Advertisement

Brain Tumor Pathology

, Volume 30, Issue 4, pp 209–214 | Cite as

Characteristics of glioma stem cells

  • Oltea Sampetrean
  • Hideyuki Saya
Review Article

Abstract

The cancer stem cell theory postulates that tumors are sustained by a select cell population with specific features, such as self-renewal ability and the capacity to give rise to a heterogeneous mass of tumor cells. The existence of such cells has been demonstrated for glioblastoma, with these cells being referred to as glioma stem cells (GSCs). Glioblastomas are notoriously heterogeneous tumors, however, and the isolation and characterization of their stem cells will require further investigations. Furthermore, the lack of unequivocal markers for GSCs and a partial overlap in characteristics with other cells often lead to confusion. Here, we review the characteristics necessary for a glioma cell to be considered a stem cell, and we adopt our murine glioblastoma model based on genetically modified neural stem cells to illustrate and discuss the GSC concept.

Keywords

Glioma stem cell (GSC) Glioma-initiating cell (GIC) Glioma cell of origin Cancer stem cell (CSC) 

References

  1. 1.
    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
  2. 2.
    Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, 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 66:9339–9344PubMedCrossRefGoogle Scholar
  3. 3.
    Zhou BB, 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 8:806–823PubMedCrossRefGoogle Scholar
  4. 4.
    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 432:396–401PubMedCrossRefGoogle Scholar
  5. 5.
    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 444:756–760PubMedCrossRefGoogle Scholar
  6. 6.
    Bleau AM, 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 4:226–235PubMedCrossRefGoogle Scholar
  7. 7.
    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 9:391–403PubMedCrossRefGoogle Scholar
  8. 8.
    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 63:5821–5828PubMedGoogle Scholar
  9. 9.
    Laks DR, Masterman-Smith M, Visnyei K, Angenieux B, Orozco NM, Foran I, Yong WH, Vinters HV, Liau LM, Lazareff JA, Mischel PS, Cloughesy TF, Horvath S, Kornblum HI (2009) Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells 27:980–987PubMedCrossRefGoogle Scholar
  10. 10.
    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 67:4010–4015PubMedCrossRefGoogle Scholar
  11. 11.
    Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B, Garcia-Verdugo JM, Doetsch F (2008) A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3:279–288PubMedCrossRefGoogle Scholar
  12. 12.
    Shen Q, Wang Y, Kokovay E, Lin G, Chuang SM, Goderie SK, Roysam B, Temple S (2008) Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell–cell interactions. Cell Stem Cell 3:289–300PubMedCrossRefGoogle Scholar
  13. 13.
    Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, Nakamura R, Tanaka T, Tomiyama H, Saito N, Fukata M, Miyamoto T, Lyons B, Ohshima K, Uchida N, Taniguchi S, Ohara O, Akashi K, Harada M, Shultz LD (2007) Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25:1315–1321PubMedCrossRefGoogle Scholar
  14. 14.
    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 (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82PubMedCrossRefGoogle Scholar
  15. 15.
    Charles N, Ozawa T, Squatrito M, Bleau AM, Brennan CW, Hambardzumyan D, Holland EC (2010) Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell 6:141–152PubMedCrossRefGoogle Scholar
  16. 16.
    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-1alpha. Oncogene 28:3949–3959PubMedCrossRefGoogle Scholar
  17. 17.
    Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60:166–193Google Scholar
  18. 18.
    Chen J, McKay RM, Parada LF (2012) Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149:36–47PubMedCrossRefGoogle Scholar
  19. 19.
    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 (2002) Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1:269–277PubMedCrossRefGoogle Scholar
  20. 20.
    Zhu H, Acquaviva J, Ramachandran P, Boskovitz A, Woolfenden S, Pfannl R, Bronson RT, Chen JW, Weissleder R, Housman DE, Charest A (2009) Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis. Proc Natl Acad Sci USA 106:2712–2716PubMedCrossRefGoogle Scholar
  21. 21.
    Chow LM, Endersby R, Zhu X, Rankin S, Qu C, Zhang J, Broniscer A, Ellison DW, Baker SJ (2011) Cooperativity within and among Pten, p53, and Rb pathways induces high-grade astrocytoma in adult brain. Cancer Cell 19:305–316PubMedCrossRefGoogle Scholar
  22. 22.
    Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O, Ellisman MH, Verma IM (2012) Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 338:1080–1084PubMedCrossRefGoogle Scholar
  23. 23.
    Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25:55–57PubMedCrossRefGoogle Scholar
  24. 24.
    Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP, Messing A, Parada LF (2005) Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8:119–130PubMedCrossRefGoogle Scholar
  25. 25.
    Llaguno S, Chen J, Kwon CH, Jackson EL, Li Y, Burns DK, Alvarez-Buylla A, Parada LF (2009) Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15:45–56CrossRefGoogle Scholar
  26. 26.
    Tamase A, Muraguchi T, Naka K, Tanaka S, Kinoshita M, Hoshii T, Ohmura M, Shugo H, Ooshio T, Nakada M, Sawamoto K, Onodera M, Matsumoto K, Oshima M, Asano M, Saya H, Okano H, Suda T, Hamada J, Hirao A (2009) Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin. Proc Natl Acad Sci USA 106:17163–17168PubMedCrossRefGoogle Scholar
  27. 27.
    Sampetrean O, Saga I, Nakanishi M, Sugihara E, Fukaya R, Onishi N, Osuka S, Akahata M, Kai K, Sugimoto H, Hirao A, Saya H (2011) Invasion precedes tumor mass formation in a malignant brain tumor model of genetically modified neural stem cells. Neoplasia 13:784–791PubMedGoogle Scholar
  28. 28.
    Schmidt EE, Ichimura K, Reifenberger G, Collins VP (1994) CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res 54:6321–6324PubMedGoogle Scholar
  29. 29.
    Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068Google Scholar
  30. 30.
    Osuka S, Sampetrean O, Shimizu T, Saga I, Onishi N, Sugihara E, Okubo J, Fujita S, Takano S, Matsumura A, Saya H (2013) IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells. Stem Cells doi: 10.1002/stem.1328Google Scholar
  31. 31.
    Canoll P, Goldman JE (2008) The interface between glial progenitors and gliomas. Acta Neuropathol 116:465–477PubMedCrossRefGoogle Scholar
  32. 32.
    Keith B, Simon MC (2007) Hypoxia-inducible factors, stem cells, and cancer. Cell 129:465–472PubMedCrossRefGoogle Scholar
  33. 33.
    Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:157–173PubMedCrossRefGoogle Scholar
  34. 34.
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110PubMedCrossRefGoogle Scholar
  35. 35.
    Gunther HS, Schmidt NO, Phillips HS, Kemming D, Kharbanda S, Soriano R, Modrusan Z, Meissner H, Westphal M, Lamszus K (2008) Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene 27:2897–2909PubMedCrossRefGoogle Scholar
  36. 36.
    Piccirillo SG, Combi R, Cajola L, Patrizi A, Redaelli S, Bentivegna A, Baronchelli S, Maira G, Pollo B, Mangiola A, DiMeco F, Dalpra L, Vescovi AL (2009) Distinct pools of cancer stem-like cells coexist within human glioblastomas and display different tumorigenicity and independent genomic evolution. Oncogene 28:1807–1811PubMedCrossRefGoogle Scholar
  37. 37.
    Sugihara E, Saya H (2013) Complexity of cancer stem cells. Int J Cancer 132:1249–1259PubMedCrossRefGoogle Scholar

Copyright information

© The Japan Society of Brain Tumor Pathology 2013

Authors and Affiliations

  1. 1.Division of Gene Regulation, Institute for Advanced Medical ResearchKeio University School of MedicineTokyoJapan
  2. 2.Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology AgencyTokyoJapan

Personalised recommendations