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Glioblastoma cancer stem cells: Basis for a functional hypothesis

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DOI: 10.4236/scd.2012.23017    3,609 Downloads   7,989 Views   Citations


GBM Cancer stem cells (CSCs) are responsible for growth, recurrence and resistance to chemo- and radio-therapy. They are supposed to originate from the transformation of Neural stem cells (NSC) of the Sub-ventricular zone (SVZ) or Sub-granular zone (SGZ) of hippocampus. Alternatively, they can be the expression of a functional status of competence or dedifferentiated cells of the tumor re-acquiring stemness properties. The origin of gliomas has been put in relation with the primitive neuroepithelial cells of the SVZ or NSC or progenitors, as showed by the development of experimental tumors in rats by transplacental ethylnitrosourea administration. The demonstration of CSCs in GBM is based on Neurosphere (NS) and Adherent cell (AC) development in culture. NS share the same genetic alterations with primary tumors and express stemness antigens, whereas AC show differentiation antigens. NS are generated by the most malignant areas of GBM. CSCs are considered at the top of a hierarchy of tumor cells of which the most immature are Nestin+/CD133– cells or established on the basis of EGFR amplification or delta-EGFR. NS in serum conditions differentiate and give origin to AC, the real nature of which is still a matter of discussion. Cells in culture could be simply in vitro entities depending on culture methodology. CSCs in GBM could be tumor cells at the end of a dedifferentiation process re-acquiring stemness properties, in an opposite way to what is realized in normal cytogenesis, where stemness is lost progressively with cell differentiation. This interpretation could fit with the origin of the two GBM types, primary and secondary. In primary GBM the tumor originates directly from stem cells or progenitors from SVZ with an accelerated transformation, whereas secondary GBM originates by transformation from astrocytomas arisen through a slow transformation from migrating stem cells and progenitors.

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The authors declare no conflicts of interest.

Cite this paper

Schiffer, D. , Mellai, M. , Annovazzi, L. , Piazzi, A. , Monzeglio, O. and Caldera, V. (2012) Glioblastoma cancer stem cells: Basis for a functional hypothesis. Stem Cell Discovery, 2, 122-131. doi: 10.4236/scd.2012.23017.


[1] Ignatova, T.N., Kukekov, V.G., Laywell, E.D., Suslov, O.N., Vrionis, F.D. and Steindler, D.A. (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
[2] Galli, R., Binda, E., Orfanelli, U., Cipelletti, B., Gritti, A., De Vitis, S., Fiocco, R., Foroni, C., Dimeco, F. and Vescovi, A. (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Research, 64, 7011-7021. doi:10.1158/0008-5472.CAN-04-1364
[3] Yuan, X., Curtin, J., Xiong, Y., Liu, G., WaschsmannHogiu, S., Farkas, D.L., Black, K.L. and Yu, J.S. (2004) Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene, 23, 9392-9400. doi:10.1038/sj.onc.1208311
[4] Visvader, J.E. and Lindeman, G.J. (2008) Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nature Reviews Cancer, 8, 755-768. doi:10.1038/nrc2499
[5] Sanai, N., Alvarez-Buylla, A. and Berger, M.S. (2005) Neural stem cells and the origin of gliomas. New England Journal of Medicine, 353, 811-822. doi:10.1056/NEJMra043666
[6] Liu, Z., Hu, X., Cai, J., Liu, B., Peng, X., Wegner, M. and Qiu, M. (2007) Induction of oligodendrocyte differentiation by Olig2 and Sox10: Evidence for reciprocal interactions and dosage-dependent mechanisms. Developmental Biology, 302, 683-693. doi:10.1016/j.ydbio.2006.10.007
[7] Stiles, C.D. and Rowitch, D.F. (2008) Glioma stem cells: A midterm exam. Neuron, 58, 832-846. doi:10.1016/j.neuron.2008.05.031
[8] Vescovi, A.L., Galli, R. and Reynolds, B.A. (2006) Brain tumour stem cells. Nature Reviews Cancer, 6, 425-436. doi:10.1038/nrc1889
[9] Uchida, K., Mukai, M., Okano, H. and Kawase, T. (2004) Possible oncogenicity of subventricular zone neural stem cells: Case report. Neurosurgery, 55, 977-978. doi:10.1227/01.NEU.0000137891.99542.43
[10] Schiffer, D., Manazza, A. and Tamagno, I. (2006) Nestin expression in neuroepithelial tumors. Neuroscience Letters, 400, 80-85. doi:10.1016/j.neulet.2006.02.034
[11] Dai, C., Celestino, J.C., Okada, Y., Louis, D.N., Fuller, G.N. and Holland, E.C. (2001) PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes & Development, 15, 1913-1925. doi:10.1016/S1535-6108(02)00046-6
[12] Bachoo, R.M., Maher, E.A., Ligon, K.L., Sharpless, N.E., Chan, S.S., You, M.J., Tang, Y., DeFrances, J., Stover, E., Weissleder, R., Rowitch, D.H., Louis, D.N. and DePinho, R.A. (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
[13] Kelly, P.N., Dakic, A., Adams, J.M., Nutt, S.L. and Strasser, A. (2007) Tumor growth need not be driven by rare cancer stem cells. Science, 317, 337. doi:10.1126/science.1142596
[14] Hadjipanayis, C.G. and Van Meir, E.G. (2009) Tumor initiating cells in malignant gliomas: Biology and implications for therapy. Journal of Molecular Medicine, 87, 363-374. doi:10.1007/s00109-009-0440-9
[15] Beier, D., Hau, P., Proescholdt, M., Lohmeier, A., Wischhusen, J., Oefner, P.J., Aigner, L., Brawanski, A. and Bogdahn, U. and Beier, C.P. (2007) CD133(+) and CD133(?) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Research, 67, 4010-4015. doi:10.1158/0008-5472.CAN-06-4180
[16] Chen, R., Nishimura, M.C., Bumbaca, S.M., Kharbanda, S., Forrest, W.F., Kasman, I.M., Greve, J.M., Soriano, R.H., Gilmour, L.L., Rivers, C.S., Modrusan, Z., Nacu, S., Guerrero, S., Edgar, K.A., Wallin, J.J., Lamszus, K., Westphal, M., Heim, S., James, C.D., VandenBerg, S.R., Costello, J.F., Moorefield, S., Cowdrey, C.J., Prados, M. and Phillips, H.S. (2010) A hierarchy of selfrenewing tumor-initiating cell types in glioblastoma. Cancer Cell, 17, 362-375. doi:10.1016/j.ccr.2009.12.049
[17] McLendon, R.E. and Rich, J.N. (2011) Glioblastoma stem cells: A neuropathologist’s view. Journal of Oncology, 2011, Article ID 397195. doi:10.1155/2011/397195
[18] Veeravagu, A., Bababeygy, S.R., Kalani, M.Y., Hou, L.C. and Tse, V. (2008) The cancer stem cell-vascular niche complex in brain tumor formation. Stem Cells and Development, 17, 859-867. doi:10.1089/scd.2008.0047
[19] Mirzadeh, Z., Merkle, F.T., Soriano-Navarro, M., GarciaVerdugo, J.M. and 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
[20] Shen, Q., Wang, Y., Kokovay, E., Lin, G., Chuang, S.M., Goderie, S.K., Roysam, B. and Temple, S. (2008) Adult SVZ stem cells lie in a vascular niche: A quantitative analysis of niche cell-cell interactions. Cell Stem Cell, 3, 289-300. doi:10.1016/j.stem.2008.07.026
[21] Coskun, V., Wu, H., Blanchi, B., Tsao, S., Kim, K., Zhao, J., Biancotti, J.C., Hutnick, L., Krueger, R.C. Jr., Fan, G., de Vellis, J. and Sun, Y.E. (2008) CD133+ neural stem cells in the ependyma of mammalian postnatal forebrain. Proceedings of the National Academy of Sciences of the United States of America, 105, 1026-1031. doi:10.1073/pnas.0710000105
[22] Holland, E.C., Celestino, J., Dai, C., Schaefer, L., Sawaya, R.E. and Fuller, G.N. (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genetics, 25, 55-57. doi:10.1038/75596
[23] Holland, E.C. (2001) Gliomagenesis: Genetic alterations and mouse models. Nature Reviews Genetics, 2, 120-129. doi:10.1038/35052535
[24] Hemmati, H.D., Nakano, I., Lazareff, J.A., Masterman-Smith, M., Geschwind, D.H., Bronner-Fraser, M. and Kornblum, H.I. (2003) Cancerous stem cells can arise from pediatric brain tumors. Proceedings of the National Academy of Sciences of the United States of America, 100, 15178-15183. doi:10.1073/pnas.2036535100
[25] Piccirillo, S.G., Combi, R., Cajola, L., Patrizi, A., Redaelli, S., Bentivegna, A., Baronchelli, S., Maira, G., Pollo, B., Mangiola, A., DiMeco, F., Dalprà, L. and Vescovi, A.L. (2009) Distinct pools of cancer stem-like cells coexist within human glioblastomas and display different tumorigenicity and independent genomic evolution. Oncogene, 28, 1807-1811. doi:10.1038/onc.2009.27
[26] Singh, S.K., Hawkins, C., Clarke, I.D., Squire, J.A., Bayani, J., Hide, T., Henkelman, R.M., Cusimano, M.D. and Dirks, P.B. (2004) Identification of human brain tumour initiating cells. Nature, 18432, 396-401. doi:10.1038/nature03128
[27] Yi, L., Zhou, Z.H., Ping, Y.F., Chen, J.H., Yao, X.H., Feng, H., Lu, J.Y., Wang J.M. and Bian, X.W. (2007) Isolation and characterization of stem cell-like precursor cells from primary human anaplastic oligoastrocytoma. Modern Pathology, 20, 1061-1068. doi:10.1038/modpathol.3800942
[28] Alcantara Llaguno, S., Chen, J., Kwon, C.H., Jackson, E.L., Li, Y., Burns, D.K., Alvarez-Buylla, A. and Parada, L.F. (2009) Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell, 15, 45-56. doi:10.1016/j.ccr.2008.12.006
[29] Facchino, S., Abdouh, M. and Bernier, G. (2011) Brain cancer stem cells: Current status on glioblastoma multiforme. Cancer, 3, 1777-1797. doi:10.3390/cancers3021777
[30] Schiffer, D. (1997) Brain tumors. Biology, pathology and clinical references. Springer, Berlin, Heidelberg, New York.
[31] Schiffer, D., Cavalla, P., Dutto, A. and Borsotti, L. (1997) Cell proliferation and invasion in malignant gliomas. Anticancer Research, 17, 61-69.
[32] Schiffer, D., Annovazzi, L., Caldera, V. and Mellai M. (2010) On the origin and growth of gliomas. Anticancer Research, 30, 1977-1998.
[33] Caldera, V., Mellai, M., Annovazzi, L., Piazzi, A., Lanotte, M., Cassoni, P. and Schiffer, D. (2011) Antigenic and genotypic similarity between primary glioblastomas and their derived neurospheres. Journal of Oncology, 2011, Article ID 314962. doi:10.1155/2011/314962
[34] Günther, H.S., Schmidt, N.O., Phillips, H.S., Kemming, D., Kharbanda, S., Soriano, R., Modrusan, Z., Meissner, H., Westphal, M. and Lamszus, K. (2008) Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene, 27, 2897-2909. doi:10.1038/sj.onc.1210949
[35] Lee, J., Kotliarova, S., Kotliarov, Y., Li, A., Su, Q., Donin, N.M., Pastorino, S., Purow, B.W., Christopher, N., Zhang, W., Park, J.K. and Fine, H.A. (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closelymirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell, 9, 391-403. doi:10.1016/j.ccr.2006.03.030
[36] Campos, B. and Herold-Mende, C.C. (2011) Insight into the complex regulation of CD133 in glioma. International Journal of Cancer, 128, 501-510. doi:10.1002/ijc.25687
[37] Mazzoleni, S., Politi, L.S., Pala, M., Cominelli, M., Franzin, A., Sergi, L., Falini, A., De Palma, M., Bulfone, A., Poliani, P.L. and Galli, R. (2010) Epidermal growth factor receptor expression identifies functionally and molecularly distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis. Cancer Research, 70, 7500-7513. doi:10.1158/0008-5472.CAN-10-2353
[38] Nomura, T., Goritz, C., Catchpole, T., Henkemeyer, M. and Frisen, J. (2010) EphB signaling controls lineage plasticity of adult neural stem cell niche cells. Cell Stem Cell, 7, 730-743. doi:10.1016/j.stem.2010.11.009
[39] Son, M.J., Woolard, K., Nam, D.H., Lee, J. and Fine, H.A. (2009) SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell, 4, 440-452. doi:10.1016/j.stem.2009.03.003
[40] Cui, H., Ma, J., Ding, J., Li, T., Alam, G. and Ding, H.F. (2006) Bmi-1 regulates the differentiation and clonogenic self-renewal of I-type neuroblastoma cells in a concentration-dependent manner. The Journal of Biological Chemistry, 281, 34696-34704. doi:10.1074/jbc.M604009200
[41] Hayry, V., Tynninen, O., Haapasalo, H.K., Wolfer, J., Paulus, W., Hasselblatt, M., Sariola, H., Paetau, A., Sarna, S., Niemela, M., Wartiovaara, K. and Nupponen, N.N. (2008) Stem cell protein BMI-1 is an independent marker for poor prognosis in oligodendroglial tumours. Neuropathology and Applied Neurobiology, 34, 555-563. doi:10.1111/j.1365-2990.2008.00949.x
[42] Sanai, N., Tramontin, A.D., Qui?ones-Hinojosa, A., Barbaro, N.M., Gupta, N., Kunwar, S., Lawton, M.T., McDermott, M.W., Parsa, A.T., Manuel-García Verdugo, J., Berger, M.S. and Alvarez-Buylla, A. (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature, 427, 740-744. doi:10.1038/nature02301
[43] Eriksson, P.S., Perfilieva, E., Bj?rk-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A. and Gage, F.H. (1998) Neurogenesis in the adult human hippocampus. Nature Medicine, 4, 1313-1317. doi:10.1038/3305
[44] Nunes, M.C., Roy, N.S., Keyoung, H.M., Goodman, R.R., McKhann, G. 2nd, Jiang, L., Kang, J., Nedergaard, M. and Goldman, S.A. (2003) Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nature Medicine, 9, 439-447. doi:10.1038/nm837
[45] He, X.C., Zhang, J. and Li, L. (2005) Cellular and molecular regulation of hematopoietic and intestinal stem cell behavior. Annals of the New York Academy of Sciences, 1049, 28-38. doi:10.1196/annals.1334.005
[46] Li, L. and Neaves, W.B. (2006) Normal stem cells and cancer stem cells: The niche matters. Cancer Research, 66, 4553-4557. doi:10.1158/0008-5472.CAN-05-3986
[47] Bao, S., Wu, O., McLendon, R.E., Hao, Y., Shi, Q., Hjelmeland, A.B., Dewhirst, M.W., Bigner, D.D. and Rich J.N. (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444, 756-760. doi:10.1038/nature05236
[48] Folkins, C., Shaked, Y., Man, S., Tang, T., Lee, C.R., Zhu, Z., Hoffman, R.M. and Kerbel, R.S. (2009) Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Cancer Research, 69, 7243-7251. doi:10.1158/0008-5472.CAN-09-0167
[49] Jensen, R.L., Ragel, B.T., Whang, K. and Gillespie, D. (2006) Inhibition of hypoxia inducible factor-1alpha (HIF-1alpha) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in malignant gliomas. Journal of Neuro-Oncology, 78, 233-247. doi:10.1007/s11060-005-9103-z
[50] Bar, E.E., Lin, A., Mahairaki, V., Matsui, W. and Eberhart, C.G. (2010) Hypoxia increases the expression of stemcell markers and promotes clonogenicity in glioblastoma neurospheres. American Journal of Pathology, 177, 1491-1502. doi:10.2353/ajpath.2010.091021
[51] Kourembanas, S., Hannan, R.L. and Faller, D.V. (1990) Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. The Journal of Clinical Investigation, 86, 670-674. doi:10.1172/JCI114759
[52] Namiki, A., Brogi, E., Kearney, M., Kim, E.A., Wu, T., Couffinhal, T., Varticovski, L. and Isner, J.M. (1995) Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. The Journal of Biological Chemistry, 270, 31189-31195. doi:10.1074/jbc.270.52.31189
[53] Wang, R., Chadalavada, K., Wilshire, J., Kowalik, U., Hovinga, K.E., Geber, A., Fligelman, B., Leversha, M., Brennan, C. and Tabar, V. (2010) Glioblastoma stem-like cells give rise to tumour endothelium. Nature, 468, 829-833. doi:10.1038/nature09624
[54] Ricci-Vitiani, L., Pallini, R., Biffoni, M., Todaro, M., Invernici, G., Cenci, T., Maira, G., Parati, E.A., Stassi, G., Larocca, L.M. and De Maria, R. (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature, 468, 824-828. doi:10.1038/nature09557
[55] Aboody, K.S., Brown, A., Rainov, N.G., Bower, K.A., Liu, S., Yang, W., Small, J.E., Herrlinger, U., Ourednik, V., Black, P.M., Breakefield, X.O. and Snyder, E.Y. (2000) Neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. Proceedings of the National Academy of Sciences of the United States of America, 97, 12846-12851. doi:10.1073/pnas.97.23.12846
[56] Glass, R., Synowitz, M., Kronenberg, G., Walzlein, J.H., Markovic, D.S., Wang, L.P., Gast, D., Kiwit, J., Kempermann, G. and Kettenmann, H. (2005) Glioblastoma-induced attraction of endogeneous neural precursor cells is associated with improved survival. The Journal of Neuroscience, 25, 2637-2646. doi:10.1523/JNEUROSCI.5118-04.2005
[57] Ehtesham, M., Yuan, X., Kabos, P., Chung, N.H., Liu, G., Akasaki, Y., Black, K.L. and Yu, J.S. (2004) Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia, 6, 287-293. doi:10.1593/neo.03427
[58] Oh, M.C. and Lim, D.A. (2009) Novel treatment strategies for malignant gliomas using neural stem cells. Neurotherapeutics, 6, 458-463. doi:10.1016/j.nurt.2009.05.003
[59] Diabira, S. and Morandi, X. (2008) Gliomagenesis and neural stem cells: Key role of hypoxia and concept of tumor “neo-niche”. Medical Hypotheses, 70, 96-104. doi:10.1016/j.mehy.2007.04.024
[60] Russo, A.L., Kwon, H.C., Burgan, W.E., Carter, D., Beam, K., Weizheng, X., Zhang, J., Slusher, B.S., Chakravarti, A., Tofilon, P.J. and Camphausen, K. (2009) In vitro and in vivo radiosensitization of glioblastoma cells by the poly (ADP-ribose) polymerase inhibitor E7016. Clinical Cancer Research, 15, 607-612. doi:10.1158/1078-0432.CCR-08-2079
[61] Chalmers, A.J. (2010) Overcoming resistance of glioblastoma to conventional cytotoxic therapies by the addition of PARP inhibitors. Anticancer Agents in Medicinal Chemistry, 10, 520-533.
[62] Tamura, K., Aoyagi, M., Wakimoto, H., Ando, N., Nariai, T., Yamamoto, M. and Ohno, K. (2010) Accumulation of CD133-positive glioma cells after high-dose irradiation by Gamma Knife surgery plus external beam radiation. Journal of Neurosurgery, 113, 310-318. doi:10.3171/2010.2.JNS091607
[63] Facchino, S., Abdouh, M., Chatoo, W. and Bernier, G. (2010) BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. The Journal of Neuroscience, 30, 10096-10111. doi:10.1523/JNEUROSCI.1634-10.2010
[64] Phillips, H.S., Kharbanda, S., Chen, R., Forrest, W.F., Soriano, R.H., Wu, T.D., Misra, A., Nigro, J.M., Colman, H., Soroceanu, L., Williams, P.M., Modrusan, Z., Feuerstein, B.G. and Aldape, K. (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell, 9, 157-173. doi:10.1016/j.ccr.2006.02.019
[65] Pollard, M., Yoshikawa, K., Clarke, I.D., Danovi, D., Stricker, S., Russell, R., Bayani, J., Head, R., Lee, M., Bernstein, M., Squire, J.A., Smith, A. and Dirks, P. (2009) Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell, 4, 568-580. doi:10.1016/j.stem.2009.03.014
[66] Reynolds, B.A. and Vescovi, A.L. (2009) Brain cancer stem cells: Think twice before going flat. Cell Stem Cell, 5, 466-467. doi:10.1016/j.stem.2009.10.017
[67] Conti, L. and Cattaneo, E. (2010) Neural stem cell systems: Physiological players or in vitro entities? Nature Reviews Neuroscience, 11, 176-187. doi:10.1038/nrn2938
[68] Natsume, A., Kinjo, S., Yuki, K., Kato, T., Ohno, M., Motomura, K., Iwami, K. and Wakabayashi, T. (2011) Glioma-initiating cells and molecular pathology: Implications for therapy. Brain Tumor Pathology, 28, 1-12. doi:10.1007/s10014-010-0011-3
[69] Calabrese, C., Poppleton, H., Kocak, M., Hogg, T.L., Fuller, C., Hamner, B., Oh, E.Y., Gaber, M.W., Finklestein, D., Allen, M., Frank, A., Bayazitov, I.T., Zakharenko, S.S., Gajjar, A., Davidoff, A. and Gilbertson, R.J. (2007) A perivascular niche for brain tumor stem cells. Cancer Cell, 11, 69-82. doi:10.1016/j.ccr.2006.11.020
[70] Kaur, B., Khwaja, F.W., Severson, E.A., Matheny, S.L., Brat, D.J. and Van Meir, E.G. (2005) Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro-Oncology, 7, 134-153. doi:10.1215/S1152851704001115
[71] Keith, B. and Simon, M.C. (2007) Hypoxia-inducible factors, stem cells, and cancer. Cell, 129, 465-472. doi:10.1016/j.cell.2007.04.019
[72] Zipori, D. (2004) The nature of stem cells: State rather than entity. Nature Reviews Genetics, 5, 873-878. doi:10.1038/nrg1475
[73] Persano, L., Rampazzo, E., Della Puppa, A., Pistollato, F. and Basso, G. (2011) The three-layer concentric model of glioblastoma: Cancer stem cells, microenvironmental regulation, and therapeutic implications. Scientific World Journal, 11, 1829-1841. doi:10.1100/2011/736480
[74] Felsher, D.W. (2008) Oncogene addiction versus oncogene amnesia: Perhaps more than just a bad habit? Cancer Research, 68, 3081-3086. doi:10.1158/0008-5472.CAN-07-5832
[75] Sharma, S.V. and Settleman, J. (2010) Exploiting the balance between life and death: Targeted cancer therapy and “oncogenic shock”. Biochemical Pharmacology, 80, 666-673. doi:10.1016/j.bcp.2010.03.001
[76] Kanamori, M., Kawaguchi, T., Nigro, J.M., Feuerstein, B.G., Berger, M.S., Miele, L. and Pieper, R.O. (2007) Contribution of Notch signaling activation to human glioblastoma multiforme. Journal of Neurosurgery, 106, 417-427. doi:10.3171/jns.2007.106.3.417
[77] Annovazzi, L., Mellai, M., Caldera, V., Valente, G. and Schiffer, D. (2011) SOX2 expression and amplification in gliomas and glioma cell lines. Cancer Genomics and Proteomics, 8, 139-147.
[78] Sherry, M.M., Reeves, A., Wu, J.K. and Cochran, B.H. (2009) STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells, 27, 2383-2392. doi:10.1002/stem.185
[79] Kim, J., Woo, A.J., Chu, J., Snow, J.W., Fujiwara, Y., Kim, C.G., Cantor, A.B. and Orkin, S.H. (2010) A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell, 143, 313-324. doi:10.1016/j.cell.2010.09.010
[80] Kleihues, P. and Ohgaki, H. (1999) Primary and seconddary glioblastomas: From concept to clinical diagnosis. Neuro Oncology, 1, 44-51.
[81] Louis, D.N., Ohgaki, H., Wiestler, O.D. and Cavenee, W.K. (2007) WHO classification of tumors of the central nervous system, 4th Edition, IARC, Lyon.
[82] Berger, F., Gay, E., Pelletier, L., Tropel, P. and Wion, D. (2004) Development of gliomas: Potential role of asymmetrical cell division of neural stem cells. The Lancet Oncology, 5, 511-514. doi:10.1016/S1470-2045(04)01531-1
[83] Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J.M. and Alvarez-Buylla, A. (2002) EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron, 36, 1021-1034. doi:10.1016/S0896-6273(02)01133-9
[84] Balss, J., Meyer, J., Mueller, W., Korshunov, A., Hartmann, C. and von Deimling, A. (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathologica, 116, 597-602. doi:10.1007/s00401-008-0455-2
[85] Hartmann, C., Meyer, J., Balss, J., Capper, D., Mueller, W., Christians, A., Felsberg, J., Wolter, M., Mawrin, C., Wick, W., Weller, M., Herold-Mende, C., Unterberg, A., Jeuken, J.W., Wesseling, P., Reifenberger, G. and von Deimling, A. (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: A study of 1010 diffuse gliomas. Acta Neuropathologica, 118, 469-474. doi:10.1007/s00401-009-0561-9
[86] Sanson, M., Marie, Y., Paris, S., Idbaih, A., Laffaire, J., Ducray, F., El Hallani, S., Boisselier, B., Mokhtari, K., Hoang-Xuan, K. and Delattre J.Y. (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. Journal of Clinical Oncology, 27, 4150-4154. doi:10.1200/JCO.2009.21.9832
[87] Yan, H., Parsons, D.W., Jin, G., McLendon, R., Rasheed, B.A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G.J., Friedman, H., Friedman, A., Reardon, D., Herndon, J., Kinzler, K.W., Velculescu, V.E., Vogelstein, B. and Bigner, D.D. (2009) IDH1 and IDH2 mutations in gliomas. The New England Journal of Medicine, 360, 765-773. doi:10.1056/NEJMoa0808710
[88] Van den Bent, M.J., Dubbink, H.J., Marie, Y., Brandes, A.A., Taphoorn, M.J., Wesseling, P., Frenay, M., Tijssen, C.C., Lacombe, D., Idbaih, A., van Marion, R., Kros, J.M., Dinjens, W.N., Gorlia, T. and Sanson, M. (2010) IDH1 and IDH2 mutations are prognostic but not predicttive for outcome in anaplastic oligodendroglial tumors: A report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clinical Cancer Research, 16, 1597-1604. doi:10.1158/1078-0432.CCR-09-2902
[89] Labussiere, M., Sanson, M., Idbaih, A. and Delattre, J.Y. (2010) IDH1 gene mutations: A new paradigm in glioma prognosis and therapy? Oncologist, 15, 196-199. doi:10.1634/theoncologist.2009-0218
[90] Mellai, M., Piazzi, A., Caldera, V., Monzeglio, O., Cassoni, P., Valente, G. and Schiffer, D. (2011) IDH1 and IDH2 mutations, immunohistochemistry and associations in a series of brain tumors. Journal of Neuro-Oncology, 105, 345-357. doi:10.1007/s11060-011-0596-3
[91] Cairncross, J.G. (1987) The biology of astrocytoma: Lessons learned from chronic myelogenous leukemia: Hypothesis. Journal of Neuro-Oncology, 5, 99-104. doi:10.1007/BF02571297
[92] Vineis, P. (2006) Misuse of genetic data in environmental epidemiology. Annals of the New York Academy of Sciences, 1076, 163-167. doi:10.1196/annals.1371.060

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