Abstract
Glioblastomas are highly malignant primary brain tumors with one of the worst survival rates among all human cancers. With a more profound understanding of the cellular and molecular mechanisms of tumor initiation and acquired resistance to conventional radio- and chemotherapy, novel therapeutic targets might be discovered to optimize therapeutic approaches. In this regard, the identification of a small cellular subpopulation, called glioblastoma stem cell or stem-like cells or glioma-initiating cells or brain tumor propagating cells, has gained attention. In this article, we briefly summarize the current state of knowledge about this tumor cell population and discuss future directions for basic and clinical research.
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References
Al-Mayhani TMF, Ball SLR, Zhao JW, Fawcett J, Ichimura J, Colins PV, Watts C (2009) An efficient method for derivation and propagation of glioblastoma cell lines that conserves the molecular profile of their original tumors. J Neuorsci Methods 176:192–199
Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, Mc Lendon RE et al (2006a) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66:7843–7848
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006b) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760
Barcelos LS, Duplaa C, Krankel N et al (2009) Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling. Circ Res 104:1095–1102
Beier D, Röhrl S, Pillai DR, Schwarz S, Kunz-Schughart LA, Leukel P et al (2008) Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Res 68:5706–5715
Calabrese C, Poppleton H, Kocak M, Hongg TL, Fuller C, Hamner B et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82
Clement V, Marino D, Cudalbu C, Hamou MF, Mlynarik MF, Tribolet N, Dietrich PY et al (2010) Marker-independent identification of glioma-initiating cells. Nat Meth 7:224–228
Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM et al (2010) Notch pathway inhibition depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 28:5–16
Galli R, Binda E, Orfanelli U, Cipeletti B, Gritti A, De Vitis S et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastomas. Cancer Res 64:7011–7021
Gallia GL, Tyler BM, Hann CL, Siu UM, Giranda VL, Vescovi AL et al (2009) Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. Mol Cancer Ther 8:386–393
Godlewski J, Newton HB, Chiocca EA, Lawler SE (2010) MicroRNAs and glioblastomas: the stem cell connection. Cell Death Differ 17:221–228
Griguer CE, Oliva CR, Gobin E, Marcorelles P, Benos DJ, Lancaster JR et al (2008) CD133 is a marker of bioenergetic stress in human glioma. PLoS ONE 3:e3655
Günther HS, Schmidt NO, Philipps HS, Kemming D, Kharbanda S, Soriano R et al (2008) Gliolastom-derived stem cell-enriched cultures from distint subgroups according to molecular and phenotypic criteria. Oncogene 27:2897–2909
Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bonner-Fraser M et al (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183
Ikushima H, Todo T, Ino Y, Takahashi M, Miyazawa K, Miyazono K (2009) Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMB-box factors. Cell Stem Cell 5:504–514
Kelly PN, Dakic A, Adams JM, Nutt SL, STrasser A (2007) Tumor growth need not be driven by rare cancer stem cells. Science 317:337
Kondo T, Setoguchi T, Taga T (2004) Persistance of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA 101:781–786
Lapidot T, Sirard C, Vormoor J et al (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648
Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE, Macwords J, Wu Q et al (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6:421–432
Ogden AT, Waziri AE, Lochhead RA, Fusco D, Lopez K, Ellis JA et al (2008) Identification of A2B5 + CD133- tumor-initiating cells in adult human gliomas. Neurosurgery 62:505–514
Pellegatta S, Poliani PL, Corno D, Menghi F, Ghielmetti F, Suarez-Merino B, Caldera V et al (2006) Neurospheres enriched in cancer stem-like cellsa re highly effective in eliciting a dendritic cell-mediated response against malignant gliomas. Cancer Res 66:10247–10252
Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F, Vescovi AL (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumor-inititaing cells. Nature 444:761–765
Pollard SM, Yoshikawa K, Clarke ID, Danovi D, Stricker S, Russell R, Bayani J, Head R, Lee M, Bernstein M et al (2009) Brain cancer stem cells: a level playing field. Cell Stem Cell 5:468–469
Rasper M, Schafer A, Piontek G, Teufel J, Brockhoff G, Ringel F et al (2010) Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacitiy. Neuro Oncol 12:1024–1033
Reynolds BA, Weiss S (1996) Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol 175:1–13
Salmaggi A, Boiardi A, Gelati M, Russo A, Calatozzolo C, Ciusani E, Sciacca FL et al (2006) Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. Glia 54:850–860
Shmelkov SV, Jun L, Clair D, McGarrigle D, Derderian JK et al (2004) Alternative promoters regulate transcription of the gene that encodes stem cell surface protein AC133. Blood 103:2055–2061
Siebzehnrubl FA, Jeske I, Muller D, Buslei R, Coras R, Hahnen E et al (2009) Spontaneous in vitro transformation of adult neural precursors into stem-like cancer cells. Brain Pathol 19:399–408
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al (2004) Identification of human brain tumor initiating cells. Nature 432:396–401
Soeda A, Inagaki A, Oka N, Ikegame Y, Aoki H, Yoshimura S et al (2008) Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells. J Biol Chem 283:10958–10966
Son MJ, Woolard K, Nam DH, Lee J, Fine H (2009) SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell 4:440–452
Tamura K, Aoyagi M, Wakimoto H, Ando N, Nariai T, Yamamoto M, Ohno K (2010) Accumulation of CD133-positive glioma cells after high-dose irradiation by gamma knife surgery plus external beam radiation. J Neurosurg (in press)
Tchoghandijan A, Baeza N, Colin C, Cayre M, Metellus P, Beclin C et al (2010) A2B5 cells from human glioblastoma have cancer stem cell properties. Brain Pathol 20:211–221
Wang J, Wakeman TP, Lathia JD, Hjemeland AB, Wang XF, White RR et al (2009) Notch promotes radioresistance of glioma stem cells. Stem Cells 28:17–28
Yan H, Parsons W, GEnglin J, McLendon R, Rasheed A, Weishi Y, Kos I, Batinic-Haberle I et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773
Acknowledgements
This study was supported by DFG (SFB 773, project A6) and by NCCR Neural Plasticity and Repair (P4).
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Tabatabai, G., Weller, M. Glioblastoma stem cells. Cell Tissue Res 343, 459–465 (2011). https://doi.org/10.1007/s00441-010-1123-0
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DOI: https://doi.org/10.1007/s00441-010-1123-0