Journal of Neuro-Oncology

, Volume 119, Issue 3, pp 547–555 | Cite as

Stem cells and gliomas: past, present, and future

  • Isabelle M. Germano
  • Emanuela Binello
Topic Review


The recognition of stem cells (SC) in the adult CNS and in association with gliomas has spawned an entire field of research and intense investigation. A large body of knowledge is being accumulated to gain insight into the pathobiology of gliomas with the intent of finally improving the grave prognosis that continues to beset patients with high grade gliomas (HGG). In this article, we provide a historical overview of the events leading to the discovery of SC and glioma stem cells (GSC). We then focus on the current understanding of GSC with respect to markers, clinical significance, and their targeting. We discuss current data and developments using SC as vehicles to delivery therapeutic agents to HGG. We conclude with a discussion of opportunities for future development and concepts aimed at reducing tumor recurrence and improving survival for patients with HGG.


Stem cells Glioma stem cells Cell therapy Gene therapy High grade glioma Glioblastoma Clinical trials 



This work was supported, in part, by a grant from the National Institutes of Health/National Cancer Institute (RO1 CA1 129489-01A1 to I.M.G).

Conflict of interest



  1. 1.
    Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124:319–335PubMedCrossRefGoogle Scholar
  2. 2.
    Goldman SA, Nottebohm F (1983) Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain. Proc Natl Acad Sci USA 80:2390–2394PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Johansson CB, Clarke DL, Momma S et al (1999) Identification of neural stem cell in the adult mammalian central nervous system. Cell 96:25–34PubMedCrossRefGoogle Scholar
  4. 4.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737PubMedCrossRefGoogle Scholar
  5. 5.
    Virchow R (1863) Die krankhaften Geschwuelste. Hirshwald, BerlinGoogle Scholar
  6. 6.
    Germano IM, Swiss V, Casaccia P (2010) Primary brain tumors, neural stem cells, and brain tumor cancer cells: where is the link? Neuro-pharmacology 58(6):903–910Google Scholar
  7. 7.
    Schiffer D, Giordana MT, Mauro A et al (1986) Immunohistochemical demonstration of vimentin in human cerebral tumors. Acta Neuropath 70:209–219PubMedCrossRefGoogle Scholar
  8. 8.
    Masui K, Suzuki SO, Torisu R et al (2010) Glial progenitors in the brainstem give rise to malignant gliomas by platelet-derived growth factor stimulation. Glia 58:1050–1065PubMedCrossRefGoogle Scholar
  9. 9.
    Liu C, Sage JC, Miller MR et al (2011) Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146:209–221PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Kondo T, Raff M (2000) Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289:1754–1757PubMedCrossRefGoogle Scholar
  11. 11.
    Parsons DW, Jones S, Zhang X (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Dougherty JD, Fomchenko EI, Akuffo AA et al (2012) Candidate pathways for promoting differentiation or quiescence of oligodendrocyte progenitor-like cells in glioma. Cancer Res 72:4856–4868PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Rosemblum ML, Gerosa M, Dougherty DV et al (1982) Age-related chemosensitivity of stem cells from human malignant brain tumors. Lancet 1:885–887CrossRefGoogle Scholar
  14. 14.
    Reya T, Morrison SJ, Clarke MF et al (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111PubMedCrossRefGoogle Scholar
  15. 15.
    Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401PubMedCrossRefGoogle Scholar
  16. 16.
    Lacks DR, Masterman-Smith M, Visnyei K et al (2009) Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells 27:980–987CrossRefGoogle Scholar
  17. 17.
    Beier D, Hau P, Proescholdt M et al (2007) CD133+ and CD133− glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67:4010–4015PubMedCrossRefGoogle Scholar
  18. 18.
    Ogden AT, Waziri AE, Lochhead RA et al (2008) Identification of A2B5+ CD133− tumor-initiating cells in adult human gliomas. Neurosurgery 62:505–515PubMedCrossRefGoogle Scholar
  19. 19.
    Mao XG, Zhang X, Xue XY et al (2009) Brain tumor stem-like cells identified by neural stem cell marker CD15. Transl Oncol 2:247–257PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Rasper M, Schafer A, Piontek G et al (2010) Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity. Neurooncology 12:1024–1033Google Scholar
  21. 21.
    Thon N, Damianoff K, Hegeman J et al (2010) Presence of pluripotent CD133 + cells correlates with malignancy of gliomas. Mol Cell Neurosci 43:51–59PubMedCrossRefGoogle Scholar
  22. 22.
    Zeppernick F, Ahmadi R, Campos B et al (2008) Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14:123–129PubMedCrossRefGoogle Scholar
  23. 23.
    Pallini R, Ricci-Vitiani L, Banna GL et al (2008) Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme. Clin Cancer Res 14:8205–8212PubMedCrossRefGoogle Scholar
  24. 24.
    Kim KJ, Lee KH, Kim HS et al (2011) The presence of stem cells marker-expressing cells is not prognostically significant in glioblastomas. Neuropathology 31:494–502PubMedCrossRefGoogle Scholar
  25. 25.
    Liu DY, Ren CP, Yuan XR et al (2012) ALDH1 expression is correlated with pathologic grade and poor clinical outcome in patients with astrocytoma. J Clin Neurosci 19:1700–1705PubMedCrossRefGoogle Scholar
  26. 26.
    Strojnik T, Rosland GV, Sakariassen PO (2007) Neural stem cell markers, nestin and musashi proteins, in the progression of human glioma: correlation of nestin with prognosis of patient survival. Surg Neurol 68:133–144PubMedCrossRefGoogle Scholar
  27. 27.
    Elsir T, Edqvist PH, Carlson J et al (2014) A study of embryonic stem cell-related proteins in human astrocytomas: identification of nanog as a predictor of survival. Int J Cancer 134:1123–1131PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang M, Song T, Yang L et al (2008) Nestin and CD133: valuable stem cell-specific markers for determining clinical outcome of glioma patients. J Exp Clin Cancer Res 27:85. doi: 10.1186/1756-9966-27-85 PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Binello E, Germano IM (2011) Targeting glioma stem cells: a novel framework for brain tumors. Cancer Sci 102:1958–1966PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Binello E, Mormone E, Emdad L, Kothari H, Germano IM (2014) Characterization of fenofibrate-mediate anti-proliferative pro-apoptotic effects on high-grade gliomas and anti-invasive effects on glioma stem cells. J Neurooncol 117:225–234PubMedCrossRefGoogle Scholar
  31. 31.
    Bao S, Wu Q, McLendon RE et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760PubMedCrossRefGoogle Scholar
  32. 32.
    Raso A, Vecchio D, Cappelli E et al (2012) Characterization of glioma stem cells through multiple stem cell markers and their specific sensitization to double-strand break-inducing agents by pharmacological inhibition of ataxia telangiectasia mutated protein. Brain Pathol 22:677–688PubMedCrossRefGoogle Scholar
  33. 33.
    Cheng L, Wu Q, Huang Z et al (2011) L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1. EMBO J 30:800–813PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Lim YC, Roberts TL, Day BW et al (2012) A role for homologous recombination and abnormal cell-cycle progression in radioresistance of glioma-initiating cells. Mol Cancer Ther 11:1863–1872PubMedCrossRefGoogle Scholar
  35. 35.
    Persano L, Pistollato F, Rampazzo E et al (2012) BMP2 sensitizes glioblastoma stem-like cells to temozolomide by affecting HIF-1α stability and MGMT expression. Cell Death Dis 3:e412. doi: 10.1038/cddis.2012.153 PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Siebzehnrubl FA, Silver DJ, Tugertimur B et al (2013) The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance. EMBO Mol Med 5:1196–1212PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Ciceroni C, Bonelli M, Mastrantoni E et al (2013) Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas. Cell Death Differ 20:396–407PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Happold C, Roth P, Silginer M et al (2014) Interferon-β induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells. Mol Cancer Ther 13(4):948–961PubMedCrossRefGoogle Scholar
  39. 39.
    Osuka S, Sampetream O, Shimizu T et al (2013) IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells. Stem Cells 31:627–640PubMedCrossRefGoogle Scholar
  40. 40.
    Kang KB, Zhu C, Wong YL et al (2012) Gefitinib radiosensitizes stem-like glioma cells: inhibition of epidermal growth factor receptor-Akt-DNA-PT signaling, accompanied by inhibition of DNA double-strand break repair. Int J Radiat Oncol Biol Phys 83:e43–e52. doi: 10.1016/j.ijrobp.2011.11.037 PubMedCrossRefGoogle Scholar
  41. 41.
    Martin V, Sanchez-Sanchez AM, Herrera F et al (2013) Melatonin-induced methylation of the ABCG2/BRCP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells. Br J Cancer 108:2005–2012PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Yang YP, Chen Y, Chiou GY et al (2012) Inhibition of cancer stem cell-like properties and reduced chemoradioresistance of glioblastoma using microRNA 145 with cationic polyurethane-short branch PEI. Biomaterials 33:1462–1476PubMedCrossRefGoogle Scholar
  43. 43.
    Asutkhar S, Velpula KK, Chetty C et al (2012) Epigenetic regulation of miRNA-211 by MMP-9 governs glioma cell apoptosis, chemosensitivity and radiosensitivity. Oncotarget 3:1439–1454Google Scholar
  44. 44.
    Hardee ME, Marciscano AE, Medina-Ramirez CM et al (2012) Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-β. Cancer Res 72:119–129CrossRefGoogle Scholar
  45. 45.
    Shi L, Wan Y, Sun G et al (2012) Functional differences of miR-125b on the invasion of primary glioblastoma CD133-negative cells and CD133-positive cells. Neuromol Med 14:303–316CrossRefGoogle Scholar
  46. 46.
    Germano IM, Binello E (2009) Gene therapy for adjuvant treatment of malignant gliomas: from bench to bedside. J Neurooncol 93:79–87PubMedCrossRefGoogle Scholar
  47. 47.
    Germano IM, Uzzaman M, Keller G (2008) Gene delivery by embryonic stem cells for malignant gliomas: hype or hope? Cancer Biol Ther 7:81–87CrossRefGoogle Scholar
  48. 48.
    Germano IM, Binello E (2012) Stem cells as vehicles for the treatment of high-grade gliomas. Neurooncology 14:256–265Google Scholar
  49. 49.
    Nakamura K, Ito Y, Kawano Y et al (2009) Antitumor effect of genetically engineered mesenchymal stem cells in rat glioma model. Gene Ther 11:1155–1164CrossRefGoogle Scholar
  50. 50.
    Benveniste R, Keller G, Germano IM (2005) Embryonic stem cell-derived astrocytes expressing drug-inducible transgenes: differentiation and allotransplantation into the mouse brain. J Neurosurg 103:115–123PubMedCrossRefGoogle Scholar
  51. 51.
    Aboody KS, Najbauer J, Metz MZ et al (2013) Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies. Sci Transl Med 5:18459CrossRefGoogle Scholar
  52. 52.
    Amariglio N, Hirshberg A, Scheithauer BW et al (2009) Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PloS Med 6:1000029CrossRefGoogle Scholar
  53. 53.
    Spaeth EL, Dembinski JL, Sasser AK et al (2009) Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One 4:e4992PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Karnoub AE, Dash AB, Vo AP et al (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449:557–563PubMedCrossRefGoogle Scholar
  55. 55.
    Akimoto K, Kimura K, Nagano M et al (2013) Umbilical cord blood-derived mesenchymal stem cells inhibit, but adipose tissue-derived mesenchymal stem cells promote, glioblastoma multiforme proliferation. Stem Cells Dev 22:1370–1386PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Emdad L, Qadeer ZA, D’Souza SL et al (2012) Efficient differentiation of human embryonic and induced pluripotent stem cells into functional astrocytes. Stem Cells Dev 21:404–4120PubMedCrossRefGoogle Scholar
  57. 57.
    Germano IM, Emdad L, Qader Z et al (2010) Embryonic stem cell (ESC)-mediated transgene delivery induces growth suppression, apoptosis, radiosensitization, and overcomes temozolomide resistance in malignant gliomas. Cancer Gene Ther 17(9):664–674PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Uzzaman M, Keller G, Germano IM (2007) Enhanced pro-apoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on temozolomide-resistant glioma cells. J Neurosurg 106:646–651PubMedCrossRefGoogle Scholar
  59. 59.
    Uzzaman M, Keller G, Germano IM (2009) In vivo gene delivery by embryonic stem cell-derived astrocytes for malignant gliomas. Neuro-oncology 11:102–108PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Mandal K, Rossi DJ (2013) Reprogramming human fibroblasts to pluripotency using modified mRNA. Nat Protoc 8:568–572PubMedCrossRefGoogle Scholar
  61. 61.
    Mormone E, D’Souza S, Alexeeva V, Bederson MM, Germano IM (2014) "Footprint-free" human induced pluripotent stem cell-derived astrocytes for in vivo cell-based therapy. Stem Cells Dev. doi: 10.1089/scd.2014.0151

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of NeurosurgeryIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Department of NeurosurgeryBoston University School of MedicineBostonUSA

Personalised recommendations