Glioblastoma Stem Cells as a Therapeutic Target

  • Devaraj Ezhilarasan
  • R. Ileng Kumaran
  • Ilangovan Ramachandran
  • Santosh Yadav
  • Muralidharan AnbalaganEmail author


Glioblastoma (GBM) is a deadly brain tumor with poor prognosis despite the improvement in the diagnosis of GBM and innovative treatment strategies. Chemotherapy and radiotherapy could only help the GBM patients to a mean survival of 15 months. One of the key reasons for this poor outcome is a complex tumor heterogeneity and the presence of cancer stem cells (CSCs). CSCs in GBM (GSCs) are responsible for drug resistance and relapse. Cancer cells (non-GSC) are normally sensitive to drug treatment, whereas GSCs are resistant to treatment. This chapter describes the complexity of GSC and their microenvironment niche, GSCs as a therapeutic target, and details on clinical trials that target GSCs. This knowledge may help us in better understanding CSCs in glioblastoma and developing new therapeutic strategies for this deadly disease.


Cancer stem cells Glioblastoma Brain tumor Radioresistance 


  1. 1.
    GBD 2016 Brain and Other CNS Cancer Collaborators (2019) Global, regional, and national burden of brain and other CNS cancer, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 18(4):376–393CrossRefGoogle Scholar
  2. 2.
    Leece R et al (2017) Global incidence of malignant brain and other central nervous system tumors by histology, 2003–2007. Neuro Oncol 19(11):1553–1564PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Hanif F et al (2017) Glioblastoma Multiforme: a review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev 18(1):3–9PubMedPubMedCentralGoogle Scholar
  4. 4.
    Jovcevska I, Kocevar N, Komel R (2013) Glioma and glioblastoma—how much do we (not) know? Mol Clin Oncol 1(6):935–941PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Ladomersky E et al (2019) The coincidence between increasing age, immunosuppression, and the incidence of patients with glioblastoma. Front Pharmacol 10:200PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Rock K et al (2012) A clinical review of treatment outcomes in glioblastoma multiforme--the validation in a non-trial population of the results of a randomised phase III clinical trial: has a more radical approach improved survival? Br J Radiol 85(1017):e729–e733PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Gimple RC et al (2019) Glioblastoma stem cells: lessons from the tumor hierarchy in a lethal cancer. Genes Dev 33(11–12):591–609PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Ostrom QT et al (2015) Epidemiology of gliomas. Cancer Treat Res 163:1–14PubMedCrossRefGoogle Scholar
  9. 9.
    Ostrom QT et al (2014) The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol 16(7):896–913PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Thakkar JP et al (2014) Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomarkers Prev 23(10):1985–1996PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Xu H et al (2017) Geographic variations in the incidence of Glioblastoma and prognostic factors predictive of overall survival in US adults from 2004–2013. Front Aging Neurosci 9:352PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Bohn A et al (2018) The association between race and survival in glioblastoma patients in the US: a retrospective cohort study. PLoS One 13(6):e0198581PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Yang M et al (2017) Mobile phone use and glioma risk: a systematic review and meta-analysis. PLoS One 12(5):e0175136PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Karipidis K et al (2018) Mobile phone use and incidence of brain tumour histological types, grading or anatomical location: a population-based ecological study. BMJ Open 8(12):e024489PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Nelson JS et al (2012) Potential risk factors for incident glioblastoma multiforme: the Honolulu Heart Program and Honolulu-Asia Aging Study. J Neurooncol 109(2):315–321PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Bahadur S et al (2019) Current promising treatment strategy for glioblastoma multiform: a review. Oncol Rev 13(2):417PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Perry JR et al (2017) Short-course radiation plus Temozolomide in elderly patients with glioblastoma. N Engl J Med 376(11):1027–1037PubMedCrossRefGoogle Scholar
  18. 18.
    Carter TC, Medina-Flores R, Lawler BE (2018) Glioblastoma treatment with Temozolomide and Bevacizumab and overall survival in a rural tertiary healthcare practice. Biomed Res Int 2018:6204676PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    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
  20. 20.
    Uchida N et al (2000) Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci U S A 97(26):14720–14725PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Ignatova TN et al (2002) Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39(3):193–206PubMedCrossRefGoogle Scholar
  22. 22.
    Hemmati HD et al (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 100(25):15178–15183PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Singh SK et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63(18):5821–5828PubMedGoogle Scholar
  24. 24.
    Galli R et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64(19):7011–7021PubMedCrossRefGoogle Scholar
  25. 25.
    Ogawa K et al (2013) Radiotherapy targeting cancer stem cells: current views and future perspectives. Anticancer Res 33(3):747–754PubMedGoogle Scholar
  26. 26.
    Singh SK et al (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401PubMedCrossRefGoogle Scholar
  27. 27.
    Eramo A et al (2006) Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ 13(7):1238–1241PubMedCrossRefGoogle Scholar
  28. 28.
    Auffinger B et al (2015) The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence. Expert Rev Neurother 15(7):741–752PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Sanai N et al (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427(6976):740–744PubMedCrossRefGoogle Scholar
  30. 30.
    Kwan K et al (2019) Tracing the origin of glioblastoma: subventricular zone neural stem cells. Neurosurgery 84(1):E15–E16PubMedCrossRefGoogle Scholar
  31. 31.
    Lee JH et al (2018) Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature 560(7717):243–247PubMedCrossRefGoogle Scholar
  32. 32.
    Gage FH (2000) Mammalian neural stem cells. Science 287(5457):1433–1438PubMedCrossRefGoogle Scholar
  33. 33.
    Shipitsin M, Polyak K (2008) The cancer stem cell hypothesis: in search of definitions, markers, and relevance. Lab Invest 88(5):459–463PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Bradshaw A et al (2016) Cancer stem cell hierarchy in glioblastoma multiforme. Front Surg 3:21PubMedPubMedCentralGoogle Scholar
  35. 35.
    Safa AR et al (2015) Glioblastoma stem cells (GSCs) epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs. Genes Dis 2(2):152–163PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Xu HS et al (2017) Cancer stem cell markers in glioblastoma—an update. Eur Rev Med Pharmacol Sci 21(14):3207–3211PubMedGoogle Scholar
  37. 37.
    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
  38. 38.
    Wang J et al (2008) CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer 122(4):761–768PubMedCrossRefGoogle Scholar
  39. 39.
    Gopisetty G et al (2013) Epigenetic regulation of CD133/PROM1 expression in glioma stem cells by Sp1/myc and promoter methylation. Oncogene 32(26):3119–3129PubMedCrossRefGoogle Scholar
  40. 40.
    Laks DR et al (2009) Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells 27(4):980–987PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Read TA et al (2009) Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell 15(2):135–147PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Son MJ et al (2009) SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell 4(5):440–452PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Brescia P, Richichi C, Pelicci G (2012) Current strategies for identification of glioma stem cells: adequate or unsatisfactory? J Oncol 2012:376894PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Kenney-Herbert E et al (2015) CD15 expression does not identify a phenotypically or genetically distinct glioblastoma population. Stem Cells Transl Med 4(7):822–831PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Dong Q et al (2019) Elevated CD44 expression predicts poor prognosis in patients with low-grade glioma. Oncol Lett 18(4):3698–3704PubMedPubMedCentralGoogle Scholar
  46. 46.
    Nishikawa M et al (2018) Significance of glioma stem-like cells in the tumor periphery that express high levels of CD44 in tumor invasion, early progression, and poor prognosis in glioblastoma. Stem Cells Int 2018:5387041PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Liu WH et al (2020) CD44-associated radioresistance of glioblastoma in irradiated brain areas with optimal tumor coverage. Cancer Med 9(1):350–360PubMedCrossRefGoogle Scholar
  48. 48.
    Lathia JD et al (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6(5):421–432PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Kowalski-Chauvel A et al (2018) Alpha-6 integrin promotes radioresistance of glioblastoma by modulating DNA damage response and the transcription factor Zeb1. Cell Death Dis 9(9):872PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Munksgaard Thoren M et al (2019) Integrin alpha10, a novel therapeutic target in glioblastoma, regulates cell migration, proliferation, and survival. Cancers (Basel) 11(4):587CrossRefGoogle Scholar
  51. 51.
    Rodda DJ et al (2005) Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem 280(26):24731–24737PubMedCrossRefGoogle Scholar
  52. 52.
    Singh S et al (2012) EGFR/Src/Akt signaling modulates Sox2 expression and self-renewal of stem-like side-population cells in non-small cell lung cancer. Mol Cancer 11:73PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Takashima Y, Kawaguchi A, Yamanaka R (2019) Promising prognosis marker candidates on the status of epithelial-mesenchymal transition and glioma stem cells in glioblastoma. Cell 8(11):1312CrossRefGoogle Scholar
  54. 54.
    Dundar TT et al (2019) Glioblastoma stem cells and comparison of isolation methods. J Clin Med Res 11(6):415–421PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Chesnelong C, Restall I, Weiss S (2019) Isolation and culture of glioblastoma brain tumor stem cells. Methods Mol Biol 1869:11–21PubMedCrossRefGoogle Scholar
  56. 56.
    Podergajs N et al (2013) Expansive growth of two glioblastoma stem-like cell lines is mediated by bFGF and not by EGF. Radiol Oncol 47(4):330–337PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Giakoumettis D, Kritis A, Foroglou N (2018) C6 cell line: the gold standard in glioma research. Hippokratia 22(3):105–112PubMedPubMedCentralGoogle Scholar
  58. 58.
    Kiseleva LN et al (2016) Characteristics of A172 and T98g cell lines. Tsitologiia 58(5):349–355PubMedGoogle Scholar
  59. 59.
    Diao W et al (2019) Behaviors of glioblastoma cells in in vitro microenvironments. Sci Rep 9(1):85PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Schiffer D et al (2018) Glioblastoma: microenvironment and niche concept. Cancers (Basel) 11(1):5CrossRefGoogle Scholar
  61. 61.
    Seano G (2018) Targeting the perivascular niche in brain tumors. Curr Opin Oncol 30(1):54–60PubMedCrossRefGoogle Scholar
  62. 62.
    Hambardzumyan D, Bergers G (2015) Glioblastoma: defining tumor niches. Trends Cancer 1(4):252–265PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Ho IAW, Shim WSN (2017) Contribution of the microenvironmental niche to glioblastoma heterogeneity. Biomed Res Int 2017:9634172PubMedPubMedCentralGoogle Scholar
  64. 64.
    Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A (2010) Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 7(2):150–161PubMedCrossRefGoogle Scholar
  65. 65.
    Colwell N et al (2017) Hypoxia in the glioblastoma microenvironment: shaping the phenotype of cancer stem-like cells. Neuro Oncol 19(7):887–896PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Heddleston JM et al (2009) The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 8(20):3274–3284PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Kalkan R (2015) Glioblastoma stem cells as a new therapeutic target for glioblastoma. Clin Med Insights Oncol 9:95–103PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Roy LO, Poirier MB, Fortin D (2015) Transforming growth factor-beta and its implication in the malignancy of gliomas. Target Oncol 10(1):1–14PubMedCrossRefGoogle Scholar
  69. 69.
    Seystahl K et al (2017) Biological role and therapeutic targeting of TGF-beta3 in glioblastoma. Mol Cancer Ther 16(6):1177–1186PubMedCrossRefGoogle Scholar
  70. 70.
    Roy LO, Poirier MB, Fortin D (2018) Differential expression and clinical significance of transforming growth factor-beta isoforms in GBM tumors. Int J Mol Sci 19(4):1113PubMedCentralCrossRefPubMedGoogle Scholar
  71. 71.
    Hardee ME et al (2012) Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-beta. Cancer Res 72(16):4119–4129PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Gonzalez-Gomez P, Anselmo NP, Mira H (2014) BMPs as therapeutic targets and biomarkers in astrocytic glioma. Biomed Res Int 2014:549742PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Xi G et al (2017) Therapeutic potential for bone morphogenetic protein 4 in human malignant glioma. Neoplasia 19(4):261–270PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Caja L et al (2018) Snail regulates BMP and TGFbeta pathways to control the differentiation status of glioma-initiating cells. Oncogene 37(19):2515–2531PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Hover LD et al (2016) Bone morphogenetic protein signaling promotes tumorigenesis in a murine model of high-grade glioma. Neuro Oncol 18(7):928–938PubMedCrossRefGoogle Scholar
  76. 76.
    Garnier D et al (2019) Glioblastoma stem-like cells, metabolic strategy to kill a challenging target. Front Oncol 9:118PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Gersey Z et al (2019) Therapeutic targeting of the notch pathway in glioblastoma multiforme. World Neurosurg 131:252–263 e2PubMedCrossRefGoogle Scholar
  78. 78.
    Rajakulendran N et al (2019) Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells. Genes Dev 33(9–10):498–510PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Rampazzo E et al (2013) Wnt activation promotes neuronal differentiation of glioblastoma. Cell Death Dis 4:e500PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Zuccarini M et al (2018) The role of Wnt signal in glioblastoma development and progression: a possible new pharmacological target for the therapy of this tumor. Genes (Basel) 9(2):105CrossRefGoogle Scholar
  81. 81.
    Liffers K, Lamszus K, Schulte A (2015) EGFR amplification and glioblastoma stem-like cells. Stem Cells Int 2015:427518PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Sharifi Z et al (2019) Mechanisms and antitumor activity of a binary EGFR/DNA-targeting strategy overcomes resistance of Glioblastoma stem cells to Temozolomide. Clin Cancer Res 25(24):7594–7608PubMedCrossRefGoogle Scholar
  83. 83.
    Oka N et al (2007) VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells. Biochem Biophys Res Commun 360(3):553–559PubMedCrossRefGoogle Scholar
  84. 84.
    Sun X et al (2017) Glioma stem cells-derived exosomes promote the angiogenic ability of endothelial cells through miR-21/VEGF signal. Oncotarget 8(22):36137–36148PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Menezes A et al (2019) Live cell imaging supports a key role for Histone Deacetylase as a molecular target during glioblastoma malignancy downgrade through tumor competence modulation. J Oncol 2019:9043675PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Haas TL et al (2017) Integrin alpha7 is a functional marker and potential therapeutic target in glioblastoma. Cell Stem Cell 21(1):35–50 e9PubMedCrossRefGoogle Scholar
  87. 87.
    Han J et al (2015) TGF-beta signaling and its targeting for glioma treatment. Am J Cancer Res 5(3):945–955PubMedPubMedCentralGoogle Scholar
  88. 88.
    Fan X et al (2010) NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 28(1):5–16PubMedPubMedCentralGoogle Scholar
  89. 89.
    Jin R et al (2013) Combination therapy using Notch and Akt inhibitors is effective for suppressing invasion but not proliferation in glioma cells. Neurosci Lett 534:316–321PubMedCrossRefGoogle Scholar
  90. 90.
    Xu R et al (2016) Molecular and clinical effects of Notch inhibition in glioma patients: a phase 0/I trial. Clin Cancer Res 22(19):4786–4796PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Seliger C et al (2016) Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-beta2. Cell Cycle 15(13):1755–1766PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Song Y et al (2018) Metformin inhibits TGF-beta1-induced epithelial-to-mesenchymal transition-like process and stem-like properties in GBM via AKT/mTOR/ZEB1 pathway. Oncotarget 9(6):7023–7035PubMedCrossRefGoogle Scholar
  93. 93.
    Song Y et al (2019) Resveratrol suppresses epithelial-mesenchymal transition in GBM by regulating Smad-dependent signaling. Biomed Res Int 2019:1321973PubMedPubMedCentralGoogle Scholar
  94. 94.
    Belda-Iniesta C et al (2006) Long term responses with cetuximab therapy in glioblastoma multiforme. Cancer Biol Ther 5(8):912–914PubMedCrossRefGoogle Scholar
  95. 95.
    Neyns B et al (2009) Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann Oncol 20(9):1596–1603PubMedCrossRefGoogle Scholar
  96. 96.
    Ueda R et al (2010) Identification of HLA-A2- and A24-restricted T-cell epitopes derived from SOX6 expressed in glioma stem cells for immunotherapy. Int J Cancer 126(4):919–929PubMedGoogle Scholar
  97. 97.
    Toda M (2013) Glioma stem cells and immunotherapy for the treatment of malignant gliomas. ISRN Oncol 2013:673793PubMedPubMedCentralGoogle Scholar
  98. 98.
    Xu Q et al (2009) Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens. Stem Cells 27(8):1734–1740PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Prasad S et al (2015) Effective eradication of glioblastoma stem cells by local application of an AC133/CD133-specific T-cell-engaging antibody and CD8 T cells. Cancer Res 75(11):2166–2176PubMedCrossRefGoogle Scholar
  100. 100.

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Devaraj Ezhilarasan
    • 1
    • 2
  • R. Ileng Kumaran
    • 3
  • Ilangovan Ramachandran
    • 4
    • 5
  • Santosh Yadav
    • 6
    • 7
  • Muralidharan Anbalagan
    • 7
    • 8
    Email author
  1. 1.Department of Pharmacology, Saveetha Dental College and HospitalsSaveetha Institute of Medical and Technical SciencesChennaiIndia
  2. 2.Biomedical Research Unit and Laboratory Animal Research Centre, Saveetha Dental College and HospitalsSaveetha Institute of Medical and Technical SciencesChennaiIndia
  3. 3.Biology DepartmentFarmingdale State CollegeFarmingdaleUSA
  4. 4.Department of Endocrinology, Dr. ALM PG Institute of Basic Medical SciencesUniversity of Madras, Taramani CampusChennaiIndia
  5. 5.Department of Obstetrics and Gynecology, David Geffen School of MedicineUniversity of California at Los AngelesLos AngelesUSA
  6. 6.Aging Centre, Tulane UniversityNew OrleansUSA
  7. 7.Louisiana Cancer Research CenterNew OrleansUSA
  8. 8.Department of Structural and Cellular BiologyTulane UniversityNew OrleansUSA

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