of metastasis and heterogeneity in solid tumours. Lancet Oncol 3:508–513PubMedCrossRefGoogle Scholar
  17. 17.
    Kondo T, Raff M (2000) Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289:1754–1757PubMedCrossRefGoogle Scholar
  18. 18.
    Laywell ED, Rakic P, Kukekov VG et al (2000) Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci USA 97:13889–13894CrossRefGoogle Scholar
  19. 19.
    Nunes MC, Roy NS, Keyoung HM et al (2003) Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med 9:439–447PubMedCrossRefGoogle Scholar
  20. 20.
    Ignatova TN, Kukekov VG, Laywell ED et al (2002) Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39:193–206PubMedCrossRefGoogle Scholar
  21. 21.
    Zhenju J, Lenhard R (2006) Telomeres and telomerase in cancer stem cell. Eur J Cancer 42:1197–1203CrossRefGoogle Scholar
  22. 22.
    Singh SK, Clarke ID, Terasaki M et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828PubMedGoogle Scholar
  23. 23.
    Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401PubMedCrossRefGoogle Scholar
  24. 24.
    Yuan X, Curtin J, Xiong Y et al (2004) Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23:9392–9400PubMedCrossRefGoogle Scholar
  25. 25.
    Hemmati HD, Nakano I, Lazareff JA et al (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183PubMedCrossRefGoogle Scholar
  26. 26.
    Hirschmann-Jax C, Foster AE, Wulf GG et al (2004) A distinct ‘‘side population’’ of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 101:14228–14233PubMedCrossRefGoogle Scholar
  27. 27.
    Kondo T, Setoguchi T, Taga T (2004) Persistence of a small population of cancer stem-like cells in the C6 rat glioma cell line. Proc Natl Acad Sci USA 101:781–786PubMedCrossRefGoogle Scholar
  28. 28.
    Patrawala L, Calhoun T, Schneider-Broussard R et al (2005) Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2 cancer cells are similarly tumorigenic. Cancer Res 65(14):6208–6219CrossRefGoogle Scholar
  29. 29.
    Weigmann A, Corbeil D, Hellwig A et al (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(23):12425–12430PubMedCrossRefGoogle Scholar
  30. 30.
    Kania G, Corbeil D, Fuchs J et al (2005) Somatic stem cell marker prominin-1/CD133 is expressed in embryonic stem cell-derived progenitors. Stem Cells 23(6):791–804PubMedCrossRefGoogle Scholar
  31. 31.
    Shmelkov SV, Jun L, St. Clair R et al (2004) Alternative promoters regulate transcription of the gene that encodes stem cell surface protein AC133. Blood 103(6):2055–2061PubMedCrossRefGoogle Scholar
  32. 32.
    Galli R, Binda E, Orfanelli U et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021PubMedCrossRefGoogle Scholar
  33. 33.
    Beier D, Hau P, Proescholdt M et al (2007) CD133+ and CD133− glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67(9):4010–4015PubMedCrossRefGoogle Scholar
  34. 34.
    Wang J, Sakariassen PO, Tsinkalovsky O et al (2008) CD133 negative glioma cells form tumors in nude rats and give rise to CD133+ cells. Int J Cancer 122:761–768PubMedCrossRefGoogle Scholar
  35. 35.
    Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5:275–284PubMedCrossRefGoogle Scholar
  36. 36.
    Bao S, Wu Q, McLendon RE et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760PubMedCrossRefGoogle Scholar
  37. 37.
    Rich JN (2007) Cancer stem cells in radiation resistance. Cancer Res 67(19):8980–8984PubMedCrossRefGoogle Scholar
  38. 38.
    Liu G, Yuan X, Zeng Z et al (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67–78PubMedCrossRefGoogle Scholar
  39. 39.
    Schimmer AD (2004) Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice. Cancer Res 64:7183–7190PubMedCrossRefGoogle Scholar
  40. 40.
    Ehtesham M, Yuan X, Kabos P et al (2004) Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 6:287–293PubMedCrossRefGoogle Scholar
  41. 41.
    Ehtesham M, Winston JA, Kabos P, Thompson RC (2006) CXCR4 expression mediates glioma cell invasiveness. Oncogene 25(19):2801–2806PubMedCrossRefGoogle Scholar
  42. 42.
    Zimmerman L, Parr B, Lendahl U et al (1994) Independent regulatory elements in the nestin gene direct transgene expression to neural stem cells or muscle precursors. Neuron 12:11–24PubMedCrossRefGoogle Scholar
  43. 43.
    Cattaneo E, McKay R (1990) Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature 347:762–765PubMedCrossRefGoogle Scholar
  44. 44.
    Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710PubMedCrossRefGoogle Scholar
  45. 45.
    Vescovi AL, Reynolds BA, Fraser DD et al (1993) bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron 11:951–966PubMedCrossRefGoogle Scholar
  46. 46.
    Morshead CM, Reynolds BA, Craig CG et al (1994) Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13:1071–1082PubMedCrossRefGoogle Scholar
  47. 47.
    Gu H, Wang S, Messam CA, Yao Z (2002) Distribution of nestin immunoreactivity in the normal adult human forebrain. Brain Res 943:174–180PubMedCrossRefGoogle Scholar
  48. 48.
    Holmin S, Almquist P, Lendahl U et al (1997) Adult nestin-expressing subependymal cells differentiate to astrocytes in response to brain injury. Eur J NeuroSci 9:65–75PubMedCrossRefGoogle Scholar
  49. 49.
    Dahlstrand J, Collins VP, Lendahl U (1992) Expression of the class VI intermediate filament nestin in human central nervous system tumors. Cancer Res 52:5334–5341PubMedGoogle Scholar
  50. 50.
    Almqvist PM, Mah R, Lendahl U et al (2002) Immunohistochemical detection of nestin in pediatric brain tumors. J Histochem Cytochem 50:147–158PubMedGoogle Scholar
  51. 51.
    Strojnik T, Røsland GV, Sakariassen PO et al (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(2):133–143PubMedCrossRefGoogle Scholar
  52. 52.
    Rutka JT, Ivanchuk S, Mondal S et al (1999) Co-expression of nestin and vimentin intermediate filaments in invasive human astrocytoma cells. Int J Dev Neurosci 17:503–515PubMedCrossRefGoogle Scholar
  53. 53.
    Veselska R, Kuglik P, Cejpek P et al (2006) Nestin expression in the cell lines derived from glioblastoma multiforme. BMC Cancer 6:32–43PubMedCrossRefGoogle Scholar
  54. 54.
    Thomas SK, Messam CA, Spengler BA et al (2004) Nestin is a potential mediator of malignancy in human neuroblastoma cells. J Biol Chem 279:27994–27999PubMedCrossRefGoogle Scholar
  55. 55.
    Nakamura Y, S-I Sakakibara, Miyata T et al (2000) The bHLH gene Hes1 as a repressor of the neuronal commitment of CNS stem cells. J Neurosci 20:283–293PubMedGoogle Scholar
  56. 56.
    Hitoshi S, Alexson T, Tropepe V et al (2002) Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev 16:846–858PubMedCrossRefGoogle Scholar
  57. 57.
    Pringle NP, Mudhar HS, Collarini EJ et al (1992) PDGF receptors in the rat CNS: during late neurogenesis, PDGF alpha-receptor expression appears to be restricted to glial cells of the oligodendrocyte lineage. Development 115:535–551PubMedGoogle Scholar
  58. 58.
    Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signalling: cell fate control and signal integration in development. Science 284:770–776PubMedCrossRefGoogle Scholar
  59. 59.
    Hitoshi S, Seaberg RM, Koscik C et al (2004) Primitive neural stem cells from the mammalian epiblast differentiate to definitive neural stem cells under the control of Notch signalling. Genes Dev 18:1806–1811PubMedCrossRefGoogle Scholar
  60. 60.
    Tanigaki K, Nogaki F, Takahashi J et al (2001) Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate. Neuron 29:45–55PubMedCrossRefGoogle Scholar
  61. 61.
    Hojo M, Ohtsuka T, Hashimoto N et al (2000) Glial cell fate specification modulated by the bHLH gene Hes5 in mouse retina. Development 127:2515–2522PubMedGoogle Scholar
  62. 62.
    Gaiano N, Nye JS, Fishell G (2000) Radial glial identity is promoted by Notch1 signalling in the murine forebrain. Neuron 26:395–404PubMedCrossRefGoogle Scholar
  63. 63.
    Mellodew K, Suhr R, Uwanogho DA et al (2004) Nestin expression is lost in a neural stem cell line through a mechanism involving the proteasome and Notch signalling. Devel Brain Res 151:13–23CrossRefGoogle Scholar
  64. 64.
    Jang MS, Zlobin A, Kast WM, Miele L (2000) Notch signalling as a target in multimodality cancer therapy. Curr Opin Mol Ther 2(1):55–65PubMedGoogle Scholar
  65. 65.
    Purow BW, Haque RM, Noel MW et al (2005) Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res 65(6):2353–2363PubMedCrossRefGoogle Scholar
  66. 66.
    Shih AH, Holland EC (2006) Notch signalling enhances nestin expression in gliomas. Neoplasia 8(12):1072–1082PubMedCrossRefGoogle Scholar
  67. 67.
    Kanamori M, Kawaguchi T, Nigro JM et al (2007) Contribution of Notch signalling activation to human glioblastoma multiforme. J Neurosurg 106(3):417–427PubMedCrossRefGoogle Scholar
  68. 68.
    Zhang XP, Zheng G, Zou L et al (2008) Notch activation promotes cell proliferation and the formation of neural stem-like colonies in human glioma cells. Mol Cell Bioch 307(1–2):101–108Google Scholar
  69. 69.
    Fan X, Matsui W, Khaki L et al (2006) Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66(15):7445–7452PubMedCrossRefGoogle Scholar
  70. 70.
    Ross R, Glomset J, KariYa L et al (1974) A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci USA 71:1207–1210PubMedCrossRefGoogle Scholar
  71. 71.
    Tallquist M, Kazlauskas A (2004) PDGF signaling in cells and mice. Cytokine Growth Factor Rev 15(4):205–213PubMedCrossRefGoogle Scholar
  72. 72.
    Yeh HJ, Silos-Santiago I, Wang YX et al (1993) Developmental expression of the platelet-derived growth factor alpha-receptor gene in mammalian central nervous system. Proc Natl Acad Sci USA 90(5):1952–1956PubMedCrossRefGoogle Scholar
  73. 73.
    Erlandsson A, Enarsson M, Forsberg-Nilsson K. (2001) Immature neurons from CNS stem cells proliferate in response to Platelet-Derived Growth Factor. J Neurosci 21(10):3483–3491PubMedGoogle Scholar
  74. 74.
    Oumesmar B, Vignais L, Baron-Van Evercooren A (1997) Developmental expression of platelet-derived growth factor-receptor in neurons and in glial cells of the mouse CNS. J Neurosci 17:125–139PubMedGoogle Scholar
  75. 75.
    Hermanson M, Funa K, Hartman M et al (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(11):3213–3219PubMedGoogle Scholar
  76. 76.
    Lokker NA, Sullivan CM, Hollenbach SJ et al (2002) Platelet-derived growth factor (PDGF) autocrine signalling 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(13):3729–3735PubMedGoogle Scholar
  77. 77.
    Puputti M, Tynninen O, Sihto H et al (2006) Amplification of KIT, PDGFRA, VEGFR », and EGFR in gliomas. Mol Cancer Res 4(12):927–934PubMedCrossRefGoogle Scholar
  78. 78.
    Dai C, Celestino JC, Okada Y et al (2001) PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15:1913–1925PubMedCrossRefGoogle Scholar
  79. 79.
    Shih AH, Holland EC (2006) Platelet-derived growth factor (PDGF) and glial tumorigenesis. Cancer Lett 232(2):139–147PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Institute of Neurological SciencesNational Research Council (CNR)CataniaItaly

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