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.
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References
Garden AS, Maor MH, Yung WK et al (1991) Outcome and patterns of failure following limited-volume irradiation for malignant astrocytomas. Radiother Oncol 20:99–110
Gage FH, Ray J, Fisher LJ (1995) Isolation, characterization, and use of stem cells from CNS. Annu Rev Neurosci 18:159–192
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 1–27
Gritti A, Vescovi AL, Galli R (2002) Adult neural stem cells: plasticity and developmental potential. J Physiol 96:81–90
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 95:3168–3171
Eriksson PS, Perfilieva E, Björk-Eriksson T et al. (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317
Ridet JL, Malhotra SK, Privat A et al (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577
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):5046–5061
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 51:187–199
Doetsch F, Caille I, Lim DA et al (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:1–20
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 71–92
Parras CM, Galli R, Britz O et al (2004) Mash1 specifies neurons and oligodendrocytes in the postnatal brain. EMBO J 23:4495–4505
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):1026–1031
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 427:740–744
Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111
Tu SM, Lin SH, Logothetis CJ (2002) Stem-cell origin of metastasis and heterogeneity in solid tumours. Lancet Oncol 3:508–513
Kondo T, Raff M (2000) Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289:1754–1757
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 97:13889–13894
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 9:439–447
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 39:193–206
Zhenju J, Lenhard R (2006) Telomeres and telomerase in cancer stem cell. Eur J Cancer 42:1197–1203
Singh SK, Clarke ID, Terasaki M et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828
Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401
Yuan X, Curtin J, Xiong Y et al (2004) Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23:9392–9400
Hemmati HD, Nakano I, Lazareff JA et al (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183
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 101:14228–14233
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 101:781–786
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):6208–6219
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):12425–12430
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):791–804
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):2055–2061
Galli R, Binda E, Orfanelli U et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021
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):4010–4015
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 122:761–768
Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5:275–284
Bao S, Wu Q, McLendon RE et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760
Rich JN (2007) Cancer stem cells in radiation resistance. Cancer Res 67(19):8980–8984
Liu G, Yuan X, Zeng Z et al (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67–78
Schimmer AD (2004) Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice. Cancer Res 64:7183–7190
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 6:287–293
Ehtesham M, Winston JA, Kabos P, Thompson RC (2006) CXCR4 expression mediates glioma cell invasiveness. Oncogene 25(19):2801–2806
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 12:11–24
Cattaneo E, McKay R (1990) Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature 347:762–765
Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710
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 11:951–966
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 13:1071–1082
Gu H, Wang S, Messam CA, Yao Z (2002) Distribution of nestin immunoreactivity in the normal adult human forebrain. Brain Res 943:174–180
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 9:65–75
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
Almqvist PM, Mah R, Lendahl U et al (2002) Immunohistochemical detection of nestin in pediatric brain tumors. J Histochem Cytochem 50:147–158
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):133–143
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 17:503–515
Veselska R, Kuglik P, Cejpek P et al (2006) Nestin expression in the cell lines derived from glioblastoma multiforme. BMC Cancer 6:32–43
Thomas SK, Messam CA, Spengler BA et al (2004) Nestin is a potential mediator of malignancy in human neuroblastoma cells. J Biol Chem 279:27994–27999
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 20:283–293
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 16:846–858
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 115:535–551
Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signalling: cell fate control and signal integration in development. Science 284:770–776
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 18:1806–1811
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 29:45–55
Hojo M, Ohtsuka T, Hashimoto N et al (2000) Glial cell fate specification modulated by the bHLH gene Hes5 in mouse retina. Development 127:2515–2522
Gaiano N, Nye JS, Fishell G (2000) Radial glial identity is promoted by Notch1 signalling in the murine forebrain. Neuron 26:395–404
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 151:13–23
Jang MS, Zlobin A, Kast WM, Miele L (2000) Notch signalling as a target in multimodality cancer therapy. Curr Opin Mol Ther 2(1):55–65
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):2353–2363
Shih AH, Holland EC (2006) Notch signalling enhances nestin expression in gliomas. Neoplasia 8(12):1072–1082
Kanamori M, Kawaguchi T, Nigro JM et al (2007) Contribution of Notch signalling activation to human glioblastoma multiforme. J Neurosurg 106(3):417–427
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):101–108
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):7445–7452
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 71:1207–1210
Tallquist M, Kazlauskas A (2004) PDGF signaling in cells and mice. Cytokine Growth Factor Rev 15(4):205–213
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):1952–1956
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):3483–3491
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 17:125–139
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):3213–3219
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):3729–3735
Puputti M, Tynninen O, Sihto H et al (2006) Amplification of KIT, PDGFRA, VEGFR », and EGFR in gliomas. Mol Cancer Res 4(12):927–934
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 15:1913–1925
Shih AH, Holland EC (2006) Platelet-derived growth factor (PDGF) and glial tumorigenesis. Cancer Lett 232(2):139–147
Acknowledgements
I would like to thank Mr. Francesco Marino for his helpful work for figure editing. I thank Dr. Maria Vincenza Catania for encouraging and help me to write this review and for useful discussion.
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Special issue article in honor of Dr. Anna Maria Giuffrida-Stella.