Asymmetric cell division: Implications for glioma development and treatment

[1] Ashkenazi R., Gentry S.N., Jackson T.L., Pathways to tumorigenesis — modeling mutation acquisition in stem cells and their progeny, Neoplasia, 2008, 10, 1170–1182 10.1593/neo.08572Search in Google Scholar PubMed PubMed Central

[2] Gomez-Lopez S., Lerner R.G., Petritsch C., Asymmetric cell division of stem and progenitor cells during homeostasis and cancer, Cell. Mol. Life Sci., 2013, [Epub ahead of print], doi: 10.1007/s00018-013-1386-1 10.1007/s00018-013-1386-1Search in Google Scholar PubMed PubMed Central

[3] Gotz M., Huttner W.B., The cell biology of neurogenesis, Nat. Rev. Mol. Cell Biol., 2005, 6, 777–788 10.1038/nrm1739Search in Google Scholar PubMed

[4] Egger B., Gold K.S., Brand A.H., Notch regulates the switch from symmetric to asymmetric neural stem cell division in the Drosophila optic lobe, Development, 2010, 137, 2981–2987 10.1242/dev.051250Search in Google Scholar PubMed PubMed Central

[5] Gotz M., Barde Y.A., Radial glial cells defined and major intermediates between embryonic stem cells and CNS neurons, Neuron, 2005, 46, 369–372 10.1016/j.neuron.2005.04.012Search in Google Scholar PubMed

[6] Suter D.M., Tirefort D., Julien S., Krause K.H., A Sox1 to Pax6 switch drives neuroectoderm to radial glia progression during differentiation of mouse embryonic stem cells, Stem Cells, 2009, 27, 49–58 10.1634/stemcells.2008-0319Search in Google Scholar PubMed

[7] Haubensak W., Attardo A., Denk W., Huttner W.B., Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: a major site of neurogenesis, Proc. Natl. Acad. Sci. USA, 2004, 101, 3196–3201 10.1073/pnas.0308600100Search in Google Scholar PubMed PubMed Central

[8] Noctor S.C., Martinez-Cerdeno V., Ivic L., Kriegstein A.R., Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases, Nat. Neurosci., 2004, 7, 136–144 10.1038/nn1172Search in Google Scholar PubMed

[9] Attardo A., Calegari F., Haubensak W., Wilsch-Bräuninger M., Huttner W.B., Live imaging at the onset of cortical neurogenesis reveals differential appearance of the neuronal phenotype in apical versus basal progenitor progeny, PLoS One, 2008, 3, e2388 10.1371/journal.pone.0002388Search in Google Scholar PubMed PubMed Central

[10] Stelzer S., Worlitzer M.M., Bahnassawy L., Hemmer K., Rugani K., Werthschulte I., et al., JAM-C is an apical surface marker for neural stem cells, Stem Cells Dev., 2012, 21, 757–766 10.1089/scd.2011.0274Search in Google Scholar PubMed

[11] Rasin M.R., Gazula V.R., Breunig J.J., Kwan K.Y., Johnson M.B., Liu-Chen S., et al., Numb and Numbl are required for maintenance of cadherinbased adhesion and polarity of neural progenitors, Nat. Neurosci., 2007, 10, 819–827 10.1038/nn1924Search in Google Scholar PubMed

[12] Dave R.K., Ellis T., Toumpas M.C., Robson J.P., Julian E., Adolphe C., et al., Sonic hedgehog and notch signaling can cooperate to regulate neurogenic divisions of neocortical progenitors, PLoS One, 2011, 6, e14680 10.1371/journal.pone.0014680Search in Google Scholar PubMed PubMed Central

[13] Miyata T., Kawaguchi D., Kawaguchi A., Gotoh Y., Mechanisms that regulate the number of neurons during mouse neocortical development, Curr. Opin. Neurobiol., 2010, 20, 22–28 10.1016/j.conb.2010.01.001Search in Google Scholar PubMed

[14] Glickstein S.B., Monaghan J.A., Koeller H.B., Jones T.K., Ross M.E., Cyclin D2 is critical for intermediate progenitor cell proliferation in the embryonic cortex, J. Neurosci., 2009, 29, 9614–9624 10.1523/JNEUROSCI.2284-09.2009Search in Google Scholar PubMed PubMed Central

[15] Englund C., Fink A., Lau C., Pham D., Daza R.A., Bulfone A., et al., Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex, J. Neurosci., 2005, 25, 247–251 10.1523/JNEUROSCI.2899-04.2005Search in Google Scholar PubMed PubMed Central

[16] LaMonica B.E., Lui J.H., Hansen D.V., Kriegstein A.R., Mitotic spindle orientation predicts outer radial glial cell generation in human neocortex, Nat. Commun., 2013, 4, 1665 10.1038/ncomms2647Search in Google Scholar PubMed PubMed Central

[17] Wang X., Tsai J.W., LaMonica B., Kriegstein A.R., A new subtype of progenitor cell in the mouse embryonic neocortex, Nat. Neurosci., 2011, 14, 555–561 10.1038/nn.2807Search in Google Scholar PubMed PubMed Central

[18] Pilz G.A., Shitamukai A., Reillo I., Pacary E., Schwausch J., Stahl R., et al., Amplification of progenitors in the mammalian telencephalon includes a new radial glial cell type, Nat. Commun., 2013, 4, 2125 10.1038/ncomms3125Search in Google Scholar PubMed PubMed Central

[19] Hansen D.V., Lui J.H., Parker P.R., Kriegstein A.R., Neurogenic radial glia in the outer subventricular zone of human neocortex, Nature, 2010, 464, 554–561 10.1038/nature08845Search in Google Scholar PubMed

[20] Fietz S.A., Kelava I., Vogt J., Wilsch-Bräuninger M., Stenzel D., Fish J.L., et al., OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling, Nature Neurosci., 2010, 13, 690–699 10.1038/nn.2553Search in Google Scholar PubMed

[21] Lui J.H., Hansen D.V., Kriegstein A.R., Development and evolution of the human neocortex, Cell, 2011, 146, 18–36 10.1016/j.cell.2011.06.030Search in Google Scholar

[22] Alvarez-Buylla A., Garcia-Verdugo J.M., Neurogenesis in adult subventricular zone, J. Neurosci., 2002, 22, 629–634 10.1523/JNEUROSCI.22-03-00629.2002Search in Google Scholar

[23] Alvarez-Buylla A., Mechanism of neurogenesis in adult avian brain, Experientia, 1990, 46, 948–955 10.1007/BF01939388Search in Google Scholar

[24] 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, 2004, 101, 17528–17532 10.1073/pnas.0407893101Search in Google Scholar

[25] Hansen D.V., Lui J.H., Flandin P., Yoshikawa K., Rubenstein J.L., Alvarez-Buylla A., et al., Non-epithelial stem cells and cortical interneuron production in the human ganglionic eminences, Nat. Neurosci., 2013, 16, 1576–1587 10.1038/nn.3541Search in Google Scholar

[26] Qian X., Shen Q., Goderie S.K., He W., Capela A., Davis A.A., et al., Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells, Neuron, 2000, 28, 69–80 10.1016/S0896-6273(00)00086-6Search in Google Scholar

[27] Li X., Newbern J.M., Wu Y., Morgan-Smith M., Zhong J., Charron J., et al., MEK is a key regulator of gliogenesis in the developing brain, Neuron, 2012, 75, 1035–1050 10.1016/j.neuron.2012.08.031Search in Google Scholar PubMed PubMed Central

[28] Hu X., Jin L., Feng L., Erk1/2 but not PI3K pathway is required for neurotrophin 3-induced oligodendrocyte differentiation of postnatal neural stem cells, J. Neurochem., 2004, 90, 1339–1347 10.1111/j.1471-4159.2004.02594.xSearch in Google Scholar PubMed

[29] Rodriguez-Martinez G., Molina-Hernandez A., Velasco I., Activin A promotes neuronal differentiation of cerebrocortical neural progenitor cells, PLoS One, 2012, 7, e43797 10.1371/journal.pone.0043797Search in Google Scholar PubMed PubMed Central

[30] Boku S., Nakagawa S., Takamura N., Kato A., Takebayashi M., Hisaoka-Nakashima K., et al., GDNF facilitates differentiation of the adult dentate gyrus-derived neural precursor cells into astrocytes via STAT3, Biochem. Biophys. Res. Comm., 2013, 434, 779–784 10.1016/j.bbrc.2013.04.011Search in Google Scholar PubMed

[31] Zhou Z.D., Kumari U., Xiao Z.C., Tan E.K., Notch as a molecular switch in neural stem cells, IUBMB Life, 2010, 62, 618–623 10.1002/iub.362Search in Google Scholar

[32] Namihira M., Kohyama J., Semi K., Sanosaka T., Deneen B., Taga T., et al., Committed neuronal precursors confer astrocytic potential on residual neural precursor cells, Dev. Cell, 2009, 16, 245–255 10.1016/j.devcel.2008.12.014Search in Google Scholar

[33] Ravin R., Hoeppner D.J., Munno D.M., Carmel L., Sullivan J., Levitt D.L., et al., Potency and fate specification in CNS stem cell populations in vitro, Cell Stem Cell, 2008, 3, 670–680 10.1016/j.stem.2008.09.012Search in Google Scholar

[34] Wang D.D., Bordey A., The astrocyte odyssey, Prog. Neurobiol., 2008, 86, 342–367 10.1016/j.pneurobio.2008.09.015Search in Google Scholar

[35] Liu Y., Han S.S., Wu Y., Tuohy T.M., Xue H., Cai J., et al., CD44 expression identifies astrocyte-restricted precursor cells, Dev. Biol., 2004, 276, 31–46 10.1016/j.ydbio.2004.08.018Search in Google Scholar

[36] Ge W.P., Miyawaki A., Gage F.H., Jan Y.N., Jan L.Y., Local generation of glia is a major astrocyte source in postnatal cortex, Nature, 2012, 484, 376–380 10.1038/nature10959Search in Google Scholar

[37] Strathmann F.G., Wang X., Mayer-Proschel M., Identification of two novel glial-restricted cell populations in the embryonic telencephalon arising from unique origins, BMC Dev. Biol., 2007, 7, 33 10.1186/1471-213X-7-33Search in Google Scholar

[38] Dawson M.R., Polito A., Levine J.M., Reynolds R., NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS, Mol. Cell. Neurosci., 2003, 24, 476–488 10.1016/S1044-7431(03)00210-0Search in Google Scholar

[39] Gregori N., Proschel C., Noble M., Mayer-Proschel M., The tripotential glial-restricted precursor (GRP) cell and glial development in the spinal cord: generation of bipotential oligodendrocyte-type-2 astrocyte progenitor cells and dorsal-ventral differences in GRP cell function, J. Neurosci., 2002, 22, 248–256 10.1523/JNEUROSCI.22-01-00248.2002Search in Google Scholar

[40] Ortega F., Gascon S., Masserdotti G., Deshpande A., Simon C., Fischer J., et al., Oligodendrogliogenic and neurogenic adult subependymal zone neural stem cells constitute distinct lineages and exhibit differential responsiveness to Wnt signalling, Nat. Cell Biol., 2013, 15, 602–613 10.1038/ncb2736Search in Google Scholar PubMed

[41] Yakovlev A.Y., Boucher K., Mayer-Proschel M., Noble M., Quantitative insight into proliferation and differentiation of oligodendrocyte type 2 astrocyte progenitor cells in vitro, Proc. Natl. Acad. Sci. USA, 1998, 95, 14164–14167 10.1073/pnas.95.24.14164Search in Google Scholar PubMed PubMed Central

[42] Klempin F., Marr R.A., Peterson D.A., Modification of pax6 and olig2 expression in adult hippocampal neurogenesis selectively induces stem cell fate and alters both neuronal and glial populations, Stem Cells, 2012, 30, 500–509 10.1002/stem.1005Search in Google Scholar PubMed PubMed Central

[43] Zhu X., Hill R.A., Dietrich D., Komitova M., Suzuki R., Nishiyama A., Age-dependent fate and lineage restriction of single NG2 cells, Development, 2011, 38, 745–753 10.1242/dev.047951Search in Google Scholar PubMed PubMed Central

[44] Sugiarto S., Persson A.I., Munoz E.G., Waldhuber M., Lamagna C., Andor N., et al., Asymmetry-defective oligodendrocyte progenitors are glioma precursors, Cancer Cell, 2011, 20, 328–340 10.1016/j.ccr.2011.08.011Search in Google Scholar PubMed PubMed Central

[45] Sjoblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., et al., The consensus coding sequences of human breast and colorectal cancers, Science, 2006, 314, 268–274 10.1126/science.1133427Search in Google Scholar PubMed

[46] Knudson A.G., Two genetic hits (more or less) to cancer, Nat. Rev. Cancer, 2001, 1, 157–162 10.1038/35101031Search in Google Scholar PubMed

[47] Chang K.C., Wang C., Wang H., Balancing self-renewal and differentiation by asymmetric division: insights from brain tumor suppressors in Drosophila neural stem cells, BioEssays, 2012, 34, 301–310 10.1002/bies.201100090Search in Google Scholar PubMed

[48] Saini N., Reichert H., Neural stem cells in Drosophila: molecular genetic mechanisms underlying normal neural proliferation and abnormal brain tumor formation, Stem Cells Int., 2012, 486169 10.1155/2012/486169Search in Google Scholar PubMed PubMed Central

[49] Albertson R., Doe C.Q., Dlg, Scrib and Lgl regulate neuroblast cell size and mitotic spindle asymmetry, Nat. Cell Biol., 2003, 5, 166–170 10.1038/ncb922Search in Google Scholar PubMed

[50] Wang C., Li S., Januschke J., Rossi F., Izumi Y., Garcia-Alvarez G., et al., An ana2/ctp/mud complex regulates spindle orientation in Drosophila neuroblasts, Dev. Cell, 2011, 21, 520–533 10.1016/j.devcel.2011.08.002Search in Google Scholar PubMed

[51] Speicher S., Fischer A., Knoblich J., Carmena A., The PDZ protein Canoe regulates the asymmetric division of Drosophila neuroblasts and muscle progenitors, Curr. Biol., 2008, 18, 831–837 10.1016/j.cub.2008.04.072Search in Google Scholar

[52] Atwood S.X., Chabu C., Penkert R.R., Doe C.Q., Prehoda K.E., Cdc42 acts downstream of Bazooka to regulate neuroblast polarity through Par-6 aPKC, J. Cell Sci., 2007, 120, 3200–3206 10.1242/jcs.014902Search in Google Scholar

[53] Bowman S.K., Neumuller R.A., Novatchkova M., Du Q., Knoblich J.A., The Drosophila NuMA Homolog Mud regulates spindle orientation in asymmetric cell division, Dev. Cell, 2006, 10, 731–742 10.1016/j.devcel.2006.05.005Search in Google Scholar

[54] Schaefer M., Petronczki M., Dorner D., Forte M., Knoblich J.A., Heterotrimeric G proteins direct two modes of asymmetric cell division in the Drosophila nervous system, Cell, 2001, 107, 183–194 10.1016/S0092-8674(01)00521-9Search in Google Scholar

[55] Lee C.Y., Robinson K.J., Doe C.Q., Lgl, Pins and aPKC regulate neuroblast self-renewal versus differentiation, Nature, 2006, 439, 594–598 10.1038/nature04299Search in Google Scholar

[56] Wang C., Chang K.C., Somers G., Virshup D., Ang B.T., Tang C., et al., Protein phosphatase 2A regulates self-renewal of Drosophila neural stem cells, Development, 2009, 136, 2287–2296 10.1242/dev.035758Search in Google Scholar

[57] Petritsch C., Tavosanis G., Turck C.W., Jan L.Y., Jan Y.N., The Drosophila myosin VI Jaguar is required for basal protein targeting and correct spindle orientation in mitotic neuroblasts, Dev. Cell, 2003, 4, 273–281 10.1016/S1534-5807(03)00020-0Search in Google Scholar

[58] Shen C.P., Jan L.Y., Jan Y.N., Miranda is required for the asymmetric localization of Prospero during mitosis in Drosophila, Cell, 1997, 90, 449–458 10.1016/S0092-8674(00)80505-XSearch in Google Scholar

[59] Smith C.A., Lau K.M., Rahmani Z., Dho S.E., Brothers G., She Y.M., et al., aPKC-mediated phosphorylation regulates asymmetric membrane localization of the cell fate determinant Numb, EMBO J., 2007, 26, 468–480 10.1038/sj.emboj.7601495Search in Google Scholar

[60] Zhong W., Feder J.N., Jiang M.M., Jan L.Y., Jan Y.N., Asymmetric localization of a mammalian numb homolog during mouse cortical neurogenesis, Neuron, 1996, 17, 43–53 10.1016/S0896-6273(00)80279-2Search in Google Scholar

[61] Schwamborn J.C., Berezikov E., Knoblich J.A., The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors, Cell, 2009, 136, 913–925 10.1016/j.cell.2008.12.024Search in Google Scholar

[62] Tsunekawa Y., Britto J.M., Takahashi M., Polleux F., Tan S.S., Osumi N., Cyclin D2 in the basal process of neural progenitors is linked to nonequivalent cell fates, EMBO J., 2012, 31, 1879–1892 10.1038/emboj.2012.43Search in Google Scholar

[63] Shen Q., Zhong W., Jan Y.N., Temple S., Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts, Development, 2002, 129, 4843–4853 10.1242/dev.129.20.4843Search in Google Scholar

[64] Andreu-Agullo C., Morante-Redolat J.M., Delgado A.C., Farinas I., Vascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone, Nat. Neuroscience, 2009, 12, 1514–1523 10.1038/nn.2437Search in Google Scholar

[65] Sun Y., Goderie S.K., Temple S., Asymmetric distribution of EGFR receptor during mitosis generates diverse CNS progenitor cells, Neuron, 2005, 45, 873–886 10.1016/j.neuron.2005.01.045Search in Google Scholar

[66] Ferron S.R., Pozo N., Laguna A., Aranda S., Porlan E., Moreno M., et al., Regulated segregation of kinase Dyrk1A during asymmetric neural stem cell division is critical for EGFR-mediated biased signaling, Cell Stem Cell, 2010, 7, 367–379 10.1016/j.stem.2010.06.021Search in Google Scholar

[67] Kusek G., Campbell M., Doyle F., Tenenbaum S.A., Kiebler M., Temple S., Asymmetric segregation of the double-stranded RNA binding protein Staufen2 during mammalian neural stem cell divisions promotes lineage progression, Cell Stem Cell, 2012, 11, 505–516 10.1016/j.stem.2012.06.006Search in Google Scholar

[68] Bultje R.S., Castaneda-Castellanos D.R., Jan L.Y., Jan Y.N., Kriegstein A.R., Shi S.H., Mammalian Par3 regulates progenitor cell asymmetric division via notch signaling in the developing neocortex, Neuron, 2009, 63, 189–202 10.1016/j.neuron.2009.07.004Search in Google Scholar

[69] Nakamura M., Okano H., Blendy J.A., Montell C., Musashi, a neural RNA-binding protein required for Drosophila adult external sensory organ development, Neuron, 1994, 13, 67–81 10.1016/0896-6273(94)90460-XSearch in Google Scholar

[70] Okano H., Kawahara H., Toriya M., Nakao K., Shibata S., Imai T., Function of RNA-binding protein Musashi-1 in stem cells, Exp. Cell Res., 2005, 306, 349–356 10.1016/j.yexcr.2005.02.021Search in Google Scholar PubMed

[71] Sakakibara S., Nakamura Y., Yoshida T., Shibata S., Koike M., Takano H., et al., RNA-binding protein Musashi family: roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation, Proc. Natl. Acad. Sci. USA, 2002, 99, 15194–15199 10.1073/pnas.232087499Search in Google Scholar PubMed PubMed Central

[72] Fish J.L., Kosodo Y., Enard W., Paabo S., Huttner W.B., Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells, Proc. Natl. Acad. Sci. USA, 2006, 103, 10438–10443 10.1073/pnas.0604066103Search in Google Scholar PubMed PubMed Central

[73] Khan M.A., Godil S.S., Tabani H., Panju S.A., Enam S.A., Clinical review of pediatric pilocytic astrocytomas treated at a tertiary care hospital in Pakistan, Surg. Neurol. Int., 2012, 3, 90 10.4103/2152-7806.99936Search in Google Scholar PubMed PubMed Central

[74] Katchy K.C., Alexander S., Al-Nashmi N.M., Al-Ramadan A., Epidemiology of primary brain tumors in childhood and adolescence in Kuwait, Springerplus, 2013, 2, 58 10.1186/2193-1801-2-58Search in Google Scholar PubMed PubMed Central

[75] Rosychuk R.J., Witol A., Wilson B., Stobart K., Central nervous system (CNS) tumor trends in children in a western Canadian province: a population-based 22-year retrospective study, J. Neurol., 2012, 259, 1131–1136 10.1007/s00415-011-6314-4Search in Google Scholar PubMed

[76] Ramanan M., Chaseling R., Paediatric brain tumours treated at a single, tertiary paediatric neurosurgical referral centre from 1999 to 2010 in Australia, J. Clin. Neurosci., 2012, 19, 1387–1391 10.1016/j.jocn.2012.01.028Search in Google Scholar PubMed

[77] Pinho R.S., Andreoni S., Silva N.S., Cappellano A.M., Masruha M.R., Cavalheiro S., et al., Pediatric central nervous system tumors: a single-center experience from 1989 to 2009, J. Pediatr. Hematol. Oncol., 2011, 33, 605–609 10.1097/MPH.0b013e31822031d9Search in Google Scholar PubMed

[78] Yamaguchi S., Kobayashi H., Terasaka S., Ishii N., Ikeda J., Kanno H., et al., The impact of extent of resection and histological subtype on the outcome of adult patients with high-grade gliomas, Jpn. J. Clin. Oncol., 2012, 42, 270–277 10.1093/jjco/hys016Search in Google Scholar PubMed

[79] Bianco Ade M., Miura F.K., Clara C., Almeida J.R., Silva C.C., Teixeira M.J., et al., Low-grade astrocytoma: surgical outcomes in eloquent versus non-eloquent brain areas, Arq. Neuro-psiquiatr., 2013, 71, 31–34 10.1590/S0004-282X2012005000017Search in Google Scholar PubMed

[80] Nuno M., Birch K., Mukherjee D., Sarmiento J.M., Black K.L., Patil C.G., Survival and prognostic factors of anaplastic gliomas, Neurosurgery, 2013, 73, 458–465 10.1227/01.neu.0000431477.02408.5eSearch in Google Scholar PubMed

[81] Johnson D.R., Leeper H.E., Uhm J.H., Glioblastoma survival in the United States improved after Food and Drug Administration approval of bevacizumab: a population-based analysis, Cancer, 2013, 119, 3489–3495 10.1002/cncr.28259Search in Google Scholar

[82] Jeswani S., Nuño M., Folkerts V., Mukherjee D., Black K.L., Patil C.G., Comparison of survival between cerebellar and supratentorial glioblastoma patients: surveillance, epidemiology, and end results (SEER) analysis, Neurosurgery, 2013, 73, 240–246 10.1227/01.neu.0000430288.85680.37Search in Google Scholar

[83] Verhaak R.G., Hoadley K.A., Purdom E., Wang V., Qi Y., Wilkerson M.D., et al., Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1, Cancer Cell, 2010, 17, 98–110 10.1016/j.ccr.2009.12.020Search in Google Scholar

[84] Stupp R., Hegi M.E., Mason W.P., van den Bent M.J., Taphoorn M.J., Janzer R.C., et al., Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial, Lancet Oncol., 2009, 10, 459–466 10.1016/S1470-2045(09)70025-7Search in Google Scholar

[85] Galldiks N., Rapp M., Stoffels G., Fink G.R., Shah N.J., Coenen H.H., et al., Response assessment of bevacizumab in patients with recurrent malignant glioma using [18F]Fluoroethyl-L-tyrosine PET in comparison to MRI, Eur. J. Nucl. Med. Mol. Imaging, 2013, 40, 22–33 10.1007/s00259-012-2251-4Search in Google Scholar PubMed

[86] Piao Y., Liang J., Holmes L., Henry V., Sulman E., de Groot J.F., Acquired resistance to anti-VEGF therapy in glioblastoma is associated with a mesenchymal transition, Clin. Cancer Res., 2013, 19, 4392–4403 10.1158/1078-0432.CCR-12-1557Search in Google Scholar PubMed

[87] Hanahan D., Weinberg R.A., Hallmarks of cancer: the next generation, Cell, 2011, 144, 646–674 10.1016/j.cell.2011.02.013Search in Google Scholar PubMed

[88] Lewis K.M., Harford-Wright E., Vink R., Nimmo A.J., Ghabriel M.N., Walker 256 tumour cells increase substance P immunoreactivity locally and modify the properties of the blood-brain barrier during extravasation and brain invasion, Clin. Exp. Metastasis, 2013, 30, 1–12 10.1007/s10585-012-9487-zSearch in Google Scholar PubMed

[89] Harford-Wright E., Lewis K.M., Vink R., The potential for substance P antagonists as anti-cancer agents in brain tumours, Recent Pat. CNS Drug Discov., 2013, 8, 13–23 10.2174/1574889811308010003Search in Google Scholar PubMed

[90] Lewis K.M., Harford-Wright E., Vink R., Ghabriel M.N., Targeting classical but not neurogenic inflammation reduces peritumoral oedema in secondary brain tumours, J. Neuroimmunol., 2012, 250, 59–65 10.1016/j.jneuroim.2012.06.001Search in Google Scholar PubMed

[91] Castillo M., Stem cells, radial glial cells, and a unified origin of brain tumors, AJNR Am. J. Neuroradiol., 2010, 31, 389–390 10.3174/ajnr.A1674Search in Google Scholar PubMed PubMed Central

[92] Scopelliti A., Cammareri P., Catalano V., Saladino V., Todaro M., Stassi G., Therapeutic implications of cancer initiating cells, Expert Opin. Biol. Ther., 2009, 9, 1005–1016 10.1517/14712590903066687Search in Google Scholar

[93] Pei Y., Wechsler-Reya R.J., A malignant oligarchy: progenitors govern the behavior of oligodendrogliomas, Cancer Cell, 2010, 18, 546–547 10.1016/j.ccr.2010.11.031Search in Google Scholar

[94] Liu C., Zong H., Developmental origins of brain tumors, Curr. Opin. Neurobiol., 2012, 22, 844–849 10.1016/j.conb.2012.04.012Search in Google Scholar

[95] Liu C., Sage J.C., Miller M.R., Verhaak R.G., Hippenmeyer S., Vogel H., et al., Mosaic analysis with double markers reveals tumor cell of origin in glioma, Cell, 2011, 146, 209–221 10.1016/j.cell.2011.06.014Search in Google Scholar

[96] Durand B., Gao F.B., Raff M., Accumulation of the cyclin-dependent kinase inhibitor p27/Kip1 and the timing of oligodendrocyte differentiation, EMBO J., 1997, 16, 306–317 10.1093/emboj/16.2.306Search in Google Scholar

[97] Ponti G., Obernier K., Guinto C., Jose L., Bonfanti L., Alvarez-Buylla A., Cell cycle and lineage progression of neural progenitors in the ventricular-subventricular zones of adult mice, Proc. Natl. Acad. Sci. USA, 2013, 110, E1045–E1054 10.1073/pnas.1219563110Search in Google Scholar

[98] Seaberg R.M., van der Kooy D., Stem and progenitor cells: the premature desertion of rigorous definitions, Trends Neurosci., 2003, 26, 125–131 10.1016/S0166-2236(03)00031-6Search in Google Scholar

[99] Muñoz D.M., Singh S., Tung T., Agnihotri S., Nagy A., Guha A., et al., Differential transformation capacity of neuro-glial progenitors during development, Proc. Natl. Acad. Sci. USA, 2013, 110, 14378–14383 10.1073/pnas.1303504110Search in Google Scholar PubMed PubMed Central

[100] Poppleton H., Gilbertson R.J., Stem cells of ependymoma, Brit. J. Cancer, 2007, 96, 6–10 10.1038/sj.bjc.6603519Search in Google Scholar PubMed PubMed Central

[101] Seaberg R.M., Smukler S.R., van der Kooy D., Intrinsic differences distinguish transiently neurogenic progenitors from neural stem cells in the early postnatal brain, Dev. Biol., 2005, 278, 71–85 10.1016/j.ydbio.2004.10.017Search in Google Scholar PubMed

[102] Lee da Y., Gianino S.M., Gutmann D.H., Innate neural stem cell heterogeneity determines the patterning of glioma formation in children, Cancer Cell, 2012, 22, 131–138 10.1016/j.ccr.2012.05.036Search in Google Scholar

[103] Caussinus E., Gonzalez C., Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster, Nat. Genet., 2005, 37, 1125–1129 10.1038/ng1632Search in Google Scholar

[104] Radke J., Bortolussi G., Pagenstecher A., Akt and c-Myc induce stemcell markers in mature primary p53(-)/(-) astrocytes and render these cells gliomagenic in the brain of immunocompetent mice, PLoS One, 2013, 8, e56691 10.1371/journal.pone.0056691Search in Google Scholar

[105] Friedmann-Morvinski D., Bushong E.A., Ke E., Soda Y., Marumoto T., Singer O., et al., Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice, Science, 2012, 338, 1080–1084 10.1126/science.1226929Search in Google Scholar

[106] Alcantara Llaguno S., Chen J., Kwon C.H., Jackson E.L., Li Y., Burns D.K., et al., Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model, Cancer Cell, 2009, 15, 45–56 10.1016/j.ccr.2008.12.006Search in Google Scholar

[107] Lei L., Sonabend A.M., Guarnieri P., Soderquist C., Ludwig T., Rosenfeld S., et al., Glioblastoma models reveal the connection between adult glial progenitors and the proneural phenotype, PLoS One, 2011, 6, e20041 10.1371/journal.pone.0020041Search in Google Scholar

[108] Hide T., Takezaki T., Nakatani Y., Nakamura H., Kuratsu J., Kondo T., Combination of a ptgs2 inhibitor and an epidermal growth factor receptor-signaling inhibitor prevents tumorigenesis of oligodendrocyte lineage-derived glioma-initiating cells, Stem Cells, 2011, 29, 590–599 10.1002/stem.618Search in Google Scholar

[109] Bachoo R.M., Maher E.A., Ligon K.L., Sharpless N.E., Chan S.S., You M.J., 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, 2002, 1, 269–277 10.1016/S1535-6108(02)00046-6Search in Google Scholar

[110] Chow L.M., Endersby R., Zhu X., Rankin S., Qu C., Zhang J., et al., Cooperativity within and among Pten, p53, and Rb pathways induces high-grade astrocytoma in adult brain, Cancer Cell, 2011, 19, 305–316 10.1016/j.ccr.2011.01.039Search in Google Scholar PubMed PubMed Central

[111] Ding H., Shannon P., Lau N., Wu X., Roncari L., Baldwin R.L., et al., Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a RAS transgenic mouse astrocytoma model, Cancer Res., 2003, 63, 1106–1113 Search in Google Scholar

[112] Persson A.I., Petritsch C., Swartling F.J., Itsara M., Sim F.J., Auvergne R., et al., Non-stem cell origin for oligodendroglioma, Cancer Cell, 2010, 18, 669–682 10.1016/j.ccr.2010.10.033Search in Google Scholar PubMed PubMed Central

[113] Weiss W.A., Burns M.J., Hackett C., Aldape K., Hill J.R., Kuriyama H., et al., Genetic determinants of malignancy in a mouse model for oligodendroglioma, Cancer Res., 2003, 63, 1589–1595 Search in Google Scholar

[114] Lindberg N., Kastemar M., Olofsson T., Smits A., Uhrbom L., Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma, Oncogene, 2009, 28, 2266–2275 10.1038/onc.2009.76Search in Google Scholar PubMed

[115] Dai C., Celestino J.C., Okada Y., Louis D.N., Fuller G.N., Holland E.C., PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo, Genes Dev., 2001, 15, 1913–1925 10.1101/gad.903001Search in Google Scholar PubMed PubMed Central

[116] Ivkovic S., Canoll P., Goldman J.E., Constitutive EGFR signaling in oligodendrocyte progenitors leads to diffuse hyperplasia in postnatal white matter, J. Neurosci., 2008, 28, 914–922 10.1523/JNEUROSCI.4327-07.2008Search in Google Scholar PubMed PubMed Central

[117] Cicalese A., Bonizzi G., Pasi C.E., Faretta M., Ronzoni S., Giulini B., et al., The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells, Cell, 2009, 138, 1083–1095 10.1016/j.cell.2009.06.048Search in Google Scholar PubMed

[118] Shiraishi S., Tada K., Nakamura H., Makino K., Kochi M., Saya H., et al., Influence of p53 mutations on prognosis of patients with glioblastoma, Cancer, 2002, 95, 249–257 10.1002/cncr.10677Search in Google Scholar PubMed

[119] Gil-Perotin S., Marin-Husstege M., Li J., Soriano-Navarro M., Zindy F., Roussel M.F., et al., Loss of p53 induces changes in the behavior of subventricular zone cells: implication for the genesis of glial tumors, J. Neurosci., 2006, 26, 1107–1116 10.1523/JNEUROSCI.3970-05.2006Search in Google Scholar PubMed PubMed Central

[120] Zhu Y., Guignard F., Zhao D., Liu L., Burns D.K., Mason R.P., et al., Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma, Cancer Cell, 2005, 8, 119–130 10.1016/j.ccr.2005.07.004Search in Google Scholar PubMed PubMed Central

[121] Hambardzumyan D., Cheng Y.K., Haeno H., Holland E.C., Michor F., The probable cell of origin of NF1- and PDGF-driven glioblastomas, PLoS One, 2011, 6, e24454 10.1371/journal.pone.0024454Search in Google Scholar PubMed PubMed Central

[122] Muñoz D.M., Guha A., Mouse models to interrogate the implications of the differentiation status in the ontogeny of gliomas, Oncotarget, 2011, 2, 590–598 10.18632/oncotarget.319Search in Google Scholar PubMed PubMed Central

[123] Zheng H., Ying H., Yan H., Kimmelman A.C., Hiller D.J., Chen A.J., et al., p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation, Nature, 2008, 455, 1129–1133 10.1038/nature07443Search in Google Scholar PubMed PubMed Central

[124] Zheng H., Ying H., Yan H., Kimmelman A.C., Hiller D.J., Chen A.J., et al., Pten and p53 converge on c-Myc to control differentiation, selfrenewal, and transformation of normal and neoplastic stem cells in glioblastoma, Cold Spring Harb. Symp. Quant. Biol., 2008, 73, 427–437 10.1101/sqb.2008.73.047Search in Google Scholar PubMed

[125] Sherley J.L., Asymmetric cell kinetics genes: the key to expansion of adult stem cells in culture, Stem Cells, 2002, 20, 561–572 10.1634/stemcells.20-6-561Search in Google Scholar PubMed

[126] Groszer M., Erickson R., Scripture-Adams D.D., Lesche R., Trumpp A., Zack J.A., et al., Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo, Science, 2001, 294, 2186–2189 10.1126/science.1065518Search in Google Scholar PubMed

[127] Gont A., Hanson J.E., Lavictoire S.J., Parolin D.A., Daneshmand M., Restall I.J., et al., PTEN loss represses glioblastoma tumor initiating cell differentiation via inactivation of Lgl1, Oncotarget, 2013, 4, 1266–1279 10.18632/oncotarget.1164Search in Google Scholar PubMed PubMed Central

[128] Jafri N.F., Clarke J.L., Weinberg V., Barani I.J., Cha S., Relationship of glioblastoma multiforme to the subventricular zone is associated with survival, Neuro Oncol., 2013, 15, 91–96 10.1093/neuonc/nos268Search in Google Scholar PubMed PubMed Central

[129] Mazzoleni S., Politi L.S., Pala M., Cominelli M., Franzin A., Sergi Sergi L., et al., Epidermal growth factor receptor expression identifies functionally and molecularly distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis, Cancer Res., 2010, 70, 7500–7513 10.1158/0008-5472.CAN-10-2353Search in Google Scholar PubMed

[130] Morrison L.C., McClelland R., Aiken C., Bridges M., Liang L., Wang X., et al., Deconstruction of medulloblastoma cellular heterogeneity reveals differences between the most highly invasive and selfrenewing phenotypes, Neoplasia, 2013, 15, 384–398 10.1593/neo.13148Search in Google Scholar PubMed PubMed Central

[131] Andor N., Harness J., Mewes H.W., Petritsch C., EXPANDS: expanding ploidy and allele frequency on nested subpopulations, Bioinformatics, 2013, [Epub ahead of print], doi: 10.1093/bioinformatics/btt622 10.1093/bioinformatics/btt622Search in Google Scholar PubMed PubMed Central

[132] Deleyrolle L.P., Harding A., Cato K., Siebzehnrubl F.A., Rahman M., Azari H., et al., Evidence for label-retaining tumour-initiating cells in human glioblastoma, Brain, 2011, 134, 1331–1343 10.1093/brain/awr081Search in Google Scholar PubMed PubMed Central

[133] Foong C.S., Sandanaraj E., Brooks H.B., Campbell R.M., Ang B.T., Chong Y.K., et al., Glioma-propagating cells as an in vitro screening platform: PLK1 as a case study, J. Biomol. Screen., 2012, 17, 1136–1150 10.1177/1087057112457820Search in Google Scholar PubMed

[134] Hambardzumyan D., Squatrito M., Holland E.C., Radiation resistance and stem-like cells in brain tumors, Cancer Cell, 2006, 10, 454–456 10.1016/j.ccr.2006.11.008Search in Google Scholar PubMed

[135] Gao X., McDonald J.T., Hlatky L., Enderling H., Acute and fractionated irradiation differentially modulate glioma stem cell division kinetics, Cancer Res., 2013, 73, 1481–1490 10.1158/0008-5472.CAN-12-3429Search in Google Scholar PubMed PubMed Central

[136] Ligon K.L., Huillard E., Mehta S., Kesari S., Liu H., Alberta J.A., et al., Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma, Neuron, 2007, 53, 503–517 10.1016/j.neuron.2007.01.009Search in Google Scholar PubMed PubMed Central

[137] Richichi C., Brescia P., Alberizzi V., Fornasari L., Pelicci G., Markerindependent method for isolating slow-dividing cancer stem cells in human glioblastoma, Neoplasia, 2013, 15, 840–847 10.1593/neo.13662Search in Google Scholar PubMed PubMed Central

[138] Deleyrolle L.P., Rohaus M.R., Fortin J.M., Reynolds B.A., Azari H., Identification and isolation of slow-dividing cells in human glioblastoma using carboxy fluorescein succinimidyl ester (CFSE), J. Vis. Exp., 2012, 3918 10.3791/3918Search in Google Scholar PubMed PubMed Central

[139] Liu Q., Nguyen D.H., Dong Q., Shitaku P., Chung K., Liu O.Y., et al., Molecular properties of CD133+ glioblastoma stem cells derived from treatment-refractory recurrent brain tumors, J. Neurooncol., 2009, 94, 1–19 10.1007/s11060-009-9919-zSearch in Google Scholar PubMed PubMed Central

[140] Fotovati A., Abu-Ali S., Wang P.S., Deleyrolle L.P., Lee C., Triscott J., et al., YB-1 bridges neural stem cells and brain tumor-initiating cells via its roles in differentiation and cell growth, Cancer Res., 2011, 71, 5569–5578 10.1158/0008-5472.CAN-10-2805Search in Google Scholar PubMed

[141] Chen J., Li Y., Yu T.S., McKay R.M., Burns D.K., Kernie S.G., et al., A restricted cell population propagates glioblastoma growth after chemotherapy, Nature, 2012, 488, 522–526 10.1038/nature11287Search in Google Scholar PubMed PubMed Central

[142] Liu W., Shen G., Shi Z., Shen F., Zheng X., Wen L., et al., Brain tumour stem cells and neural stem cells: still explored by the same approach?, J. Int. Med. Res., 2008, 36, 890–895 10.1177/147323000803600504Search in Google Scholar PubMed

[143] Qiu B., Zhang D., Wang Y., Ou S., Wang J., Tao J., et al., Interleukin-6 is overexpressed and augments invasiveness of human glioma stem cells in vitro, Clin. Exp. Metastasis, 2013, 30, 1009–1018 10.1007/s10585-013-9599-0Search in Google Scholar PubMed

[144] Nakada M., Nambu E., Furuyama N., Yoshida Y., Takino T., Hayashi Y., et al., Integrin alpha3 is overexpressed in glioma stem-like cells and promotes invasion, Brit. J. Cancer, 2013, 108, 2516–2524 10.1038/bjc.2013.218Search in Google Scholar PubMed PubMed Central

[145] Kushibiki T., Sakai M., Awazu K., Differential effects of photodynamic therapy on morphologically distinct tumor cells derived from a single precursor cell, Cancer Lett., 2008, 268, 244–251 10.1016/j.canlet.2008.03.054Search in Google Scholar PubMed

[146] Lathia J.D., Hitomi M., Gallagher J., Gadani S.P., Adkins J., Vasanji A., et al., Distribution of CD133 reveals glioma stem cells self-renew through symmetric and asymmetric cell divisions, Cell Death Dis., 2011, 2, e200 10.1038/cddis.2011.80Search in Google Scholar PubMed PubMed Central

[147] Tamura K., Aoyagi M., Wakimoto H., Ando N., Nariai T., Yamamoto M., et al., Accumulation of CD133-positive glioma cells after high-dose irradiation by Gamma Knife surgery plus external beam radiation, J. Neurosurg., 2010, 113, 310–318 10.3171/2010.2.JNS091607Search in Google Scholar PubMed

[148] Kang M.K., Hur B.I., Ko M.H., Kim C.H., Cha S.H., Kang S.K., Potential identity of multi-potential cancer stem-like subpopulation after radiation of cultured brain glioma, BMC Neurosci., 2008, 9, 15 10.1186/1471-2202-9-15Search in Google Scholar PubMed PubMed Central

[149] Bao S., Wu Q., Li Z., Sathornsumetee S., Wang H., McLendon R.E., et al., Targeting cancer stem cells through L1CAM suppresses glioma growth, Cancer Res., 2008, 68, 6043–6048 10.1158/0008-5472.CAN-08-1079Search in Google Scholar PubMed PubMed Central

[150] Elsir T., Qu M., Berntsson S.G., Orrego A., Olofsson T., Lindstrom M.S., et al., PROX1 is a predictor of survival for gliomas WHO grade II, Brit. J. Cancer, 2011, 104, 1747–1754 10.1038/bjc.2011.162Search in Google Scholar PubMed PubMed Central

[151] Elsir T., Eriksson A., Orrego A., Lindstrom M.S., Nister M., Expression of PROX1 Is a common feature of high-grade malignant astrocytic gliomas, J. Neuropathol. Exp. Neurol., 2010, 69, 129–138 10.1097/NEN.0b013e3181ca4767Search in Google Scholar PubMed

[152] Elsir T., Smits A., Lindstrom M.S., Nister M., Transcription factor PROX1: its role in development and cancer, Cancer Metastasis Rev., 2012, 31, 793–805 10.1007/s10555-012-9390-8Search in Google Scholar PubMed

[153] Yamazaki H., Xu C.W., Naito M., Nishida H., Okamoto T., Ghani F.I., et al., Regulation of cancer stem cell properties by CD9 in human B-acute lymphoblastic leukemia, Biochem. Biophys. Res. Comm., 2011, 409, 14–21 10.1016/j.bbrc.2011.04.098Search in Google Scholar PubMed

[154] Tian T., Zhang Y., Wang S., Zhou J., Xu S., Sox2 enhances the tumorigenicity and chemoresistance of cancer stem-like cells derived from gastric cancer, J. Biomed. Res., 2012, 26, 336–345 10.7555/JBR.26.20120045Search in Google Scholar PubMed PubMed Central

[155] Toda M., Iizuka Y., Yu W., Imai T., Ikeda E., Yoshida K., et al., Expression of the neural RNA-binding protein Musashi1 in human gliomas, Glia, 2001, 34, 1–7 10.1002/glia.1034Search in Google Scholar PubMed

[156] Kanemura Y., Mori K., Sakakibara S., Fujikawa H., Hayashi H., Nakano A., et al., Musashi1, an evolutionarily conserved neural RNA-binding protein, is a versatile marker of human glioma cells in determining their cellular origin, malignancy, and proliferative activity, Differentiation, 2001, 68, 141–152 10.1046/j.1432-0436.2001.680208.xSearch in Google Scholar PubMed

[157] Muto J., Imai T., Ogawa D., Nishimoto Y., Okada Y., Mabuchi Y., et al., RNA-binding protein Musashi1 modulates glioma cell growth through the post-transcriptional regulation of Notch and PI3 kinase/Akt signaling pathways, PLoS One, 2012, 7, e33431 10.1371/journal.pone.0033431Search in Google Scholar PubMed PubMed Central

[158] Jiang X., Xing H., Kim T.M., Jung Y., Huang W., Yang H.W., et al., Numb regulates glioma stem cell fate and growth by altering epidermal growth factor receptor and Skp1-Cullin-F-box ubiquitin ligase activity, Stem Cells, 2012, 30, 1313–1326 10.1002/stem.1120Search in Google Scholar PubMed PubMed Central

[159] Klezovitch O., Fernandez T.E., Tapscott S.J., Vasioukhin V., Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice, Genes Dev., 2004, 18, 559–571 10.1101/gad.1178004Search in Google Scholar PubMed PubMed Central

[160] Yan B., Omar F.M., Das K., Ng W.H., Lim C., Shiuan K., et al., Characterization of Numb expression in astrocytomas, Neuropathology, 2008, 28, 479–484 10.1111/j.1440-1789.2008.00907.xSearch in Google Scholar PubMed

[161] Xu P., Qiu M., Zhang Z., Kang C., Jiang R., Jia Z., et al., The oncogenic roles of Notch1 in astrocytic gliomas in vitro and in vivo, J. Neurooncol., 2010, 97, 41–51 10.1007/s11060-009-0007-1Search in Google Scholar PubMed

[162] El Hindy N., Keyvani K., Pagenstecher A., Dammann P., Sandalcioglu I.E., Sure U., et al., Implications of Dll4-Notch signaling activation in primary glioblastoma multiforme, Neuro Oncol., 2013, 15, 1366–1378 10.1093/neuonc/not071Search in Google Scholar PubMed PubMed Central

[163] Phillips H.S., Kharbanda S., Chen R., Forrest W.F., Soriano R.H., Wu T.D., et al., Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis, Cancer Cell, 2006, 9, 157–173 10.1016/j.ccr.2006.02.019Search in Google Scholar PubMed

[164] Kristoffersen K., Villingshoj M., Poulsen H.S., Stockhausen M.T., Level of Notch activation determines the effect on growth and stem cell-like features in glioblastoma multiforme neurosphere cultures, Cancer Biol. Ther., 2013, 14, 625–637 10.4161/cbt.24595Search in Google Scholar PubMed PubMed Central

[165] Tchorz J.S., Tome M., Cloetta D., Sivasankaran B., Grzmil M., Huber R.M., et al., Constitutive Notch2 signaling in neural stem cells promotes tumorigenic features and astroglial lineage entry, Cell Death Dis., 2012, 3, e325 10.1038/cddis.2012.65Search in Google Scholar PubMed PubMed Central

[166] Gursel D.B., Berry N., Boockvar J.A., The contribution of Notch signaling to glioblastoma via activation of cancer stem cell selfrenewal: the role of the endothelial network, Neurosurgery, 2012, 70, N19–N21 10.1227/01.neu.0000410937.38828.6fSearch in Google Scholar PubMed

[167] Zhu T.S., Costello M.A., Talsma C.E., Flack C.G., Crowley J.G., Hamm L.L., et al., Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stemlike cells, Cancer Res., 2011, 71, 6061–6072 10.1158/0008-5472.CAN-10-4269Search in Google Scholar PubMed PubMed Central

[168] Hovinga K.E., Shimizu F., Wang R., Panagiotakos G., Van Der Heijden M., Moayedpardazi H., et al., Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate, Stem Cells, 2010, 28, 1019–1029 10.1002/stem.429Search in Google Scholar PubMed PubMed Central

[169] Wang J., Wang C., Meng Q., Li S., Sun X., Bo Y., et al., siRNA targeting Notch-1 decreases glioma stem cell proliferation and tumor growth, Mol. Biol. Rep., 2012, 39, 2497–2503 10.1007/s11033-011-1001-1Search in Google Scholar PubMed

[170] Zhen Y., Zhao S., Li Q., Li Y., Kawamoto K., Arsenic trioxide-mediated Notch pathway inhibition depletes the cancer stem-like cell population in gliomas, Cancer Lett., 2010, 292, 64–72 10.1016/j.canlet.2009.11.005Search in Google Scholar PubMed

[171] Dai L., He J., Liu Y., Byun J., Vivekanandan A., Pennathur S., et al., Dose-dependent proteomic analysis of glioblastoma cancer stem cells upon treatment with gamma-secretase inhibitor, Proteomics, 2011, 11, 4529–4540 10.1002/pmic.201000730Search in Google Scholar PubMed PubMed Central

[172] Fan X., Khaki L., Zhu T.S., Soules M.E., Talsma C.E., Gul N., et al., NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts, Stem Cells, 2010, 28, 5–16 10.1002/stem.254Search in Google Scholar PubMed PubMed Central

[173] Chen J., Kesari S., Rooney C., Strack P.R., Shen H., Wu L., et al., Inhibition of notch signaling blocks growth of glioblastoma cell lines and tumor neurospheres, Genes Cancer, 2010, 1, 822–835 10.1177/1947601910383564Search in Google Scholar PubMed PubMed Central

[174] Wang J., Wakeman T.P., Lathia J.D., Hjelmeland A.B., Wang X.F., White R.R., et al., Notch promotes radioresistance of glioma stem cells, Stem Cells, 2010, 28, 17–28 10.1002/stem.261Search in Google Scholar

[175] Lo H.W., EGFR-targeted therapy in malignant glioma: novel aspects and mechanisms of drug resistance, Curr. Mol. Pharmacol., 2010, 3, 37–52 10.2174/1874467211003010037Search in Google Scholar

[176] Solomon M.T., Selva J.C., Figueredo J., Vaquer J., Toledo C., Quintanal N., et al., Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial, BMC Cancer, 2013, 13, 299 10.1186/1471-2407-13-299Search in Google Scholar

[177] Howng S.L., Wu C.H., Cheng T.S., Sy W.D., Lin P.C., Wang C., et al., Differential expression of Wnt genes, beta-catenin and E-cadherin in human brain tumors, Cancer Lett., 2002, 183, 95–101 10.1016/S0304-3835(02)00085-XSearch in Google Scholar

[178] Ohgaki H., Kim Y.H., Steinbach J.P., Nervous system tumors associated with familial tumor syndromes, Curr. Opin. Neurol., 2010, 23, 583–591 10.1097/WCO.0b013e3283405b5fSearch in Google Scholar PubMed

[179] Noles S.R., Chenn A., Cadherin inhibition of beta-catenin signaling regulates the proliferation and differentiation of neural precursor cells, Mol. Cell. Neurosci., 2007, 35, 549–558 10.1016/j.mcn.2007.04.012Search in Google Scholar PubMed

[180] Habib S.J., Chen B.C., Tsai F.C., Anastassiadis K., Meyer T., Betzig E., et al., A localized Wnt signal orients asymmetric stem cell division in vitro, Science, 2013, 339, 1445–1448 10.1126/science.1231077Search in Google Scholar PubMed PubMed Central

[181] Rampazzo E., Persano L., Pistollato F., Moro E., Frasson C., Porazzi P., et al., Wnt activation promotes neuronal differentiation of glioblastoma, Cell Death Dis., 2013, 4, e500 10.1038/cddis.2013.32Search in Google Scholar PubMed PubMed Central

[182] Sandberg C.J., Altschuler G., Jeong J., Stromme K.K., Stangeland B., Murrell W., et al., Comparison of glioma stem cells to neural stem cells from the adult human brain identifies dysregulated Wnt-signaling and a fingerprint associated with clinical outcome, Exp. Cell Res., 2013, 319, 2230–2243 10.1016/j.yexcr.2013.06.004Search in Google Scholar PubMed

[183] Kim Y., Kim K.H., Lee J., Lee Y.A., Kim M., Lee S.J., et al., Wnt activation is implicated in glioblastoma radioresistance, Lab. Invest., 2012, 92, 466–473 10.1038/labinvest.2011.161Search in Google Scholar PubMed

[184] Sakai D., Dixon J., Dixon M.J., Trainor P.A., Mammalian neurogenesis requires Treacle-Plk1 for precise control of spindle orientation, mitotic progression, and maintenance of neural progenitor cells, PLoS Genet., 2012, 8, e1002566 10.1371/journal.pgen.1002566Search in Google Scholar PubMed PubMed Central

[185] Takaki T., Trenz K., Costanzo V., Petronczki M., Polo-like kinase 1 reaches beyond mitosis—cytokinesis, DNA damage response, and development, Curr. Opin. Cell Biol., 2008, 20, 650–660 10.1016/j.ceb.2008.10.005Search in Google Scholar PubMed

[186] Budirahardja Y., Gonczy P., PLK-1 asymmetry contributes to asynchronous cell division of C. elegans embryos, Development, 2008, 135, 1303–1313 10.1242/dev.019075Search in Google Scholar PubMed

[187] Dietzmann K., Kirches E., von B., Jachau K., Mawrin C., Increased human polo-like kinase-1 expression in gliomas, J. Neurooncol., 2001, 53, 1–11 10.1023/A:1011808200978Search in Google Scholar

[188] Lee C., Fotovati A., Triscott J., Chen J., Venugopal C., Singhal A., et al., Polo-like kinase 1 inhibition kills glioblastoma multiforme brain tumor cells in part through loss of SOX2 and delays tumor progression in mice, Stem Cells, 2012, 30, 1064–1075 10.1002/stem.1081Search in Google Scholar PubMed

[189] Ducray F., Idbaih A., de Reynies A., Bieche I., Thillet J., Mokhtari K., et al., Anaplastic oligodendrogliomas with 1p19q codeletion have a proneural gene expression profile, Mol. Cancer, 2008, 7, 41 10.1186/1476-4598-7-41Search in Google Scholar PubMed PubMed Central

[190] Denysenko T., Gennero L., Juenemann C., Morra I., Masperi P., Ceroni V., et al., Heterogeneous phenotype of human glioblastoma. In vitro study, Cell Biochem. Funct., 2013, [Epub ahead of print], doi: 10.1002/cbf.2988 10.1002/cbf.2988Search in Google Scholar PubMed

[191] Felling R.J., Snyder M.J., Romanko M.J., Rothstein R.P., Ziegler A.N., Yang Z., et al., Neural stem/progenitor cells participate in the regenerative response to perinatal hypoxia/ischemia, J. Neurosci., 2006, 26, 4359–4369 10.1523/JNEUROSCI.1898-05.2006Search in Google Scholar PubMed PubMed Central

[192] Linnik I.V., Scott M.L., Holliday K.F., Woodhouse N., Waterton J.C., O’Connor B., et al., Noninvasive tumor hypoxia measurement using magnetic resonance imaging in murine U87 glioma xenografts and in patients with glioblastoma, Magn. Reson. Med., 2013, [Epub ahead of print], doi: 10.1002/mrm.24826 10.1002/mrm.24826Search in Google Scholar PubMed

[193] Pistollato F., Abbadi S., Rampazzo E., Persano L., Della Puppa A., Frasson C., et al., Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma, Stem Cells, 2010, 28, 851–862 10.1002/stem.415Search in Google Scholar PubMed

[194] McCord A.M., Jamal M., Shankavaram U.T., Lang F.F., Camphausen K., Tofilon P.J., Physiologic oxygen concentration enhances the stemlike properties of CD133+ human glioblastoma cells in vitro, Mol. Cancer Res., 2009, 7, 489–497 10.1158/1541-7786.MCR-08-0360Search in Google Scholar PubMed PubMed Central

[195] Lehnus K.S., Donovan L.K., Huang X., Zhao N., Warr T.J., Pilkington G.J., et al., CD133 glycosylation is enhanced by hypoxia in cultured glioma stem cells, Int. J. Oncol., 2013, 42, 1011–1017 10.3892/ijo.2013.1787Search in Google Scholar PubMed

[196] Bar E.E., Lin A., Mahairaki V., Matsui W., Eberhart C.G., Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres, Am. J. Pathol., 2010, 177, 1491–1502 10.2353/ajpath.2010.091021Search in Google Scholar PubMed PubMed Central

[197] Sgubin D., Wakimoto H., Kanai R., Rabkin S.D., Martuza R.L., Oncolytic herpes simplex virus counteracts the hypoxia-induced modulation of glioblastoma stem-like cells, Stem Cells Transl. Med., 2012, 1, 322–332 10.5966/sctm.2011-0035Search in Google Scholar PubMed PubMed Central

[198] Pine S.R., Ryan B.M., Varticovski L., Robles A.I., Harris C.C., Microenvironmental modulation of asymmetric cell division in human lung cancer cells, Proc. Natl. Acad. Sci. USA, 2010, 107, 2195–2200 10.1073/pnas.0909390107Search in Google Scholar PubMed PubMed Central