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Radiation Therapy for Glioma Stem Cells

  • Anthony E. Rizzo
  • Jennifer S. YuEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 853)

Abstract

Radiation therapy is the most effective adjuvant treatment modality for virtually all patients with high-grade glioma. Its ability to improve patient survival has been recognized for decades. Cancer stem cells provide new insights into how tumor biology is affected by radiation and the role that this cell population can play in disease recurrence. Glioma stem cells possess a variety of intracellular mechanisms to resist and even flourish in spite of radiation, and their proliferation and maintenance appear tied to supportive stimuli from the tumor microenvironment. This chapter reviews the basis for our current use of radiation to treat high-grade gliomas, and addresses this model in the context of therapeutically resistant stem cells. We discuss the available evidence highlighting current clinical efforts to improve radiosensitivity, and newer targets worthy of further development.

Keywords

Glioma Stem cell Initiating cell Glioblastoma Radiation Radioresistance Microenvironment Hypoxia DNA damage repair 

References

  1. 1.
    Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol. 2012;14 Suppl 5:v1–49.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, Stroup NE, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol. 2013;15 Suppl 2:ii1–56.PubMedCentralPubMedGoogle Scholar
  3. 3.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.PubMedGoogle Scholar
  4. 4.
    Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, Lang FF, McCutcheon IE, Hassenbusch SJ, Holland E, Hess K, Michael C, Miller D, Sawaya R. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95(2):190–8.PubMedGoogle Scholar
  5. 5.
    Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys. 1979;5(10):1725–31.PubMedGoogle Scholar
  6. 6.
    Bleehen NM, Stenning SP. A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. Br J Cancer. 1991;64(4):769–74.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Chaichana KL, Cabrera-Aldana EE, Jusue-Torres I, Wijesekera O, Olivi A, Rahman M, Quinones-Hinojosa A. When gross total resection of a glioblastoma is possible, how much resection should be achieved? World Neurosurg. 2014;82(1–2):e257–65.PubMedGoogle Scholar
  8. 8.
    Shapiro WR, Young DF. Treatment of malignant glioma. A controlled study of chemotherapy and irradiation. Arch Neurol. 1976;33(7):494–550.PubMedGoogle Scholar
  9. 9.
    Walker MD, Alexander Jr E, Hunt WE, MacCarty CS, Mahaley Jr MS, Mealey Jr J, Norrell HA, Owens G, Ransohoff J, Wilson CB, Gehan EA, Strike TA. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg. 1978;49(3):333–43.PubMedGoogle Scholar
  10. 10.
    Lee SW, Fraass BA, Marsh LH, Herbort K, Gebarski SS, Martel MK, Radany EH, Lichter AS, Sandler HM. Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. Int J Radiat Oncol Biol Phys. 1999;43(1):79–88.PubMedGoogle Scholar
  11. 11.
    Walker MD, Green SB, Byar DP, Alexander Jr E, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley Jr MS, Mealey Jr J, Owens G, Ransohoff 2nd J, Robertson JT, Shapiro WR, Smith Jr KR, Wilson CB, Strike TA. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980;303(23):1323–9.PubMedGoogle Scholar
  12. 12.
    Shapiro WR, Green SB, Burger PC, Mahaley Jr MS, Selker RG, VanGilder JC, Robertson JT, Ransohoff J, Mealey Jr J, Strike TA. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. J Neurosurg. 1989;71(1):1–9.PubMedGoogle Scholar
  13. 13.
    DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology. 1989;39(6):789–96.PubMedGoogle Scholar
  14. 14.
    Chang CH, Horton J, Schoenfeld D, Salazer O, Perez-Tamayo R, Kramer S, Weinstein A, Nelson JS, Tsukada Y. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. Cancer. 1983;52(6):997–1007.PubMedGoogle Scholar
  15. 15.
    Nelson DF, Diener-West M, Horton J, Chang CH, Schoenfeld D, Nelson JS. Combined modality approach to treatment of malignant gliomas–re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group. NCI Monogr. 1988;(6):279–84.Google Scholar
  16. 16.
    Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology. 1980;30(9):907–11.PubMedGoogle Scholar
  17. 17.
    Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys. 1989;16(6):1405–9.PubMedGoogle Scholar
  18. 18.
    Thornton Jr AF, Sandler HM, Ten Haken RK, McShan DL, Fraass BA, La Vigne ML, Yanke BR. The clinical utility of magnetic resonance imaging in 3-dimensional treatment planning of brain neoplasms. Int J Radiat Oncol Biol Phys. 1992;24(4):767–75.PubMedGoogle Scholar
  19. 19.
    Lattanzi JP, Fein DA, McNeeley SW, Shaer AH, Movsas B, Hanks GE. Computed tomography-magnetic resonance image fusion: a clinical evaluation of an innovative approach for improved tumor localization in primary central nervous system lesions. Radiat Oncol Investig. 1997;5(4):195–205.PubMedGoogle Scholar
  20. 20.
    Fiorentino A, Caivano R, Pedicini P, Fusco V. Clinical target volume definition for glioblastoma radiotherapy planning: magnetic resonance imaging and computed tomography. Clin Transl Oncol. 2013;15(9):754–8.PubMedGoogle Scholar
  21. 21.
    Pirzkall A, McKnight TR, Graves EE, Carol MP, Sneed PK, Wara WW, Nelson SJ, Verhey LJ, Larson DA. MR-spectroscopy guided target delineation for high-grade gliomas. Int J Radiat Oncol Biol Phys. 2001;50(4):915–28.PubMedGoogle Scholar
  22. 22.
    Petrecca K, Guiot M-C, Panet-Raymond V, Souhami L. Failure pattern following complete resection plus radiotherapy and temozolomide is at the resection margin in patients with glioblastoma. J Neurooncol. 2013;111(1):19–23.PubMedGoogle Scholar
  23. 23.
    Rahman M, Deleyrolle L, Vedam-Mai V, Azari H, Abd-El-Barr M, Reynolds BA. The cancer stem cell hypothesis: failures and pitfalls. Neurosurgery. 2011;68(2):531–45. discussion 545.PubMedGoogle Scholar
  24. 24.
    Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.PubMedGoogle Scholar
  25. 25.
    Zhou B-BS, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov. 2009;8(10):806–23.PubMedGoogle Scholar
  26. 26.
    O’Connor ML, Xiang D, Shigdar S, Macdonald J, Li Y, Wang T, Pu C, Wang Z, Qiao L, Duan W. Cancer stem cells: a contentious hypothesis now moving forward. Cancer Lett. 2014;344(2):180–7.PubMedGoogle Scholar
  27. 27.
    Lathia JD, Gallagher J, Myers JT, Li M, Vasanji A, McLendon RE, Hjelmeland AB, Huang AY, Rich JN. Direct in vivo evidence for tumor propagation by glioblastoma cancer stem cells. PLoS One. 2011;6(9):e24807.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401.PubMedGoogle Scholar
  29. 29.
    Schonberg DL, Lubelski D, Miller TE, Rich JN. Brain tumor stem cells: molecular characteristics and their impact on therapy. Mol Aspects Med. 2014;39:82–101.PubMedGoogle Scholar
  30. 30.
    Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 2009;8(20):3274–84.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Hjelmeland AB, Wu Q, Heddleston JM, Choudhary GS, MacSwords J, Lathia JD, McLendon R, Lindner D, Sloan A, Rich JN. Acidic stress promotes a glioma stem cell phenotype. Cell Death Differ. 2011;18(5):829–40.PubMedCentralPubMedGoogle Scholar
  32. 32.
    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. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene. 2009;28(45):3949–59.PubMedGoogle Scholar
  33. 33.
    Seidel S, Garvalov BK, Wirta V, von Stechow L, Schänzer A, Meletis K, Wolter M, Sommerlad D, Henze A-T, Nistér M, Reifenberger G, Lundeberg J, Frisén J, Acker T. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain J Neurol. 2010;133(Pt 4):983–95.Google Scholar
  34. 34.
    Cheng L, Bao S, Rich JN. Potential therapeutic implications of cancer stem cells in glioblastoma. Biochem Pharmacol. 2010;80(5):654–65.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Roos WP, Kaina B. DNA damage-induced apoptosis: From specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2012;332(2):237–48.PubMedGoogle Scholar
  36. 36.
    Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010;40(2):179–204.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481(7381):287–94.PubMedGoogle Scholar
  38. 38.
    Bartkova J, Hamerlik P, Stockhausen M-T, Ehrmann J, Hlobilkova A, Laursen H, Kalita O, Kolar Z, Poulsen HS, Broholm H, Lukas J, Bartek J. Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas. Oncogene. 2010;29(36):5095–102.PubMedGoogle Scholar
  39. 39.
    Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.PubMedGoogle Scholar
  40. 40.
    Firat E, Gaedicke S, Tsurumi C, Esser N, Weyerbrock A, Niedermann G. Delayed cell death associated with mitotic catastrophe in γ-irradiated stem-like glioma cells. Radiat Oncol. 2011;6:71.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Tamura K, Aoyagi M, Ando N, Ogishima T, Wakimoto H, Yamamoto M, Ohno K. Expansion of CD133-positive glioma cells in recurrent de novo glioblastomas after radiotherapy and chemotherapy. J Neurosurg. 2013;119(5):1145–55.PubMedGoogle Scholar
  42. 42.
    Chan JL, Lee SW, Fraass BA, Normolle DP, Greenberg HS, Junck LR, Gebarski SS, Sandler HM. Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. J Clin Oncol. 2002;20(6):1635–42.PubMedGoogle Scholar
  43. 43.
    Souhami L, Seiferheld W, Brachman D, Podgorsak EB, Werner-Wasik M, Lustig R, Schultz CJ, Sause W, Okunieff P, Buckner J, Zamorano L, Mehta MP, Curran Jr WJ. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys. 2004;60(3):853–60.PubMedGoogle Scholar
  44. 44.
    Tsao MN, Mehta MP, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, Mills M, Rogers CL, Souhami L. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys. 2005;63(1):47–55.PubMedGoogle Scholar
  45. 45.
    Laperriere NJ, Leung PM, McKenzie S, Milosevic M, Wong S, Glen J, Pintilie M, Bernstein M. Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma. Int J Radiat Oncol Biol Phys. 1998;41(5):1005–11.PubMedGoogle Scholar
  46. 46.
    Selker RG, Shapiro WR, Burger P, Blackwood MS, Arena VC, Gilder JC, Malkin MG, Mealey Jr JJ, Neal JH, Olson J, Robertson JT, Barnett GH, Bloomfield S, Albright R, Hochberg FH, Hiesiger E, Green S, Brain Tumor Cooperative Group. The Brain Tumor Cooperative Group NIH Trial 87-01: a randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial radiotherapy boost, external radiation therapy, and carmustine. Neurosurgery. 2002;51(2):343–55. discussion 355–7.PubMedGoogle Scholar
  47. 47.
    McCord AM, Jamal M, Williams ES, Camphausen K, Tofilon PJ. CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clin Cancer Res. 2009;15(16):5145–53.PubMedGoogle Scholar
  48. 48.
    Squatrito M, Brennan CW, Helmy K, Huse JT, Petrini JH, Holland EC. Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas. Cancer Cell. 2010;18(6):619–29.PubMedGoogle Scholar
  49. 49.
    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(3):383–92.PubMedGoogle Scholar
  50. 50.
    Williams RS, Williams JS, Tainer JA. Mre11-Rad50-Nbs1 is a keystone complex connecting DNA repair machinery, double-strand break signaling, and the chromatin template. Biochem Cell Biol Biochim Biol Cell. 2007;85(4):509–20.Google Scholar
  51. 51.
    Maser RS, Monsen KJ, Nelms BE, Petrini JH. hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks. Mol Cell Biol. 1997;17(10):6087–96.PubMedCentralPubMedGoogle Scholar
  52. 52.
    Lavin MF. ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks. Oncogene. 2007;26(56):7749–58.PubMedGoogle Scholar
  53. 53.
    Matsuoka S, Ballif BA, Smogorzewska A, McDonald 3rd ER, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007;316(5828):1160–6.PubMedGoogle Scholar
  54. 54.
    Bao S, Wu Q, Li Z, Sathornsumetee S, Wang H, McLendon RE, Hjelmeland AB, Rich JN. Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res. 2008;68(15):6043–8.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Cheng L, Wu Q, Huang Z, Guryanova OA, Huang Q, Shou W, Rich JN, Bao S. L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1. EMBO J. 2011;30(5):800–13.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Chiang Y-C, Teng S-C, Su Y-N, Hsieh F-J, Wu K-J. c-Myc directly regulates the transcription of the NBS1 gene involved in DNA double-strand break repair. J Biol Chem. 2003;278(21):19286–91.PubMedGoogle Scholar
  57. 57.
    Guerra L, Albihn A, Tronnersjö S, Yan Q, Guidi R, Stenerlöw B, Sterzenbach T, Josenhans C, Fox JG, Schauer DB, Thelestam M, Larsson L-G, Henriksson M, Frisan T. Myc is required for activation of the ATM-dependent checkpoints in response to DNA damage. PloS One. 2010;5(1):e8924.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Benetatos L, Vartholomatos G, Hatzimichael E. Polycomb group proteins and MYC: the cancer connection. Cell Mol Life Sci. 2014;71(2):257–69.PubMedGoogle Scholar
  59. 59.
    Vita M, Henriksson M. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol. 2006;16(4):318–30.PubMedGoogle Scholar
  60. 60.
    Wang J, Wang H, Li Z, Wu Q, Lathia JD, McLendon RE, Hjelmeland AB, Rich JN. c-Myc is required for maintenance of glioma cancer stem cells. PloS One. 2008;3(11):e3769.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Lee J-H, Paull TT. Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science. 2004;304(5667):93–6.PubMedGoogle Scholar
  62. 62.
    Lee J-H, Paull TT. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science. 2005;308(5721):551–4.PubMedGoogle Scholar
  63. 63.
    Matsuoka S, Huang M, Elledge SJ. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science. 1998;282(5395):1893–7.PubMedGoogle Scholar
  64. 64.
    Guo Z, Kumagai A, Wang SX, Dunphy WG. Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts. Genes Dev. 2000;14(21):2745–56.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Gobbini E, Cesena D, Galbiati A, Lockhart A, Longhese MP. Interplays between ATM/Tel1 and ATR/Mec1 in sensing and signaling DNA double-strand breaks. DNA Repair. 2013;12(10):791–9.PubMedGoogle Scholar
  66. 66.
    Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature. 2000;408(6811):433–9.PubMedGoogle Scholar
  67. 67.
    Tribius S, Pidel A, Casper D. ATM protein expression correlates with radioresistance in primary glioblastoma cells in culture. Int J Radiat Oncol Biol Phys. 2001;50(2):511–23.PubMedGoogle Scholar
  68. 68.
    Nadkarni A, Shrivastav M, Mladek AC, Schwingler PM, Grogan PT, Chen J, Sarkaria JN. ATM inhibitor KU-55933 increases the TMZ responsiveness of only inherently TMZ sensitive GBM cells. J Neurooncol. 2012;110(3):349–57.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Vecchio D, Daga A, Carra E, Marubbi D, Baio G, Neumaier CE, Vagge S, Corvò R, Pia Brisigotti M, Louis Ravetti J, Zunino A, Poggi A, Mascelli S, Raso A, Frosina G. Predictability, efficacy and safety of radiosensitization of glioblastoma-initiating cells by the ATM inhibitor KU-60019. Int J Cancer. 2014;135(2):479–91.PubMedGoogle Scholar
  70. 70.
    De Bacco F, Luraghi P, Medico E, Reato G, Girolami F, Perera T, Gabriele P, Comoglio PM, Boccaccio C. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J Natl Cancer Inst. 2011;103(8):645–61.PubMedGoogle Scholar
  71. 71.
    Organ SL, Tsao M-S. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011;3(1 Suppl):S7–19.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8.Google Scholar
  73. 73.
    Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, Akhavanfard S, Cahill DP, Aldape KD, Betensky RA, Louis DN, Iafrate AJ. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell. 2011;20(6):810–7.PubMedGoogle Scholar
  74. 74.
    Kong D-S, Song S-Y, Kim D-H, Joo KM, Yoo J-S, Koh JS, Dong SM, Suh Y-L, Lee J-I, Park K, Kim JH, Nam D-H. Prognostic significance of c-Met expression in glioblastomas. Cancer. 2009;115(1):140–8.PubMedGoogle Scholar
  75. 75.
    Brennan C, Momota H, Hambardzumyan D, Ozawa T, Tandon A, Pedraza A, Holland E. Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PloS One. 2009;4(11):e7752.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Maher EA, Brennan C, Wen PY, Durso L, Ligon KL, Richardson A, Khatry D, Feng B, Sinha R, Louis DN, Quackenbush J, Black PM, Chin L, DePinho RA. Marked genomic differences characterize primary and secondary glioblastoma subtypes and identify two distinct molecular and clinical secondary glioblastoma entities. Cancer Res. 2006;66(23):11502–13.PubMedGoogle Scholar
  77. 77.
    Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, Agarwalla PK, Chheda MG, Campos B, Wang A, Brennan C, Ligon KL, Furnari F, Cavenee WK, Depinho RA, Chin L, Hahn WC. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 2012;26(8):756–84.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Joo KM, Jin J, Kim E, Ho Kim K, Kim Y, Kang BG, Kang Y-J, Lathia JD, Cheong KH, Song PH, Kim H, Seol HJ, Kong D-S, Lee J-I, Rich JN, Lee J, Nam D-H. MET signaling regulates glioblastoma stem cells. Cancer Res. 2012;72(15):3828–38.PubMedGoogle Scholar
  79. 79.
    Vogel S, Peters C, Etminan N, Börger V, Schimanski A, Sabel MC, Sorg RV. Migration of mesenchymal stem cells towards glioblastoma cells depends on hepatocyte-growth factor and is enhanced by aminolaevulinic acid-mediated photodynamic treatment. Biochem Biophys Res Commun. 2013;431(3):428–32.PubMedGoogle Scholar
  80. 80.
    Abounader R, Ranganathan S, Lal B, Fielding K, Book A, Dietz H, Burger P, Laterra J. Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expression. J Natl Cancer Inst. 1999;91(18):1548–56.PubMedGoogle Scholar
  81. 81.
    Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, Isachenko N, Fouse SD, Phillips JJ, Cheresh DA, Park M, Bergers G. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell. 2012;22(1):21–35.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Jin J, Bae KH, Yang H, Lee SJ, Kim H, Kim Y, Joo KM, Seo SW, Park TG, Nam D-H. In vivo specific delivery of c-Met siRNA to glioblastoma using cationic solid lipid nanoparticles. Bioconjug Chem. 2011;22(12):2568–72.PubMedGoogle Scholar
  83. 83.
    Cao B, Su Y, Oskarsson M, Zhao P, Kort EJ, Fisher RJ, Wang LM, Vande Woude GF. Neutralizing monoclonal antibodies to hepatocyte growth factor/scatter factor (HGF/SF) display antitumor activity in animal models. Proc Natl Acad Sci U S A. 2001;98(13):7443–8.PubMedCentralPubMedGoogle Scholar
  84. 84.
    Lal B, Xia S, Abounader R, Laterra J. Targeting the c-Met pathway potentiates glioblastoma responses to gamma-radiation. Clin Cancer Res. 2005;11(12):4479–86.PubMedGoogle Scholar
  85. 85.
    Exelixis. Safety study of XL184 (Cabozantinib) in combination with temozolomide and radiation therapy in the initial treatment of adults with glioblastoma. [Online]. Available http://clinicaltrials.gov/ct2/show/NCT00960492?term=cabozantinib&rank=10. Accessed 11 Mar 2014.
  86. 86.
    Liu X, Newton RC, Scherle PA. Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol Med. 2010;16(1):37–45.PubMedGoogle Scholar
  87. 87.
    Zhang Y, Guessous F, Kofman A, Schiff D, Abounader R. XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC. IDrugs Investig Drugs J. 2010;13(2):112–21.Google Scholar
  88. 88.
    Exelixis. Study of XL184 (Cabozantinib) in adults with glioblastoma multiforme. [Online]. Available http://clinicaltrials.gov/ct2/show/NCT00704288?term=cabozantinib&rank=43. Accessed 11 Mar 2014.
  89. 89.
    Amgen. A phase II study to treat advanced malignant glioma.[Online]. Available http://www.clinicaltrials.gov/ct2/show/NCT00427440?term=rilotumumab&rank=12. Accessed 11 Mar 2014.
  90. 90.
    Peters K, Amgen. AMG 102 and avastin for recurrent malignant glioma. [Online]. Available http://www.clinicaltrials.gov/ct2/show/NCT01113398?term=rilotumumab&rank=6. Accessed 11 Mar 2014.
  91. 91.
    Acquati S, Greco A, Licastro D, Bhagat H, Ceric D, Rossini Z, Grieve J, Shaked-Rabi M, Henriquez NV, Brandner S, Stupka E, Marino S. Epigenetic regulation of survivin by Bmi1 is cell type specific during corticogenesis and in gliomas. Stem Cells (Dayton Ohio). 2013;31(1):190–202.Google Scholar
  92. 92.
    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(30):10096–111.PubMedGoogle Scholar
  93. 93.
    Valk-Lingbeek ME, Bruggeman SWM, van Lohuizen M. Stem cells and cancer; the polycomb connection. Cell. 2004;118(4):409–18.PubMedGoogle Scholar
  94. 94.
    Häyry V, Tynninen O, Haapasalo HK, Wölfer J, Paulus W, Hasselblatt M, Sariola H, Paetau A, Sarna S, Niemelä M, Wartiovaara K, Nupponen NN. Stem cell protein BMI-1 is an independent marker for poor prognosis in oligodendroglial tumours. Neuropathol Appl Neurobiol. 2008;34(5):555–63.PubMedGoogle Scholar
  95. 95.
    Jamal M, Rath BH, Williams ES, Camphausen K, Tofilon PJ. Microenvironmental regulation of glioblastoma radioresponse. Clin Cancer Res. 2010;16(24):6049–59.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Wang J, Sullenger BA, Rich JN. Notch signaling in cancer stem cells. Adv Exp Med Biol. 2012;727:174–85.PubMedGoogle Scholar
  97. 97.
    Rizzo P, Osipo C, Foreman K, Golde T, Osborne B, Miele L. Rational targeting of Notch signaling in cancer. Oncogene. 2008;27(38):5124–31.PubMedGoogle Scholar
  98. 98.
    Guruharsha KG, Kankel MW, Artavanis-Tsakonas S. The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet. 2012;13(9):654–66.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Stockhausen M-T, Kristoffersen K, Poulsen HS. The functional role of Notch signaling in human gliomas. Neuro Oncol. 2010;12(2):199–211.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang X-F, White RR, Rich JN, Sullenger BA. Notch promotes radioresistance of glioma stem cells. Stem Cells (Dayton Ohio). 2010;28(1):17–28.Google Scholar
  101. 101.
    Barcellos-Hoff MH. Radiation-induced transforming growth factor beta and subsequent extracellular matrix reorganization in murine mammary gland. Cancer Res. 1993;53(17):3880–6.PubMedGoogle Scholar
  102. 102.
    Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, Koh C, Zhang J, Li Y-M, Maciaczyk J, Nikkhah G, Dimeco F, Piccirillo S, Vescovi AL, Eberhart CG. NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells (Dayton Ohio). 2010;28(1):5–16.Google Scholar
  103. 103.
    Hovinga KE, Shimizu F, Wang R, Panagiotakos G, Van Der Heijden M, Moayedpardazi H, Correia AS, 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 (Dayton Ohio). 2010;28(6):1019–29.Google Scholar
  104. 104.
    Rivera M, Sukhdeo K, Yu J. Ionizing radiation in glioblastoma initiating cells. Front Oncol. 2013;3:74.PubMedCentralPubMedGoogle Scholar
  105. 105.
    National Cancer Institute. RO4929097, temozolomide, and radiation therapy in treating patients with newly diagnosed malignant glioma. [Online]. http://www.clinicaltrials.gov/ct2/show/NCT01119599?term=RO4929097&rank=25. [Accessed: 11-Mar-2014].
  106. 106.
    National Cancer Institute. Gamma-secretase/notch signalling pathway inhibitor ro4929097 in treating patients with recurrent or progressive glioblastoma. [Online]. Available: http://www.clinicaltrials.gov/ct2/show/NCT01122901?term=RO4929097&rank=6. Accessed 11 Mar 2014.
  107. 107.
    National Cancer Institute. RO4929097 in treating patients with recurrent invasive gliomas. [Online]. Available http://www.clinicaltrials.gov/ct2/show/NCT01269411?term=RO4929097&rank=18. Accessed 11 Mar 2014.
  108. 108.
    National Cancer Institute. Gamma-secretase inhibitor RO4929097 and Cediranib Maleate in Treating Patients With Advanced Solid Tumors. [Online]. Available http://www.clinicaltrials.gov/ct2/show/NCT01131234?term=RO4929097&rank=13. Accessed 11 Mar 2014.
  109. 109.
    National Cancer Institute. RO4929097 and Bevacizumab in Treating Patients With Progressive or Recurrent Malignant Glioma. [Online]. Available http://www.clinicaltrials.gov/ct2/show/NCT01189240?term=RO4929097&rank=31. Accessed: 11 Mar 2014.
  110. 110.
    Hambardzumyan D, Becher OJ, Holland EC. Cancer stem cells and survival pathways. Cell Cycle. 2008;7(10):1371–8.PubMedGoogle Scholar
  111. 111.
    Broderick DK, Di C, Parrett TJ, Samuels YR, Cummins JM, McLendon RE, Fults DW, Velculescu VE, Bigner DD, Yan H. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Res. 2004;64(15):5048–50.PubMedGoogle Scholar
  112. 112.
    Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JKV, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304(5670):554.PubMedGoogle Scholar
  113. 113.
    Hurtt MR, Moossy J, Donovan-Peluso M, Locker J. Amplification of epidermal growth factor receptor gene in gliomas: histopathology and prognosis. J Neuropathol Exp Neurol. 1992;51(1):84–90.PubMedGoogle Scholar
  114. 114.
    Knobbe CB, Merlo A, Reifenberger G. Pten signaling in gliomas. Neuro Oncol. 2002;4(3):196–211.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A. 1992;89(7):2965–9.PubMedCentralPubMedGoogle Scholar
  116. 116.
    Eyler CE, Foo W-C, LaFiura KM, McLendon RE, Hjelmeland AB, Rich JN. Brain cancer stem cells display preferential sensitivity to Akt inhibition. Stem Cells (Dayton Ohio). 2008;26(12):3027–36.Google Scholar
  117. 117.
    Gallia GL, Tyler BM, Hann CL, Siu I-M, Giranda VL, Vescovi AL, Brem H, Riggins GJ. Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. Mol Cancer Ther. 2009;8(2):386–93.PubMedGoogle Scholar
  118. 118.
    Li H-F, Kim J-S, Waldman T. Radiation-induced Akt activation modulates radioresistance in human glioblastoma cells. Radiat Oncol Lond Engl. 2009;4:43.Google Scholar
  119. 119.
    Park C-M, Park M-J, Kwak H-J, Lee H-C, Kim M-S, Lee S-H, Park I-C, Rhee CH, Hong S-I. Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways. Cancer Res. 2006;66(17):8511–9.PubMedGoogle Scholar
  120. 120.
    Zhai GG, Malhotra R, Delaney M, Latham D, Nestler U, Zhang M, Mukherjee N, Song Q, Robe P, Chakravarti A. Radiation enhances the invasive potential of primary glioblastoma cells via activation of the Rho signaling pathway. J Neurooncol. 2006;76(3):227–37.PubMedGoogle Scholar
  121. 121.
    Nakamura JL, Karlsson A, Arvold ND, Gottschalk AR, Pieper RO, Stokoe D, Haas-Kogan DA. PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human malignant gliomas. J Neurooncol. 2005;71(3):215–22.PubMedGoogle Scholar
  122. 122.
    Kao GD, Jiang Z, Fernandes AM, Gupta AK, Maity A. Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem. 2007;282(29):21206–12.PubMedCentralPubMedGoogle Scholar
  123. 123.
    Kuger S, Graus D, Brendtke R, Günther N, Katzer A, Lutyj P, Polat B, Chatterjee M, Sukhorukov VL, Flentje M, Djuzenova CS. Radiosensitization of Glioblastoma Cell Lines by the Dual PI3K and mTOR Inhibitor NVP-BEZ235 Depends on Drug-Irradiation Schedule. Transl Oncol. 2013;6(2):169–79.PubMedCentralPubMedGoogle Scholar
  124. 124.
    Anandharaj A, Cinghu S, Park W-Y. Rapamycin-mediated mTOR inhibition attenuates survivin and sensitizes glioblastoma cells to radiation therapy. Acta Biochim Biophys Sin. 2011;43(4):292–300.PubMedGoogle Scholar
  125. 125.
    Burris 3rd HA. Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol. 2013;71(4):829–42.PubMedGoogle Scholar
  126. 126.
    Janku F, McConkey DJ, Hong DS, Kurzrock R. Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol. 2011;8(9):528–39.PubMedGoogle Scholar
  127. 127.
    Lomonaco SL, Finniss S, Xiang C, Decarvalho A, Umansky F, Kalkanis SN, Mikkelsen T, Brodie C. The induction of autophagy by gamma-radiation contributes to the radioresistance of glioma stem cells. Int J Cancer. 2009;125(3):717–22.PubMedGoogle Scholar
  128. 128.
    Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471–84.PubMedGoogle Scholar
  129. 129.
    Wang W, Long L, Yang N, Zhang Q, Ji W, Zhao J, Qin Z, Wang Z, Chen G, Liang Z. NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro. Acta Pharmacol Sin. 2013;34(5):681–90.PubMedCentralPubMedGoogle Scholar
  130. 130.
    Zhuang W, Li B, Long L, Chen L, Huang Q, Liang Z. Induction of autophagy promotes differentiation of glioma-initiating cells and their radiosensitivity. Int J Cancer. 2011;129(11):2720–31.PubMedGoogle Scholar
  131. 131.
    Lomonaco SL, Finniss S, Xiang C, Lee HK, Jiang W, Lemke N, Rempel SA, Mikkelsen T, Brodie C. Cilengitide induces autophagy-mediated cell death in glioma cells. Neuro Oncol. 2011;13(8):857–65.PubMedCentralPubMedGoogle Scholar
  132. 132.
    Jamal M, Rath BH, Tsang PS, Camphausen K, Tofilon PJ. The brain microenvironment preferentially enhances the radioresistance of CD133(+) glioblastoma stem-like cells. Neoplasia. 2012;14(2):150–8.PubMedCentralPubMedGoogle Scholar
  133. 133.
    Cooper LAD, Gutman DA, Chisolm C, Appin C, Kong J, Rong Y, Kurc T, Van Meir EG, Saltz JH, Moreno CS, Brat DJ. The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma. Am J Pathol. 2012;180(5):2108–19.PubMedCentralPubMedGoogle Scholar
  134. 134.
    Barcellos-Hoff MH, Newcomb EW, Zagzag D, Narayana A. Therapeutic targets in malignant glioblastoma microenvironment. Semin Radiat Oncol. 2009;19(3):163–70.PubMedCentralPubMedGoogle Scholar
  135. 135.
    Lathia JD, Heddleston JM, Venere M, Rich JN. Deadly teamwork: neural cancer stem cells and the tumor microenvironment. Cell Stem Cell. 2011;8(5):482–5.PubMedCentralPubMedGoogle Scholar
  136. 136.
    Heddleston JM, Hitomi M, Venere M, Flavahan WA, Yang K, Kim Y, Minhas S, Rich JN, Hjelmeland AB. Glioma stem cell maintenance: the role of the microenvironment. Curr Pharm Des. 2011;17(23):2386–401.PubMedCentralPubMedGoogle Scholar
  137. 137.
    Zeman EM. Biologic basis of radiation oncology, in Clinical radiation oncology, Gunderson LL and Tepper JE, Eds., 3rd ed. Philadelphia, PA Elsevier Saunders; 2012, Chapter 1, pp. 3–42.Google Scholar
  138. 138.
    Denysenko T, Gennero L, Roos MA, Melcarne A, Juenemann C, Faccani G, Morra I, Cavallo G, Reguzzi S, Pescarmona G, Ponzetto A. Glioblastoma cancer stem cells: heterogeneity, microenvironment and related therapeutic strategies. Cell Biochem Funct. 2010;28(5):343–51.PubMedGoogle Scholar
  139. 139.
    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, Gajjar A, Davidoff A, Gilbertson RJ. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11(1):69–82.PubMedGoogle Scholar
  140. 140.
    Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64(19):7011–21.PubMedGoogle Scholar
  141. 141.
    Borovski T, Beke P, van Tellingen O, Rodermond HM, Verhoeff JJ, Lascano V, Daalhuisen JB, Medema JP, Sprick MR. Therapy-resistant tumor microvascular endothelial cells contribute to treatment failure in glioblastoma multiforme. Oncogene. 2013;32(12):1539–48.PubMedGoogle Scholar
  142. 142.
    Zhu TS, Costello MA, Talsma CE, Flack CG, Crowley JG, Hamm LL, He X, Hervey-Jumper SL, Heth JA, Muraszko KM, DiMeco F, Vescovi AL, Fan X. Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res. 2011;71(18):6061–72.PubMedCentralPubMedGoogle Scholar
  143. 143.
    Gürsel DB, Berry N, Boockvar JA. The contribution of Notch signaling to glioblastoma via activation of cancer stem cell self-renewal: the role of the endothelial network. Neurosurgery. 2012;70(2):N19–21.PubMedGoogle Scholar
  144. 144.
    Charles N, Ozawa T, Squatrito M, Bleau A-M, Brennan CW, Hambardzumyan D, Holland EC. Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell. 2010;6(2):141–52.PubMedGoogle Scholar
  145. 145.
    Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, Min W, McLendon RE, Rich JN, Bao S. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153(1):139–52.PubMedCentralPubMedGoogle Scholar
  146. 146.
    Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 2006;66(16):7843–8.PubMedGoogle Scholar
  147. 147.
    Oka N, Soeda A, Inagaki A, Onodera M, Maruyama H, Hara A, Kunisada T, Mori H, Iwama T. VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells. Biochem Biophys Res Commun. 2007;360(3):553–9.PubMedGoogle Scholar
  148. 148.
    Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3(6):401–10.PubMedGoogle Scholar
  149. 149.
    Rahmathulla G, Hovey EJ, Hashemi-Sadraei N, Ahluwalia MS. Bevacizumab in high-grade gliomas: a review of its uses, toxicity assessment, and future treatment challenges. OncoTargets Ther. 2013;6:371–89.Google Scholar
  150. 150.
    Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran Jr WJ, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708.PubMedCentralPubMedGoogle Scholar
  151. 151.
    Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, Yee H, Voura EB, Newcomb EW. Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest. 2006;86(12):1221–32.PubMedGoogle Scholar
  152. 152.
    Zagzag D, Esencay M, Mendez O, Yee H, Smirnova I, Huang Y, Chiriboga L, Lukyanov E, Liu M, Newcomb EW. Hypoxia- and vascular endothelial growth factor-induced stromal cell-derived factor-1alpha/CXCR4 expression in glioblastomas: one plausible explanation of Scherer’s structures. Am J Pathol. 2008;173(2):545–60.PubMedCentralPubMedGoogle Scholar
  153. 153.
    Ehtesham M, Winston JA, Kabos P, Thompson RC. CXCR4 expression mediates glioma cell invasiveness. Oncogene. 2006;25(19):2801–6.PubMedGoogle Scholar
  154. 154.
    Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001;29(2):117–29.PubMedGoogle Scholar
  155. 155.
    Jachimczak P, Hessdörfer B, Fabel-Schulte K, Wismeth C, Brysch W, Schlingensiepen KH, Bauer A, Blesch A, Bogdahn U. Transforming growth factor-beta-mediated autocrine growth regulation of gliomas as detected with phosphorothioate antisense oligonucleotides. Int J Cancer. 1996;65(3):332–7.PubMedGoogle Scholar
  156. 156.
    Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol. 1998;16:137–61.PubMedGoogle Scholar
  157. 157.
    Peñuelas S, Anido J, Prieto-Sánchez RM, Folch G, Barba I, Cuartas I, García-Dorado D, Poca MA, 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(4):315–27.PubMedGoogle Scholar
  158. 158.
    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(5):504–14.PubMedGoogle Scholar
  159. 159.
    Anido J, Sáez-Borderías A, Gonzàlez-Juncà A, Rodón L, Folch G, Carmona MA, Prieto-Sánchez RM, Barba I, Martínez-Sáez E, Prudkin L, Cuartas I, Raventós C, Martínez-Ricarte F, Poca MA, García-Dorado D, Lahn MM, Yingling JM, Rodón J, Sahuquillo J, Baselga J, Seoane J. TGF-β receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell. 2010;18(6):655–68.PubMedGoogle Scholar
  160. 160.
    Hardee ME, Marciscano AE, Medina-Ramirez CM, Zagzag D, Narayana A, Lonning SM, Barcellos-Hoff MH. Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-β. Cancer Res. 2012;72(16):4119–29.PubMedCentralPubMedGoogle Scholar
  161. 161.
    Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249–57.PubMedGoogle Scholar
  162. 162.
    Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008;8(6):425–37.PubMedCentralPubMedGoogle Scholar
  163. 163.
    Evans SM, Jenkins KW, Jenkins WT, Dilling T, Judy KD, Schrlau A, Judkins A, Hahn SM, Koch CJ. Imaging and analytical methods as applied to the evaluation of vasculature and hypoxia in human brain tumors. Radiat Res. 2008;170(6):677–90.PubMedCentralPubMedGoogle Scholar
  164. 164.
    Evans SM, Judy KD, Dunphy I, Jenkins WT, Nelson PT, Collins R, Wileyto EP, Jenkins K, Hahn SM, Stevens CW, Judkins AR, Phillips P, Geoerger B, Koch CJ. Comparative measurements of hypoxia in human brain tumors using needle electrodes and EF5 binding. Cancer Res. 2004;64(5):1886–92.PubMedGoogle Scholar
  165. 165.
    Evans SM, Jenkins KW, Chen HI, Jenkins WT, Judy KD, Hwang W-T, Lustig RA, Judkins AR, Grady MS, Hahn SM, Koch CJ. The relationship among hypoxia, proliferation, and outcome in patients with de novo glioblastoma: a pilot study. Transl Oncol. 2010;3(3):160–9.PubMedCentralPubMedGoogle Scholar
  166. 166.
    Sathornsumetee S, Cao Y, Marcello JE, Herndon 2nd JE, McLendon RE, Desjardins A, Friedman HS, Dewhirst MW, Vredenburgh JJ, Rich JN. Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol. 2008;26(2):271–8.PubMedCentralPubMedGoogle Scholar
  167. 167.
    Platet N, Liu SY, Atifi ME, Oliver L, Vallette FM, Berger F, Wion D. Influence of oxygen tension on CD133 phenotype in human glioma cell cultures. Cancer Lett. 2007;258(2):286–90.PubMedGoogle Scholar
  168. 168.
    Pistollato F, Abbadi S, Rampazzo E, Persano L, Della Puppa A, Frasson C, Sarto E, Scienza R, D’avella D, Basso G. Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem Cells (Dayton Ohio). 2010;28(5):851–62.Google Scholar
  169. 169.
    Persano L, Rampazzo E, Basso G, Viola G. Glioblastoma cancer stem cells: role of the microenvironment and therapeutic targeting. Biochem Pharmacol. 2013;85(5):612–22.PubMedGoogle Scholar
  170. 170.
    McCord AM, Jamal M, Shankavaram UT, Shankavarum UT, Lang FF, Camphausen K, Tofilon PJ. Physiologic oxygen concentration enhances the stem-like properties of CD133+ human glioblastoma cells in vitro. Mol Cancer Res. 2009;7(4):489–97.PubMedGoogle Scholar
  171. 171.
    Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40(2):294–309.PubMedCentralPubMedGoogle Scholar
  172. 172.
    Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu C-J, Labosky PA, Simon MC, Keith B. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 2006;20(5):557–70.PubMedCentralPubMedGoogle Scholar
  173. 173.
    Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, Rich JN. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15(6):501–13.PubMedCentralPubMedGoogle Scholar
  174. 174.
    Zhao T, Zhang C, Liu Z, Wu L, Huang X, Wu H, Xiong L, Wang X, Wang X, Zhu L, Fan M. Hypoxia-driven proliferation of embryonic neural stem/progenitor cells—role of hypoxia-inducible transcription factor-1alpha. FEBS J. 2008;275(8):1824–34.PubMedGoogle Scholar
  175. 175.
    Simon M-P, Tournaire R, Pouyssegur J. The angiopoietin-2 gene of endothelial cells is up-regulated in hypoxia by a HIF binding site located in its first intron and by the central factors GATA-2 and Ets-1. J Cell Physiol. 2008;217(3):809–18.PubMedGoogle Scholar
  176. 176.
    Yamakawa M, Liu LX, Belanger AJ, Date T, Kuriyama T, Goldberg MA, Cheng SH, Gregory RJ, Jiang C. Expression of angiopoietins in renal epithelial and clear cell carcinoma cells: regulation by hypoxia and participation in angiogenesis. Am J Physiol Renal Physiol. 2004;287(4):F649–57.PubMedGoogle Scholar
  177. 177.
    Bar EE, Lin A, Mahairaki V, Matsui W, Eberhart CG. Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am J Pathol. 2010;177(3):1491–502.PubMedCentralPubMedGoogle Scholar
  178. 178.
    Zimmer M, Ebert BL, Neil C, Brenner K, Papaioannou I, Melas A, Tolliday N, Lamb J, Pantopoulos K, Golub T, Iliopoulos O. Small-molecule inhibitors of HIF-2a translation link its 5′UTR iron-responsive element to oxygen sensing. Mol Cell. 2008;32(6):838–48.PubMedCentralPubMedGoogle Scholar
  179. 179.
    Amundson SA, Bittner M, Chen Y, Trent J, Meltzer P, Fornace Jr AJ. Fluorescent cDNA microarray hybridization reveals complexity and heterogeneity of cellular genotoxic stress responses. Oncogene. 1999;18(24):3666–72.PubMedGoogle Scholar
  180. 180.
    Burns TF, El-Deiry WS. Microarray analysis of p53 target gene expression patterns in the spleen and thymus in response to ionizing radiation. Cancer Biol Ther. 2003;2(4):431–43.PubMedGoogle Scholar
  181. 181.
    Rødningen OK, Overgaard J, Alsner J, Hastie T, Børresen-Dale A-L. Microarray analysis of the transcriptional response to single or multiple doses of ionizing radiation in human subcutaneous fibroblasts. Radiother Oncol. 2005;77(3):231–40.PubMedGoogle Scholar
  182. 182.
    Glantz M, Kesari S, Recht L, Fleischhack G, Van Horn A. Understanding the origins of gliomas and developing novel therapies: cerebrospinal fluid and subventricular zone interplay. Semin Oncol. 2009;36(4 Suppl 2):S17–24.PubMedGoogle Scholar
  183. 183.
    Tada E, Yang C, Gobbel GT, Lamborn KR, Fike JR. Long-term impairment of subependymal repopulation following damage by ionizing irradiation. Exp Neurol. 1999;160(1):66–77.PubMedGoogle Scholar
  184. 184.
    Panagiotakos G, Alshamy G, Chan B, Abrams R, Greenberg E, Saxena A, Bradbury M, Edgar M, Gutin P, Tabar V. Long-term impact of radiation on the stem cell and oligodendrocyte precursors in the brain. PloS One. 2007;2(7):e588.PubMedCentralPubMedGoogle Scholar
  185. 185.
    Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002;8(9):955–62.PubMedGoogle Scholar
  186. 186.
    Redmond KJ, Mahone EM, Terezakis S, Ishaq O, Ford E, McNutt T, Kleinberg L, Cohen KJ, Wharam M, Horska A. Association between radiation dose to neuronal progenitor cell niches and temporal lobes and performance on neuropsychological testing in children: a prospective study. Neuro Oncol. 2013;15(3):360–9.PubMedCentralPubMedGoogle Scholar
  187. 187.
    Llaguno SA, Chen J, Kwon C-H, Parada LF. Neural and cancer stem cells in tumor suppressor mouse models of malignant astrocytoma. Cold Spring Harb Symp Quant Biol. 2008;73:421–6.PubMedGoogle Scholar
  188. 188.
    Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet. 2000;25(1):55–7.PubMedGoogle Scholar
  189. 189.
    Uhrbom L, Dai C, Celestino JC, Rosenblum MK, Fuller GN, Holland EC. Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res. 2002;62(19):5551–8.PubMedGoogle Scholar
  190. 190.
    Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, Tang Y, DeFrances J, Stover E, Weissleder R, Rowitch DH, Louis DN, DePinho RA. 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(3):269–77.PubMedGoogle Scholar
  191. 191.
    Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP, Messing A, Parada LF. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell. 2005;8(2):119–30.PubMedCentralPubMedGoogle Scholar
  192. 192.
    Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, Roy M, Quinones-Hinojosa A, VandenBerg S, Alvarez-Buylla A. PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron. 2006;51(2):187–99.PubMedGoogle Scholar
  193. 193.
    Glass R, Synowitz M, Kronenberg G, Walzlein J-H, Markovic DS, Wang L-P, Gast D, Kiwit J, Kempermann G, Kettenmann H. Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci. 2005;25(10):2637–46.PubMedGoogle Scholar
  194. 194.
    Duntsch C, Zhou Q, Weimar JD, Frankel B, Robertson JH, Pourmotabbed T. Up-regulation of neuropoiesis generating glial progenitors that infiltrate rat intracranial glioma. J Neurooncol. 2005;71(3):245–55.PubMedGoogle Scholar
  195. 195.
    Gibbs IC, Haas-Kogan D, Terezakis S, Kavanagh BD. The subventricular zone neural progenitor cell hypothesis in glioblastoma: epiphany, Trojan Horse, or Cheshire fact? Int J Radiat Oncol Biol Phys. 2013;86(4):606–8.PubMedGoogle Scholar
  196. 196.
    Jafri NF, Clarke JL, Weinberg V, Barani IJ, Cha S. Relationship of glioblastoma multiforme to the subventricular zone is associated with survival. Neuro Oncol. 2013;15(1):91–6.PubMedCentralPubMedGoogle Scholar
  197. 197.
    Chaichana KL, McGirt MJ, Frazier J, Attenello F, Guerrero-Cazares H, Quinones-Hinojosa A. Relationship of glioblastoma multiforme to the lateral ventricles predicts survival following tumor resection. J Neurooncol. 2008;89(2):219–24.PubMedGoogle Scholar
  198. 198.
    Chen L, Guerrero-Cazares H, Ye X, Ford E, McNutt T, Kleinberg L, Lim M, Chaichana K, Quinones-Hinojosa A, Redmond K. Increased subventricular zone radiation dose correlates with survival in glioblastoma patients after gross total resection. Int J Radiat Oncol Biol Phys. 2013;86(4):616–22.PubMedCentralPubMedGoogle Scholar
  199. 199.
    Lee P, Eppinga W, Lagerwaard F, Cloughesy T, Slotman B, Nghiemphu PL, Wang P-C, Kupelian P, Agazaryan N, Demarco J, Selch MT, Steinberg M, Kang JJ. Evaluation of high ipsilateral subventricular zone radiation therapy dose in glioblastoma: a pooled analysis. Int J Radiat Oncol Biol Phys. 2013;86(4):609–15.PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Stem Cell Biology and Regenerative Medicine, Lerner Research InstituteCleveland ClinicClevelandUSA
  2. 2.Department of Radiation OncologyCleveland ClinicClevelandUSA

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