Glioblastoma (World Health Organization/WHO grade IV) is the most common and most aggressive adult glial tumor. Patients with glioblastoma, despite being treated with gross total resection and post-operative radiation/chemotherapy, will almost always develop tumor recurrence. Glioblastoma stem cells (GSC), a minor subpopulation within the tumor mass, have been recently characterized as tumor-initiating cells and hypothesized to be responsible for post-treatment recurrence because of their enhanced radio-/chemo-resistant phenotype and ability to reconstitute tumors in mouse brains. Genome-wide expression profile analysis uncovered molecular properties of GSC distinct from their differentiated, proliferative progeny that comprise the majority of the tumor mass. In contrast to the hyperproliferative and hyperangiogenic phenotype of glioblastoma tumors, GSC possess neuroectodermal properties and express genes associated with neural stem cells, radial glial cells, and neural crest cells, as well as portray a migratory, quiescent, and undifferentiated phenotype. Thus, cell cycle-targeted radio-chemotherapy, which aims to kill fast-growing tumor cells, may not completely eliminate glioblastoma tumors. To prevent tumor recurrence, a strategy targeting essential gene pathways of GSC must be identified and incorporated into the standard treatment regimen. Identifying intrinsic and extrinsic cues by which GSC maintain stemness properties and sustain both tumorigenesis and anti-apoptotic features may provide new insights into potentially curative strategies for treating brain cancers.
Zhang, M.; Song, T.; Yang, L.; Chen, R.; Wu, L.; Yang, Z.; Fang, J. Nestin and CD133: valuable stem cell-specific markers for determining clinical outcome of glioma patients. J. Exp. Clin. Cancer Res. 2008, 27, 85.
[12]
Laks, D.R.; Masterman-Smith, M.; Visnyei, K.; Angenieux, B.; Orozco, N.M.; Foran, I.; Yong, W.H.; Vinters, H.V.; Liau, L.M.; Lazareff, J.A.; Mischel, P.S.; Cloughesy, T.F.; Horvath, S.; Kornblum, H.I. Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells 2009, 27, 980–987.
[13]
Pallini, R.; Ricci-Vitiani, L.; Montano, N.; Mollinari, C.; Biffoni, M.; Cenci, T.; Pierconti, F.; Martini, M.; De Maria, R.; Larocca, L.M. Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis. Cancer 2011, 117, 162–174.
[14]
Pallini, R.; Ricci-Vitiani, L.; Banna, G.L.; Signore, M.; Lombardi, D.; Todaro, M.; Stassi, G.; Martini, M.; Maira, G.; Larocca, L.M.; De Maria, R. Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme. Clin. Cancer Res. 2008, 14, 8205–8212.
[15]
Sang, L.; Coller, H.A.; Roberts, J.M. Control of the reversibility of cellular quiescence by the transcriptional repressor HES1. Science 2008, 321, 1095–1100.
[16]
Chapouton, P.; Skupien, P.; Hesl, B.; Coolen, M.; Moore, J.C.; Madelaine, R.; Kremmer, E.; Faus-Kessler, T.; Blader, P.; Lawson, N.D.; Bally-Cuif, L. Notch activity levels control the balance between quiescence and recruitment of adult neural stem cells. J. Neurosci. 2010, 30, 7961–7974.
Jundt, F.; Schwarzer, R.; Dorken, B. Notch signaling in leukemias and lymphomas. Curr. Mol. Med. 2008, 8, 51–59.
[20]
Jeon, H.M.; Jin, X.; Lee, J.S.; Oh, S.Y.; Sohn, Y.W.; Park, H.J.; Joo, K.M.; Park, W.Y.; Nam, D.H.; DePinho, R.A.; Chin, L.; Kim, H. Inhibitor of differentiation 4 drives brain tumor-initiating cell genesis through cyclin E and notch signaling. Genes Dev. 2008, 22, 2028–2033.
[21]
Sakamoto, M.; Hirata, H.; Ohtsuka, T.; Bessho, Y.; Kageyama, R. The basic helix-loop-helix genes Hesr1/Hey1 and Hesr2/Hey2 regulate maintenance of neural precursor cells in the brain. J. Biol. Chem. 2003, 278, 44808–44815.
[22]
Liang, Y.; Bollen, A.W.; Nicholas, M.K.; Gupta, N. Id4 and FABP7 are preferentially expressed in cells with astrocytic features in oligodendrogliomas and oligoastrocytomas. BMC Clin. Pathol. 2005, 5, 6.
[23]
Anthony, T.E.; Mason, H.A.; Gridley, T.; Fishell, G.; Heintz, N. Brain lipid-binding protein is a direct target of Notch signaling in radial glial cells. Genes Dev. 2005, 19, 1028–1033.
[24]
Mita, R.; Coles, J.E.; Glubrecht, D.D.; Sung, R.; Sun, X.; Godbout, R. B-FABP-expressing radial glial cells: The malignant glioma cell of origin? Neoplasia 2007, 9, 734–744.
[25]
Kaloshi, G.; Mokhtari, K.; Carpentier, C.; Taillibert, S.; Lejeune, J.; Marie, Y.; Delattre, J.Y.; Godbout, R.; Sanson, M. FABP7 expression in glioblastomas: relation to prognosis, invasion and EGFR status. J. Neurooncol. 2007, 84, 245–248.
[26]
Edenfeld, G.; Altenhein, B.; Zierau, A.; Cleppien, D.; Krukkert, K.; Technau, G.; Klambt, C. Notch and Numb are required for normal migration of peripheral glia in Drosophila. Dev. Biol. 2007, 301, 27–37.
[27]
Deneen, B.; Ho, R.; Lukaszewicz, A.; Hochstim, C.J.; Gronostajski, R.M.; Anderson, D.J. The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 2006, 52, 953–968.
Hovinga, K.E.; Shimizu, F.; Wang, R.; Panagiotakos, G.; Van Der Heijden, M.; Moayedpardazi, H.; Correia, A.S.; Soulet, D.; Major, T.; Menon, J.; Tabar, V. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells 2010, 28, 1019–1029.
[30]
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.
[31]
Soeda, A.; Park, M.; Lee, D.; Mintz, A.; Androutsellis-Theotokis, A.; McKay, R.D.; Engh, J.; Iwama, T.; Kunisada, T.; Kassam, A.B.; Pollack, I.F.; Park, D.M. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 2009, 28, 3949–3959.
Heddleston, J.M.; Li, Z.; McLendon, R.E.; Hjelmeland, A.B.; Rich, J.N. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 2009, 8, 3274–3284.
[35]
Clement, V.; Sanchez, P.; de Tribolet, N.; Radovanovic, I.; Ruiz i Altaba, A. HEDGEHOG-GLI1signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol. 2007, 17, 165–172.
[36]
Zbinden, M.; Duquet, A.; Lorente-Trigos, A.; Ngwabyt, S.N.; Borges, I.; Ruiz i Altaba, A. NANOG regulates glioma stem cells and is essential in vivo acting in a cross-functional network with GLI1and p53. EMBO J. 2010, 29, 2659–2674.
[37]
Po, A.; Ferretti, E.; Miele, E.; De Smaele, E.; Paganelli, A.; Canettieri, G.; Coni, S.; Di Marcotullio, L.; Biffoni, M.; Massimi, L.; Di Rocco, C.; Screpanti, I.; Gulino, A. Hedgehog controls neural stem cells through p53-independent regulation of Nanog. EMBO J. 2010, 29, 2646–2658.
[38]
Stecca, B.; Ruiz i Altaba, A. A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. EMBO J. 2009, 28, 663–676.
[39]
Aigner, L.; Bogdahn, U. TGF-beta in neural stem cells and in tumors of the central nervous system. Cell Tissue Res. 2008, 331, 225–241.
Zhao, S.; Venkatasubbarao, K.; Lazor, J.W.; Sperry, J.; Jin, C.; Cao, L.; Freeman, J.W. Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Res. 2008, 68, 4221–4228.
[42]
Golestaneh, N.; Mishra, B. TGF-beta, neuronal stem cells and glioblastoma. Oncogene 2005, 24, 5722–5730.
[43]
Penuelas, S.; Anido, J.; Prieto-Sanchez, R.M.; Folch, G.; Barba, I.; Cuartas, I.; Garcia-Dorado, D.; Poca, M.A.; Sahuquillo, J.; Baselga, J.; Seoane, J. TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 2009, 15, 315–327.
[44]
Sherry, M.M.; Reeves, A.; Wu, J.K.; Cochran, B.H. STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 2009, 27, 2383–2392.
[45]
Li, G.H.; Wei, H.; Lv, S.Q.; Ji, H.; Wang, D.L. Knockdown of STAT3 expression by RNAi suppresses growth and induces apoptosis and differentiation in glioblastoma stem cells. Int. J. Oncol. 2010, 37, 103–110.
Ikushima, H.; Todo, T.; Ino, Y.; Takahashi, M.; Miyazawa, K.; Miyazono, K. Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 2009, 5, 504–514.
[48]
Gangemi, R.M.; Griffero, F.; Marubbi, D.; Perera, M.; Capra, M.C.; Malatesta, P.; Ravetti, G.L.; Zona, G.L.; Daga, A.; Corte, G. SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem Cells 2009, 27, 40–48.
[49]
Piccirillo, S.G.; Reynolds, B.A.; Zanetti, N.; Lamorte, G.; Binda, E.; Broggi, G.; Brem, H.; Olivi, A.; Dimeco, F.; Vescovi, A.L. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 2006, 444, 761–765.
[50]
Lee, J.; Son, M.J.; Woolard, K.; Donin, N.M.; Li, A.; Cheng, C.H.; Kotliarova, S.; Kotliarov, Y.; Walling, J.; Ahn, S.; Kim, M.; Totonchy, M.; Cusack, T.; Ene, C.; Ma, H.; Su, Q.; Zenklusen, J.C.; Zhang, W.; Maric, D.; Fine, H.A. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 2008, 13, 69–80.
[51]
Mazzoleni, S.; Politi, L.S.; Pala, M.; Cominelli, M.; Franzin, A.; Sergi Sergi, L.; Falini, A.; De Palma, M.; Bulfone, A.; Poliani, P.L.; Galli, R. 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.
[52]
Soeda, A.; Inagaki, A.; Oka, N.; Ikegame, Y.; Aoki, H.; Yoshimura, S.; Nakashima, S.; Kunisada, T.; Iwama, T. Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells. J. Biol. Chem. 2008, 283, 10958–10966.
[53]
Griffero, F.; Daga, A.; Marubbi, D.; Capra, M.C.; Melotti, A.; Pattarozzi, A.; Gatti, M.; Bajetto, A.; Porcile, C.; Barbieri, F.; Favoni, R.E.; Lo Casto, M.; Zona, G.; Spaziante, R.; Florio, T.; Corte, G. Different response of human glioma tumor-initiating cells to epidermal growth factor receptor kinase inhibitors. J. Biol. Chem. 2009, 284, 7138–7148.
Abdouh, M.; Facchino, S.; Chatoo, W.; Balasingam, V.; Ferreira, J.; Bernier, G. BMI1 sustains human glioblastoma multiforme stem cell renewal. J. Neurosci. 2009, 29, 8884–8896.
[65]
Suva, M.L.; Riggi, N.; Janiszewska, M.; Radovanovic, I.; Provero, P.; Stehle, J.C.; Baumer, K.; Le Bitoux, M.A.; Marino, D.; Cironi, L.; Marquez, V.E.; Clement, V.; Stamenkovic, I. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res. 2009, 69, 9211–9218.
[66]
Whitley, M.; Treloar, H.; De Arcangelis, A.; Georges Labouesse, E.; Greer, C.A. The alpha6 integrin subunit in the developing mouse olfactory bulb. J. Neurocytol. 2005, 34, 81–96.
Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U.; Curschmann, J.; Janzer, R.C.; Ludwin, S.K.; Gorlia, T.; Allgeier, A.; Lacombe, D.; Cairncross, J.G.; Eisenhauer, E.; Mirimanoff, R.O. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 2005, 352, 987–996.
[69]
Stupp, R.; Hegi, M.E.; Mason, W.P.; van den Bent, M.J.; Taphoorn, M.J.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K.; Hau, P.; Brandes, A.A.; Gijtenbeek, J.; Marosi, C.; Vecht, C.J.; Mokhtari, K.; Wesseling, P.; Villa, S.; Eisenhauer, E.; Gorlia, T.; Weller, M.; Lacombe, D.; Cairncross, J.G.; Mirimanoff, R.O. 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.
[70]
Hegi, M.E.; Diserens, A.C.; Gorlia, T.; Hamou, M.F.; de Tribolet, N.; Weller, M.; Kros, J.M.; Hainfellner, J.A.; Mason, W.; Mariani, L.; Bromberg, J.E.; Hau, P.; Mirimanoff, R.O.; Cairncross, J.G.; Janzer, R.C.; Stupp, R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 2005, 352, 997–1003.
[71]
Murat, A.; Migliavacca, E.; Gorlia, T.; Lambiv, W.L.; Shay, T.; Hamou, M.F.; de Tribolet, N.; Regli, L.; Wick, W.; Kouwenhoven, M.C.; Hainfellner, J.A.; Heppner, F.L.; Dietrich, P.Y.; Zimmer, Y.; Cairncross, J.G.; Janzer, R.C.; Domany, E.; Delorenzi, M.; Stupp, R.; Hegi, M.E. Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J. Clin. Oncol. 2008, 26, 3015–3024.
[72]
Mellor, H.R.; Ferguson, D.J.; Callaghan, R. A model of quiescent tumour microregions for evaluating multicellular resistance to chemotherapeutic drugs. Br. J. Cancer 2005, 93, 302–309.
[73]
Liu, Y.; Perdreau, S.A.; Chatterjee, P.; Wang, L.; Kuan, S.F.; Duensing, A. Imatinib mesylate induces quiescence in gastrointestinal stromal tumor cells through the CDH1-SKP2-p27Kip1 signaling axis. Cancer Res. 2008, 68, 9015–9023.
[74]
Masunaga, S.; Ono, K.; Hori, H.; Suzuki, M.; Kinashi, Y.; Takagaki, M.; Kasai, S.; Nagasawa, H.; Uto, Y. Potentially lethal damage repair by total and quiescent tumor cells following various DNA-damaging treatments. Radiat. Med. 1999, 17, 259–264.
Nakai, E.; Park, K.; Yawata, T.; Chihara, T.; Kumazawa, A.; Nakabayashi, H.; Shimizu, K. Enhanced MDR1 expression and chemoresistance of cancer stem cells derived from glioblastoma. Cancer Invest. 2009, 27, 901–908.
[83]
Hsieh, A.; Ellsworth, R.; Hsieh, D. Hedgehog/GLI1 regulates IGF dependent malignant behaviors in glioma stem cells. J. Cell Physiol. 2011, 226, 1118–1127.
Gilbert, C.A.; Daou, M.C.; Moser, R.P.; Ross, A.H. Gamma-secretase inhibitors enhance temozolomide treatment of human gliomas by inhibiting neurosphere repopulation and xenograft recurrence. Cancer Res. 2010, 70, 6870–6879.
[86]
Simon, J.A.; Kingston, R.E. Mechanisms of polycomb gene silencing: knowns and unknowns. Nat. Rev. Mol. Cell Biol. 2009, 10, 697–708.
[87]
Cao, R.; Tsukada, Y.; Zhang, Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol. Cell 2005, 20, 845–854.
[88]
Facchino, S.; Abdouh, M.; Chatoo, W.; Bernier, G. BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J. Neurosci. 2010, 30, 10096–10111.
[89]
McCord, A.M.; Jamal, M.; Williams, E.S.; Camphausen, K.; Tofilon, P.J. CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clin. Cancer Res. 2009, 15, 5145–5153.
[90]
Ropolo, M.; Daga, A.; Griffero, F.; Foresta, M.; Casartelli, G.; Zunino, A.; Poggi, A.; Cappelli, E.; Zona, G.; Spaziante, R.; Corte, G.; Frosina, G. Comparative analysis of DNA repair in stem and nonstem glioma cell cultures. Mol. Cancer Res. 2009, 7, 383–392.
Wang, H.; Shen, W.; Huang, H.; Hu, L.; Ramdas, L.; Zhou, Y.H.; Liao, W.S.; Fuller, G.N.; Zhang, W. Insulin-like growth factor binding protein 2 enhances glioblastoma invasion by activating invasion-enhancing genes. Cancer Res. 2003, 63, 4315–4321.
[94]
Fukushima, T.; Tezuka, T.; Shimomura, T.; Nakano, S.; Kataoka, H. Silencing of insulin-like growth factor-binding protein-2 in human glioblastoma cells reduces both invasiveness and expression of progression-associated gene CD24. J. Biol. Chem. 2007, 282, 18634–18644.
Evers, P.; Lee, P.P.; DeMarco, J.; Agazaryan, N.; Sayre, J.W.; Selch, M.; Pajonk, F. Irradiation of the potential cancer stem cell niches in the adult brain improves progression-free survival of patients with with malignant glioma. BMC Cancer 2010, 10, 384.
[97]
Sneddon, J.B.; Werb, Z. Location, location, location: The cancer stem cell niche. Cell Stem Cell 2007, 1, 607–611.
