Journal of Neuro-Oncology

, Volume 103, Issue 3, pp 397–408 | Cite as

Understanding the role of tumor stem cells in glioblastoma multiforme: a review article

  • Aalya Fatoo
  • Michael J. Nanaszko
  • Baxter B. Allen
  • Christina L. Mok
  • Elena N. Bukanova
  • Robel Beyene
  • Jennifer A. Moliterno
  • John A. Boockvar
Topic Review


It has been hypothesized that cancer stem cells (CSC) may account for the pathogenesis underlying various tumors, including GBM. Markers of these CSCs can be potentially used as therapeutic targets. In this review, we discuss the most recent information regarding CSCs, their molecular biology and their potential role in GBM.


Neural stem cells Glioma Brain tumors 


  1. 1.
    Buckner JC, Brown PD, O’Neill BP, Meyer FB, Wetmore CJ, Uhm JH (2007) Central nervous system tumors. Mayo Clin Proc 82(10):1271–1286. doi:10.4065/82.10.1271 PubMedCrossRefGoogle Scholar
  2. 2.
    Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir I, Lu L, Irvin D, Black K, Yu J (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5(1):67PubMedCrossRefGoogle Scholar
  3. 3.
    Kang MK, Kang SK (2007) Tumorigenesis of chemotherapeutic drug-resistant cancer stem-like cells in brain glioma. Stem Cells Dev 16(5):837–847PubMedCrossRefGoogle Scholar
  4. 4.
    Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson C, Jones DL, Visvader J, Weissman IL, Wahl GM (2006) Cancer stem cells-perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res 66(19):9339–9344PubMedCrossRefGoogle Scholar
  5. 5.
    Till JE, McCulloch EA (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–222PubMedCrossRefGoogle Scholar
  6. 6.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737PubMedCrossRefGoogle Scholar
  7. 7.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988PubMedCrossRefGoogle Scholar
  8. 8.
    Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946–10951PubMedCrossRefGoogle Scholar
  9. 9.
    Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschie C, DeMaria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115PubMedCrossRefGoogle Scholar
  10. 10.
    Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64(19):7011–7021PubMedCrossRefGoogle Scholar
  11. 11.
    Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA (2002) Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39(3):193–206PubMedCrossRefGoogle Scholar
  12. 12.
    Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63(18):5821–5828PubMedGoogle Scholar
  13. 13.
    Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100(25):15178–15183. doi:10.1073/pnas.2036535100 PubMedCrossRefGoogle Scholar
  14. 14.
    Stiles CD, Rowitch DH (2008) Glioma stem cells: a midterm exam. Neuron 58(6):832–846PubMedCrossRefGoogle Scholar
  15. 15.
    Zhou B-BS, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB (2009) Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 8(10):806–823PubMedCrossRefGoogle Scholar
  16. 16.
    Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J, Buck DW (1997) AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 90(12):5002–5012PubMedGoogle Scholar
  17. 17.
    Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL (2000) Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 97(26):14720–14725PubMedCrossRefGoogle Scholar
  18. 18.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401PubMedCrossRefGoogle Scholar
  19. 19.
    Corbeil D, Röper K, Hellwig A, Tavian M, Miraglia S, Watt SM, Simmons PJ, Peault B, Buck DW, Huttner WB (2000) The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem 275(8):5512–5520. doi:10.1074/jbc.275.8.5512 PubMedCrossRefGoogle Scholar
  20. 20.
    Blazek ER, Foutch JL, Maki G (2007) Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133− cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys 67(1):1–5PubMedCrossRefGoogle Scholar
  21. 21.
    Zeppernick F, Ahmadi R, Campos B (2008) Stem cell marker CD133 affects clinical outcomes in glioma patients. Clin Cancer Res 14:123–129PubMedCrossRefGoogle Scholar
  22. 22.
    Platet N, Liu S, Atifi M, Oliver L, Vallette F, Berger F, Wion D (2007) Influence of oxygen tension on CD133 phenotype in human glioma cell cultures. Cancer Lett 258(2):286–290PubMedCrossRefGoogle Scholar
  23. 23.
    McCord AM, Jamal M, Shankavarum UT, Lang FF, Camphausen K, Tofilon PJ (2009) Physiologic oxygen concentration enhances the stem-like properties of CD133+ human glioblastoma cells in vitro. Mol Cancer Res 7(4):489–497. doi:10.1158/1541-7786.mcr-08-0360 PubMedCrossRefGoogle Scholar
  24. 24.
    Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, Engh J, Iwama T, Kunisada T, Kassam AB, Pollack IF, Park DM (2009) Hypoxia promotes expansion of the cd133− positive glioma stem cells through activation of hif-1[alpha]. Oncogene 28(45):3949–3959. Google Scholar
  25. 25.
    Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U, Beier CP (2007) Cd133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67(9):4010–4015PubMedCrossRefGoogle Scholar
  26. 26.
    Mizrak D, Brittan M, Alison MR (2008) CD133: molecule of the moment. J Pathol 214(1):3–9PubMedCrossRefGoogle Scholar
  27. 27.
    Bidlingmaier S, Zhu X, Liu B (2008) The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. J Mol Med 86(9):1025–1032PubMedCrossRefGoogle Scholar
  28. 28.
    Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA (2006) Tumor stem cells derived from glioblastomas cultured in BFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9(5):391–403. doi:10.1016/j.ccr.2006.03.030 PubMedCrossRefGoogle Scholar
  29. 29.
    Vescovi AL, Galli R, Reynolds BA (2006) Brain tumour stem cells. Nat Rev Cancer 6(6):425–436PubMedCrossRefGoogle Scholar
  30. 30.
    Morshead CM, Reynolds BA, Craig CG, W MM, Staines WA, Morassutti D, Weiss S, van der Kooy D (1994) Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13(5):1071–1082Google Scholar
  31. 31.
    Dahlstrand J, Zimmerman LB, McKay RD, Lendahl U (1992) Characterization of the human nestin gene reveals a close evolutionary relationship to neurofilaments. J Cell Sci 103(2):589–597PubMedGoogle Scholar
  32. 32.
    Dell’Albani P (2008) Stem cell markers in gliomas. Neurochem Res 33(12):2407–2415PubMedCrossRefGoogle Scholar
  33. 33.
    Sakakibara S, Imai T, Hamaguchi K, Okabe M, Aruga J, Nakajima K, Yasutomi D, Nagata T, Kurihara Y, Uesugi S, Miyata T, Ogawa M, Mikoshiba K, Okano H (1996) Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell. Dev Biol 176(2):230–242PubMedCrossRefGoogle Scholar
  34. 34.
    Okano H, Kawahara H, Toriya M, Nakao K, Shibata S, Imai T (2005) Function of RNA-binding protein Musashi-1 in stem cells. Exp Cell Res 306(2):349–356PubMedCrossRefGoogle Scholar
  35. 35.
    Ma YH, Mentlein R, Knerlich F, Kruse ML, Mehdorn HM, Held-Feindt J (2008) Expression of stem cell markers in human astrocytomas of different who grades. J Neurooncol 86(1):31–45PubMedCrossRefGoogle Scholar
  36. 36.
    Thon N, Damianoff K, Hegermann J, Grau S, Krebs B, Schnell O, Tonn JC, Goldbrunner R (2010) Presence of pluripotent CD133+ cells correlates with malignancy of gliomas. Mol Cell Neurosci 43(1):51–59Google Scholar
  37. 37.
    Sureban SM, May R, George RJ, Dieckgraefe BK, McLeod HL, Ramalingam S, Bishnupuri KS, Natarajan G, Anant S, Houchen CW (2008) Knockdown of RNA binding protein Musashi-1 leads to tumor regression in vivo. Gastroenterology 134(5):1448–1458PubMedCrossRefGoogle Scholar
  38. 38.
    Park DM, Li J, Okamoto H, Akeju O, Kim SH, Lubensky I, Vortemeyer A, Dambrosia J, Weil RJ, Oldfield EH, Park JK, Zhuang Z (2007) N-CoR pathway targeting induces glioblastoma derived cancer stem cell differentiation. Cell Cycle 6(4):467–470PubMedCrossRefGoogle Scholar
  39. 39.
    Bao S, Wu Q, Li Z, Sathornsumetee S, Wang H, McLendon RE, Hjelmeland AB, Rich JN (2008) Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res 68(15):6043–6048PubMedCrossRefGoogle Scholar
  40. 40.
    Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE, MacSwords J, Wu Q, Vasanji A, McLendon RE, Hjelmeland AB, Rich JN (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6(5):421–432. doi:10.1016/j.stem.2010.02.018 PubMedCrossRefGoogle Scholar
  41. 41.
    Gangemi RM, Grifferno F, Marubbi D, Perera M, Capra MC, Malatesta P, Ravetti GL, Zona GL, Daga A, Corte G (2009) SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem Cells 27(1):40–48PubMedCrossRefGoogle Scholar
  42. 42.
    Abdouh M, Facchino S, Chatoo W, Balasingam V, Ferreira J, Bernier G (2009) BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci Res 29(28):8884–8896Google Scholar
  43. 43.
    Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, Chaudhury AR, Newton HB, Chiocca A, Lawler S (2008) Targeting of the BMI-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res 68(22):9125–9130PubMedCrossRefGoogle Scholar
  44. 44.
    Son MJ, Woolard K, Nam D, Lee J, Fine HA (2009) SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell 4(5):440–452PubMedCrossRefGoogle Scholar
  45. 45.
    Forristal CE, Wright KL, Hanley NA, Oreffo RO, Houghton FD (2009) Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions. Reproduction 139:85–97Google Scholar
  46. 46.
    Kaur B, Khwaja FW, Severson EA, Matheny SL, Brat DJ, Van Meir EG (2005) Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 7(2):134–153PubMedCrossRefGoogle Scholar
  47. 47.
    Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, Rich JN (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15(6):501–513PubMedCrossRefGoogle Scholar
  48. 48.
    Hu T, Liu S, Breiter DR, Wang F, Tang Y, Sun S (2008) Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res 68(16):6533–6540PubMedCrossRefGoogle Scholar
  49. 49.
    Chen R, Nishimura MC, Bumbaca SM, Kharbanda S, Forrest WF, Kasman IM, Greve JM, Soriano RH, Gilmour LL, Rivers CS, Modrusan Z, Nacu S, Guerrero S, Edgar KA, Wallin JJ, Lamszus K, Westphal M, Heim S, James CD, VandenBerg SR, Costello JF, Moorefield S, Cowdrey CJ, Prados M, Phillips HS (2010) A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 17(4):362–375Google Scholar
  50. 50.
    Ekstrand AJ, James CD, Cavenee WK, Seliger B, Pettersson RF, Collins VP (1991) Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res 51:2164–2172PubMedGoogle Scholar
  51. 51.
    Damiano V, Melisi D, Bianco C, Raben D, Caputo R, Fontanini G, Bianco R, Ryan A, Bianco AR, DePlacido S, Ciardiello F, Giampaolo T (2005) Cooperative anti-tumor effect of multitargeted kinase inhibitor ZD6474 and ionizing radiation in glioblastoma. Clin Cancer Res 11:5639–5644PubMedCrossRefGoogle Scholar
  52. 52.
    Mellinghoff IK, Cloughesy TF, Mischel PS (2007) PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res 13(2):378–381. doi:10.1158/1078-0432.ccr-06-1992 PubMedCrossRefGoogle Scholar
  53. 53.
    Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JHY, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353(19):2012–2024. doi:10.1056/NEJMoa051918 PubMedCrossRefGoogle Scholar
  54. 54.
    Kelly JJP, Stechishin O, Chojnacki A, Lun X, Sun B, Senger DL, Forsyth P, Auer RN, Dunn JF, Cairncross JG, Parney IF, Weiss S (2009) Proliferation of human glioblastoma stem cells occurs independently of exogenous mitogens. Stem Cells 27(8):1722–1733PubMedCrossRefGoogle Scholar
  55. 55.
    Loilome W, Joshi AD, Rhys CM, Picorillo S, Angelo VL, Gallia GL, Riggins GJ (2009) Glioblastoma cell growth is suppressed by disruption of fibroblast growth factor pathway signaling. Neurooncology 94(3):359–366CrossRefGoogle Scholar
  56. 56.
    Chearwae W, Bright JJ (2008) Ppargamma agonists inhibit growth and expansion of CD133+ brain tumour stem cells. Br J Cancer 99(12):2044–2053PubMedCrossRefGoogle Scholar
  57. 57.
    Vita M, Henriksson M (2006) The MYC oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol 16(4):318–330. doi:10.1016/j.semcancer.2006.07.015 PubMedCrossRefGoogle Scholar
  58. 58.
    Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang X-F, White RR, Rich JN, Sullenger BA (2010) Notch promotes radioresistance of glioma stem cells. Stem Cells 28(1):17–28PubMedCrossRefGoogle Scholar
  59. 59.
    Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A (2007) HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17(2):165–172PubMedCrossRefGoogle Scholar
  60. 60.
    Xu Q, Yuan X, Liu G, Black KL, Yu JS (2008) Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas. Stem Cells 26(12):3018–3026PubMedCrossRefGoogle Scholar
  61. 61.
    Zbinden M, Duquet A, Lorente-Trigos A, Ngwabyt S-N, Borges I, Ruiz i Altaba A (2010) Nanog regulates glioma stem cells and is essential in vivo acting in a cross-functional network with gli1 and p53. EMBO J.
  62. 62.
    Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 248(5415):770–776CrossRefGoogle Scholar
  63. 63.
    Kanamori M, Kawaguchi T, Nigro JM, Feuerstein BG, Berger MS, Miele L, Pieper RO (2007) Contribution of notch signaling activation to human glioblastoma multiforme. J Neurosurg 106(3):417–427PubMedCrossRefGoogle Scholar
  64. 64.
    Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, Koh C, Zhang J, Li YM, Maciaczyk J, Nikkhah G, Dimeco F, Piccirillo S, Vescovi AL, Eberhart CG (2010) Notch pathway blockade depletes cd133− positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 28 (1):5–16Google Scholar
  65. 65.
    Sun P, Xia S, Lal B, Eberhart CG, Quinones-Hinojosa A, Maciaczyk J, Matsui W, Dimeco F, Picorillo SM, Vescovi AL, Laterra J (2009) DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation. Stem Cells 27(7):1473–1486PubMedCrossRefGoogle Scholar
  66. 66.
    Hjelmeland AB, Wu Q, Wickman S, Eyler C, Heddleston J, Shi Q, Lathia JD, Macswords J, Lee J, McLendon RE, Rich JN (2010) Targeting a20 decreases glioma stem cell survival and tumor growth. PLoS Biol 8(2):e1000319PubMedCrossRefGoogle Scholar
  67. 67.
    De la Iglesia N, Konopka G, Purnam SV, Chan JA, Bachoo RM, You MJ, Levy DE, DePinho RA, Bonni A (2008) Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Gene Dev 22(4):449–462CrossRefGoogle Scholar
  68. 68.
    Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, Kotliarova S, Kotilarov Y, Walling J, Ahn S, Kim M, Totonchy M, Cusack T, Ene C, Ma H, Zenklusen JC, Zhang W, Maric D, Fine HA (2008) Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13(1):69–80PubMedCrossRefGoogle Scholar
  69. 69.
    Pistollato F, Rampazzo E, Abbadi S, DellaPuppa A, Scienza R, D’Avella D, Denaro L, TeKronnie G, Panshision DM, Basso G (2009) Molecular mechanisms of HIF-1alpha modulation induced by oxygen tension and BMP2 in glioblastoma derived cells. PLoS One 4(7):e6206PubMedCrossRefGoogle Scholar
  70. 70.
    Piccirillo SGM, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F, Vescovi AL (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444(7120):761–765PubMedCrossRefGoogle Scholar
  71. 71.
    Yu JM, Jun E, Jung J, Suh S, Han J, Kim J, Kim K, Jung J (2007) Role of WNT5A in the proliferation of human glioblastoma cells. Cancer Lett 257(2):172–181PubMedCrossRefGoogle Scholar
  72. 72.
    Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR, Gage FH (2005) WNT signalling regulates adult hippocampal neurogenesis. Nature 437(7063):1370–1375PubMedCrossRefGoogle Scholar
  73. 73.
    Wang J, Wang X, Jiang S, Lin P, Zhang J, Wu Y, Xiong Z, Ren J, Yang H (2008) Partial biological characterization of cancer stem-like cell line (WJ(2)) of human glioblastoma multiforme. Cell Mol Neurobiol 28(7):991–1003PubMedCrossRefGoogle Scholar
  74. 74.
    Nakano I, Masterman-Smith M, Saigusa K, Paucar AA, Horvath S, Shoemaker L, Watanbe M, Negro A, Bajpai R, Howes A, Lelievre V, Waschek JA, Lazareff JA, Freije WA, Liau LM, Gilbertson RJ, Cloughesy TF, Geschwind DH, Nelson SF, Mischel PS, Terskikh AV, Kornblum HI (2008) Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. J Neurosci Res 86:48–60PubMedCrossRefGoogle Scholar
  75. 75.
    Meletis K, Wirta V, Hede SM, Nister M, Lundeberg J, Frisen J (2006) P53 suppresses the self-renewal of adult neural stem cells. Development 133(2):363–369PubMedCrossRefGoogle Scholar
  76. 76.
    Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P, McKeever PE, Lee EY, Zhu Y (2009) Expression of mutant P53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell 15(6):514–526PubMedCrossRefGoogle Scholar
  77. 77.
    Ropolo M, Daga A, Griffero F, Foresta M, Casartelli G, Zunino A, Poggi A, Cappelli E, Zona G, Spaziante R, Corte G, Frosina G (2009) Comparative analysis of DNA repair in stem and nonstem glioma cell cultures. Mol Cancer Res 7(3):383–392PubMedCrossRefGoogle Scholar
  78. 78.
    Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760PubMedCrossRefGoogle Scholar
  79. 79.
    Metellus P, Coulibaly B, Nanni I, Fina F, Eudes N, Giogri R, Barrie M, Chinot O, Fuentes S, Dufour H, Ouafik L, Figarella-Branger D (2009) Prognostic impact of o(6)-methylguanine-DNA methyltransferase silencing in patients with recurrent glioblastoma multiforme who undergo surgery and carmustine wafer implantation: a prospective patient cohort. Cancer 115(20):4783–4794PubMedCrossRefGoogle Scholar
  80. 80.
    Beier D, Rohrl S, Pillai DR, Schwarz S, Kunz-Schugart LA, Leukel P, Proescholdt M, Brawanski A, Bogdahn U, Trampe-Keislich A, Giebel B, Wischhusen J, Reifenberger G, Hau P, Beier CP (2008) Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Res 68(14):5706–5715PubMedCrossRefGoogle Scholar
  81. 81.
    Huszthy PC, Goplen D, Thorsen F, Immervoll H, Wang J, Gutermann A, Miletic H, Bjerkvig R (2008) Oncolytic herpes simplex virus type-1 therapy in a highly infiltrative animal model of human glioblastoma. Clin Cancer Res 14:1571–1580PubMedCrossRefGoogle Scholar
  82. 82.
    Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vanderberg SR, Ginzinger DG, James CD, Costello JF, Bergers G, Weiss WA, Alvarez-Buylla A, Hodgeson JG (2008) Mir-124 and mir-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 6:14–22Google Scholar
  83. 83.
    Gallia GL, Tyler BM, Hann CL, Siu IM, Giranda VL, Vescovi AL, Brem H, Riggins GJ (2009) Inhibition of AKT inhibits growth of glioblastoma and glioblastoma stem-like cells. Mole Cancer Ther 8(2):386–393CrossRefGoogle Scholar
  84. 84.
    Bleau A-M, Hambardzumyan D, Ozawa T, Fomchenko EI, Huse JT, Brennan CW, Holland EC (2009) PTEN/PI3K/AKT pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4(3):226–235. doi:10.1016/j.stem.2009.01.007 PubMedCrossRefGoogle Scholar
  85. 85.
    Eyler CE, Foo W-C, LaFiura KM, McLendon RE, Hjelmeland AB, Rich JN (2008) Brain cancer stem cells display preferential sensitivity to AKT inhibition. Stem Cells 26(12):3027–3036PubMedCrossRefGoogle Scholar
  86. 86.
    Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Picorillo S, Vescovi AL, DiMeco F, Olivi A, Eberhart CG (2007) Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 25:2524–2533PubMedCrossRefGoogle Scholar
  87. 87.
    Aghi MK, Chiocca EA (2008) Phase IB trial of oncolytic herpes virus G207 shows safety of multiple injections and documents viral replication. Mol Ther 17(1):8–9CrossRefGoogle Scholar
  88. 88.
    Wakimoto H, Kesari S, Farrell CJ, Curry WT, Zaupa C, Aghi M, Kuroda T, Stemmer-Rachaminov A, Shah K, Liu TC, Jeyaretna DS, Pruszak J, Martuza RL, Rabkin SD (2009) Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. Cancer Res 69(8):3472–3481PubMedCrossRefGoogle Scholar
  89. 89.
    Jiang H, Gomez-Manzano C, Aoki H, Alonso MA, Kondo S, McCormick F, Xu J, Kondo Y, Bekele N, Colman H, Lang FF, Fueyo J (2007) Examination of the therapeutic potential of delta-24-RGD in brain tumor stem cells: role of autophagic cell death. J Nat Cancer Ins 99:1410–1414CrossRefGoogle Scholar
  90. 90.
    Wei J, Barr J, Kong L-Y, Wang Y, Wu A, Sharma AK, Gumin J, Henry V, Colman H, Sawaya R, Lang FF, Heimberger AB (2010) Glioma-associated cancer-initiating cells induce immunosuppression. Clin Cancer Res 16(2):461–473. doi:10.1158/1078-0432.ccr-09-1983 PubMedCrossRefGoogle Scholar
  91. 91.
    Rodrigues JC, Gonzalez GC, Zhang L, Ibrahim G, Kelly JJ, Gustafson MP, Lin Y, Dietz AB, Forsyth PA, Yong VW, Parney IF (2010) Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol 12(4):351–365. doi:10.1093/neuonc/nop023 PubMedGoogle Scholar
  92. 92.
    Wei J, Barr J, Kong L-Y, Wang Y, Wu A, Sharma AK, Gumin J, Henry V, Colman H, Priebe W, Sawaya R, Lang FF, Heimberger AB (2010) Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. Mol Cancer Ther 9(1):67–78. doi:10.1158/1535-7163.mct-09-0734 PubMedCrossRefGoogle Scholar
  93. 93.
    Ahmed N, Salsman VS, Kew Y, Shaffer D, Powell S, Zhang YJ, Grossman RG, Heslop HE, Gottschalk S (2010) HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res 16(2):474–485. doi:10.1158/1078-0432.ccr-09-1322 PubMedCrossRefGoogle Scholar
  94. 94.
    Kinoshita Y, Kamitani H, Mamun MH, Wasita B, Kazuki Y, Hiratsuka M, Oshimura M, Watanabe T (2009) A gene delivery system with a human artificial chromosome vector based on migration of mesenchymal stem cells towards human glioblastoma HTB14 cells. Neurol Res 32(4):429–437Google Scholar
  95. 95.
    Menon LG, Kelly K, Yang HW, Kim SK, Black PM, Carroll RS (2009) Human bone marrow-derived mesenchymal stromal cells expressing s-trail as a cellular delivery vehicle for human glioma therapy. Stem Cells 27(9):2320–2330PubMedCrossRefGoogle Scholar
  96. 96.
    Frank JA, Miller BR, Arbab AS, Zywicke HA, Jordan EK, Lewis BK, Bryant LH, Bulte JW (2003) Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfecting agents. Radiology 228(2):480–487PubMedCrossRefGoogle Scholar
  97. 97.
    Miyoshi S, Flexman JA, Cross DJ, Maravilla KR, Kim Y, Anzai Y, Oshima J, Minoshima S (2005) Transfection of neuroprogenitor cells with iron nanoparticles for magnetic resonance imaging tracking: cell viability, differentiation, and intracellular localization. Mol Imag Biol 7(4):286–295CrossRefGoogle Scholar
  98. 98.
    Gilbertson RJ, Rich JN (2007) Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 7(10):733–736PubMedCrossRefGoogle Scholar
  99. 99.
    Leon SP, Folkerth RD, Black PM (1996) Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77:362–372PubMedCrossRefGoogle Scholar
  100. 100.
    Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66(16):7843–7848PubMedCrossRefGoogle Scholar
  101. 101.
    Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M, Frank A, Bayazitov IT, Zakharenko SS, Gajjare A, Davidoff A, Gilbertson RJ (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82PubMedCrossRefGoogle Scholar
  102. 102.
    Oka N, Soeda A, Inagaki A, Onodera M, Maruyama H, Hara A, Kunisada T, Mori H, Iwama T (2007) VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells. Biochem Biophys Res Commun 360(3):553–559PubMedCrossRefGoogle Scholar
  103. 103.
    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WKA, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733–4740. doi:10.1200/jco.2008.19.8721 PubMedCrossRefGoogle Scholar
  104. 104.
    Norden AD, Drappatz J, Wen PY (2008) Novel anti-angiogenic therapies for malignant gliomas. Lancet Neurol 7(12):1152–1160. doi:10.1016/s1474-4422(08)70260-6 CrossRefGoogle Scholar
  105. 105.
    Vredenburgh JJ, Desjardins A, Herndon JE II, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729. doi:10.1200/jco.2007.12.2440 PubMedCrossRefGoogle Scholar
  106. 106.
    Batchelor TT, Sorensen AG, di Tomaso E, Zhang W-T, Duda Dan G, Cohen KS, Kozak KR, Cahill DP, Chen P-J, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden David T, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1):83–95. doi:10.1016/j.ccr.2006.11.021 PubMedCrossRefGoogle Scholar
  107. 107.
    Clark PA, Treisman DM, Ebben J, Kuo JS (2007) Developmental signaling pathways in brain tumor-derived stem-like cells. Dev Dyn 236(12):3297–3308PubMedCrossRefGoogle Scholar
  108. 108.
    Das A, Banik N, Ray S (2008) Retinoids induced astrocytic differentiation with down regulation of telomerase activity and enhanced sensitivity to taxol for apoptosis in human glioblastoma T98G and U87MG cells. J Neurooncol 87(1):9–22PubMedCrossRefGoogle Scholar
  109. 109.
    Zang C, Wächter M, Liu H, Posch MG, Fenner MH, Stadelmann C, von Deimling A, Possinger K, Black KL, Phillip Koeffler H, Elstner E (2003) Ligands for PPARγ and RAR cause induction of growth inhibition and apoptosis in human glioblastomas. J Neurooncol 65(2):107–118PubMedCrossRefGoogle Scholar
  110. 110.
    Kaba SE, Kyritsis AP, Conrad C, Gleason MJ, Newman R, Levin VA, Yung WKA (1997) The treatment of recurrent cerebral gliomas with all-trans-retinoic acid (tretinoin). J Neurooncol 34(2):145–151PubMedCrossRefGoogle Scholar
  111. 111.
    Phuphanich S, Scott C, Fischbach AJ, Langer C, Yung WKA (1997) All-trans-retinoic acid: a phase ii radiation therapy oncology group study (RTOG 91–13) in patients with recurrent malignant astrocytoma. J Neurooncol 34(2):193–200PubMedCrossRefGoogle Scholar
  112. 112.
    Campos B, Wan F, Farhadi M, Ernst A, Zeppernick F, Tagscherer KE, Ahmadi R, Lohr J, Dictus C, Gdynia G, Combs SE, Goidts V, Helmke BM, Eckstein V, Roth W, Beckhove P, Lichter P, Unterberg A, Radlwimmer B, Herold-Mende C (2010) Differentiation therapy exerts antitumor effects on stem-like glioma cells. Clin Cancer Res 16(10):2715–2728. doi:10.1158/1078-0432.ccr-09-1800 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Aalya Fatoo
    • 1
  • Michael J. Nanaszko
    • 1
  • Baxter B. Allen
    • 1
  • Christina L. Mok
    • 1
  • Elena N. Bukanova
    • 1
  • Robel Beyene
    • 1
  • Jennifer A. Moliterno
    • 1
    • 2
  • John A. Boockvar
    • 1
  1. 1.Neurosurgical Laboratory for Translational Stem Cell Research, Department of Neurosurgery, Weill Cornell Brain Tumor CenterWeill Cornell Medical College of Cornell UniversityNew YorkUSA
  2. 2.Department of NeurosurgeryYale University School of MedicineNew HavenUSA

Personalised recommendations