Skip to main content

Advertisement

SpringerLink
Log in

Tumor initiating cells in malignant gliomas: biology and implications for therapy

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

A rare subpopulation of cells within malignant gliomas, which shares canonical properties with neural stem cells (NSCs), may be integral to glial tumor development and perpetuation. These cells, also known as tumor initiating cells (TICs), have the ability to self-renew, develop into any cell in the overall tumor population (multipotency), and proliferate. A defining property of TICs is their ability to initiate new tumors in immunocompromised mice with high efficiency. Mounting evidence suggests that TICs originate from the transformation of NSCs and their progenitors. New findings show that TICs may be more resistant to chemotherapy and radiation than the bulk of tumor cells, thereby permitting recurrent tumor formation and accounting for the failure of conventional therapies. The development of new therapeutic strategies selectively targeting TICs while sparing NSCs may provide for more effective treatment of malignant gliomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Jordan CT, Guzman ML, Noble M (2006) Cancer stem cells. N Engl J Med 355:1253–1261. doi:355/12/1253 [pii] 10.1056/NEJMra061808

    PubMed  CAS  Google Scholar 

  2. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    PubMed  CAS  Google Scholar 

  3. Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF (2004) Therapeutic implications of cancer stem cells. Curr Opin Genet Dev 14:43–47

    PubMed  CAS  Google Scholar 

  4. Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea—a paradigm shift. Cancer Res 66:1883–1890 (discussion 1895–1886)

    PubMed  CAS  Google Scholar 

  5. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648

    PubMed  CAS  Google Scholar 

  6. Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183

    PubMed  CAS  Google Scholar 

  7. 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

    PubMed  CAS  Google Scholar 

  8. Kennedy JA, Barabe F, Poeppl AG, Wang JC, Dick JE (2007) Comment on “Tumor growth need not be driven by rare cancer stem cells”. Science 318:1722 (author reply 1722)

    PubMed  CAS  Google Scholar 

  9. Reilly KM, Rubin JB, Gilbertson RJ, Garbow JR, Roussel MF, Gutmann DH (2008) Rethinking brain tumors: The fourth mouse models of human cancers consortium nervous system tumors workshop. Cancer Res 68:5508–5511

    PubMed  CAS  Google Scholar 

  10. 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 432:396–401

    PubMed  CAS  Google Scholar 

  11. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021

    PubMed  CAS  Google Scholar 

  12. Shmelkov SV, St Clair R, Lyden D, Rafii S (2005) AC133/CD133/Prominin-1. Int J Biochem Cell Biol 37:715–719. doi:S1357-2725(04)00350-4 [pii] 10.1016/j.biocel.2004.08.010

    PubMed  CAS  Google Scholar 

  13. Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL (2000) Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 97:14720–14725

    PubMed  CAS  Google Scholar 

  14. Tamaki S, Eckert K, He D, Sutton R, Doshe M, Jain G, Tushinski R, Reitsma M, Harris B, Tsukamoto A, Gage F, Weissman I, Uchida N (2002) Engraftment of sorted/expanded human central nervous system stem cells from fetal brain. J Neurosci Res 69:976–986

    PubMed  CAS  Google Scholar 

  15. Legler JM, Ries LA, Smith MA, Warren JL, Heineman EF, Kaplan RS, Linet MS (1999) Cancer surveillance series [corrected]: brain and other central nervous system cancers: recent trends in incidence and mortality. J Natl Cancer Inst 91:1382–1390

    PubMed  CAS  Google Scholar 

  16. Van Meir EG, Polverini PJ, Chazin VR, Su Huang HJ, de Tribolet N, Cavenee WK (1994) Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat Genet 8:171–176. doi:10.1038/ng1094-171

    PubMed  Google Scholar 

  17. Van Meir EG, Bellail A, Phuphanich S (2004) Emerging molecular therapies for brain tumors. Semin Oncol 31:38–46. doi:S0093775404000788 [pii]

    PubMed  Google Scholar 

  18. Kaur B, Khwaja FW, Severson EA, Matheny SL, Brat DJ, Van Meir EG (2005) Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 7:134–153. doi:10.1215/S1152851704001115

    PubMed  CAS  Google Scholar 

  19. 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 11:69–82

    PubMed  CAS  Google Scholar 

  20. 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 444:756–760

    PubMed  CAS  Google Scholar 

  21. Rich JN (2007) Cancer stem cells in radiation resistance. Cancer Res 67:8980–8984

    PubMed  CAS  Google Scholar 

  22. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5:275–284

    PubMed  CAS  Google Scholar 

  23. Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, Goodell MA, Brenner MK (2004) A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 101:14228–14233

    PubMed  CAS  Google Scholar 

  24. Donnenberg VS, Donnenberg AD (2005) Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis. J Clin Pharmacol 45:872–877

    PubMed  CAS  Google Scholar 

  25. Reynolds BA, Tetzlaff W, Weiss S (1992) A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 12:4565–4574

    PubMed  CAS  Google Scholar 

  26. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710

    PubMed  CAS  Google Scholar 

  27. Gritti A, Frolichsthal-Schoeller P, Galli R, Parati EA, Cova L, Pagano SF, Bjornson CR, Vescovi AL (1999) Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain. J Neurosci 19:3287–3297

    PubMed  CAS  Google Scholar 

  28. Vescovi AL, Parati EA, Gritti A, Poulin P, Ferrario M, Wanke E, Frolichsthal-Schoeller P, Cova L, Arcellana-Panlilio M, Colombo A, Galli R (1999) Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cell lines by epigenetic stimulation. Exp Neurol 156:71–83

    PubMed  CAS  Google Scholar 

  29. 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

    PubMed  CAS  Google Scholar 

  30. Gritti A, Parati EA, Cova L, Frolichsthal P, Galli R, Wanke E, Faravelli L, Morassutti DJ, Roisen F, Nickel DD, Vescovi AL (1996) Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci 16:1091–1100

    PubMed  CAS  Google Scholar 

  31. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317

    PubMed  CAS  Google Scholar 

  32. Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S, Lawton MT, McDermott MW, Parsa AT, Manuel-Garcia Verdugo J, Berger MS, Alvarez-Buylla A (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427:740–744

    PubMed  CAS  Google Scholar 

  33. Nunes MC, Roy NS, Keyoung HM, Goodman RR, McKhann G 2nd, Jiang L, Kang J, Nedergaard M, Goldman SA (2003) Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med 9:439–447

    PubMed  CAS  Google Scholar 

  34. Ayuso-Sacido A, Roy NS, Schwartz TH, Greenfield JP, Boockvar JA (2008) Long-term expansion of adult human brain subventricular zone precursors. Neurosurgery 62:223–229 (discussion 229–231)

    Article  PubMed  Google Scholar 

  35. Sanai N, Alvarez-Buylla A, Berger MS (2005) Neural stem cells and the origin of gliomas. N Engl J Med 353:811–822

    PubMed  CAS  Google Scholar 

  36. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716

    PubMed  CAS  Google Scholar 

  37. Rao MS, Noble M, Mayer-Proschel M (1998) A tripotential glial precursor cell is present in the developing spinal cord. Proc Natl Acad Sci USA 95:3996–4001

    PubMed  CAS  Google Scholar 

  38. Mayer-Proschel M, Kalyani AJ, Mujtaba T, Rao MS (1997) Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron 19:773–785. doi:S0896-6273(00)80960-5 [pii]

    PubMed  CAS  Google Scholar 

  39. Vescovi AL, Galli R, Reynolds BA (2006) Brain tumour stem cells. Nat Rev Cancer 6:425–436. doi:nrc1889 [pii] 10.1038/nrc1889

    PubMed  CAS  Google Scholar 

  40. Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250. doi:10.1146/annurev.neuro.28.051804.101459

    PubMed  CAS  Google Scholar 

  41. Fulci G, Ishii N, Maurici D, Gernert KM, Hainaut P, Kaur B, Van Meir EG (2002) Initiation of human astrocytoma by clonal evolution of cells with progressive loss of p53 functions in a patient with a 283H TP53 germ-line mutation: evidence for a precursor lesion. Cancer Res 62:2897–2905

    PubMed  CAS  Google Scholar 

  42. Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA (2002) Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39:193–206

    PubMed  Google Scholar 

  43. 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 9:391–403

    PubMed  CAS  Google Scholar 

  44. Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, Kotliarova S, Kotliarov Y, Walling J, Ahn S, Kim M, Totonchy M, Cusack T, Ene C, Ma H, Su Q, Zenklusen JC, Zhang W, Maric D, Fine HA (2008) Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13:69–80

    PubMed  CAS  Google Scholar 

  45. 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 63:5821–5828

    PubMed  CAS  Google Scholar 

  46. 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 67:4010–4015

    PubMed  CAS  Google Scholar 

  47. Sakariassen PO, Prestegarden L, Wang J, Skaftnesmo KO, Mahesparan R, Molthoff C, Sminia P, Sundlisaeter E, Misra A, Tysnes BB, Chekenya M, Peters H, Lende G, Kalland KH, Oyan AM, Petersen K, Jonassen I, van der Kogel A, Feuerstein BG, Terzis AJ, Bjerkvig R, Enger PO (2006) Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc Natl Acad Sci USA 103:16466–16471

    PubMed  CAS  Google Scholar 

  48. Zheng X, Shen G, Yang X, Liu W (2007) Most C6 cells are cancer stem cells: evidence from clonal and population analyses. Cancer Res 67:3691–3697

    PubMed  CAS  Google Scholar 

  49. Wang J, Sakariassen PO, Tsinkalovsky O, Immervoll H, Boe SO, Svendsen A, Prestegarden L, Rosland G, Thorsen F, Stuhr L, Molven A, Bjerkvig R, Enger PO (2008) CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer 122:761–768. doi:10.1002/ijc.23130

    PubMed  CAS  Google Scholar 

  50. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG (2005) Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Res 65:6207–6219. doi:65/14/6207 [pii] 10.1158/0008-5472.CAN-05-0592

    PubMed  CAS  Google Scholar 

  51. Kondo T, Setoguchi T, Taga T (2004) Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA 101:781–786. doi:10.1073/pnas.03076181000307618100 [pii]

    PubMed  CAS  Google Scholar 

  52. Goodell MA, Rosenzweig M, Kim H, Marks DF, DeMaria M, Paradis G, Grupp SA, Sieff CA, Mulligan RC, Johnson RP (1997) Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med 3:1337–1345

    PubMed  CAS  Google Scholar 

  53. Harris MA, Yang H, Low BE, Mukherje J, Guha A, Bronson RT, Shultz LD, Israel MA, Yun K (2008) Cancer stem cells are enriched in the side population cells in a mouse model of glioma. Cancer Res 68:10051–10059. doi:68/24/10051 [pii] 10.1158/0008-5472.CAN-08-0786

    PubMed  CAS  Google Scholar 

  54. Ramirez-Castillejo C, Sanchez-Sanchez F, Andreu-Agullo C, Ferron SR, Aroca-Aguilar JD, Sanchez P, Mira H, Escribano J, Farinas I (2006) Pigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nat Neurosci 9:331–339

    PubMed  CAS  Google Scholar 

  55. Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K, Temple S (2004) Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304:1338–1340

    PubMed  CAS  Google Scholar 

  56. Yang ZJ, Wechsler-Reya RJ (2007) Hit ‘em where they live: targeting the cancer stem cell niche. Cancer Cell 11:3–5

    PubMed  CAS  Google Scholar 

  57. Gilbertson RJ, Rich JN (2007) Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 7:733–736

    PubMed  CAS  Google Scholar 

  58. Brat DJ, Van Meir EG (2001) Glomeruloid microvascular proliferation orchestrated by VPF/VEGF: a new world of angiogenesis research. Am J Pathol 158:789–796

    PubMed  CAS  Google Scholar 

  59. Studer L, Csete M, Lee SH, Kabbani N, Walikonis J, Wold B, McKay R (2000) Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J Neurosci 20:7377–7383

    PubMed  CAS  Google Scholar 

  60. Keith B, Simon MC (2007) Hypoxia-inducible factors, stem cells, and cancer. Cell 129:465–472. doi:S0092-8674(07)00525-9 [pii] 10.1016/j.cell.2007.04.019

    PubMed  CAS  Google Scholar 

  61. Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67:3560–3564

    PubMed  CAS  Google Scholar 

  62. Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66:7843–7848

    PubMed  CAS  Google Scholar 

  63. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    PubMed  CAS  Google Scholar 

  64. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21:2683–2710

    PubMed  CAS  Google Scholar 

  65. Ishii N, Tada M, Hamou MF, Janzer RC, Meagher-Villemure K, Wiestler OD, Tribolet N, Van Meir EG (1999) Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor. Oncogene 18:5870–5878. doi:10.1038/sj.onc.1203241

    PubMed  CAS  Google Scholar 

  66. Dietrich J, Imitola J, Kesari S (2008) Mechanisms of Disease: the role of stem cells in the biology and treatment of gliomas. Nat Clin Pract Oncol 5:393–404. doi:ncponc1132 [pii] 10.1038/ncponc1132

    PubMed  CAS  Google Scholar 

  67. Ligon KL, Huillard E, Mehta S, Kesari S, Liu H, Alberta JA, Bachoo RM, Kane M, Louis DN, Depinho RA, Anderson DJ, Stiles CD, Rowitch DH (2007) Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 53:503–517

    PubMed  CAS  Google Scholar 

  68. Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902. doi:10.1038/nrc1232nrc1232 [pii]

    PubMed  CAS  Google Scholar 

  69. 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 9:157–173

    PubMed  CAS  Google Scholar 

  70. 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 25:55–57

    PubMed  CAS  Google Scholar 

  71. Barnett SC, Robertson L, Graham D, Allan D, Rampling R (1998) Oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells transformed with c-myc and H-ras form high-grade glioma after stereotactic injection into the rat brain. Carcinogenesis 19:1529–1537

    PubMed  CAS  Google Scholar 

  72. 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 1:269–277

    PubMed  CAS  Google Scholar 

  73. Sonoda Y, Ozawa T, Hirose Y, Aldape KD, McMahon M, Berger MS, Pieper RO (2001) Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. Cancer Res 61:4956–4960

    PubMed  CAS  Google Scholar 

  74. Sonoda Y, Ozawa T, Aldape KD, Deen DF, Berger MS, Pieper RO (2001) Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res 61:6674–6678

    PubMed  CAS  Google Scholar 

  75. Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A (2007) HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17:165–172

    PubMed  CAS  Google Scholar 

  76. Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, Roy M, Quinones-Hinojosa A, VandenBerg S, Alvarez-Buylla A (2006) 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 51:187–199

    PubMed  CAS  Google Scholar 

  77. 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 8:119–130

    PubMed  CAS  Google Scholar 

  78. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, 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 (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    PubMed  CAS  Google Scholar 

  79. Ehtesham M, Mapara KY, Stevenson CB, Thompson RC (2009) CXCR4 mediates the proliferation of glioblastoma progenitor cells. Cancer Lett 274:305–312. doi:S0304-3835(08)00785-4 [pii] 10.1016/j.canlet.2008.09.034

    Google Scholar 

  80. Canoll P, Goldman JE (2008) The interface between glial progenitors and gliomas. Acta Neuropathol 116:465–477. doi:10.1007/s00401-008-0432-9

    PubMed  Google Scholar 

  81. Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, Kunkel LM, Mulligan RC (1999) Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401:390–394

    PubMed  CAS  Google Scholar 

  82. Jackson KA, Mi T, Goodell MA (1999) Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci USA 96:14482–14486

    PubMed  CAS  Google Scholar 

  83. Dietrich J, Han R, Yang Y, Mayer-Proschel M, Noble M (2006) CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol 5:22. doi:jbiol50 [pii] 10.1186/jbiol50

    PubMed  Google Scholar 

  84. Panchision DM, McKay RD (2002) The control of neural stem cells by morphogenic signals. Curr Opin Genet Dev 12:478–487

    PubMed  CAS  Google Scholar 

  85. Nakano I, Saigusa K, Kornblum HI (2008) BMPing off glioma stem cells. Cancer Cell 13:3–4

    PubMed  CAS  Google Scholar 

  86. Lim DA, Tramontin AD, Trevejo JM, Herrera DG, Garcia-Verdugo JM, Alvarez-Buylla A (2000) Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28:713–726

    PubMed  CAS  Google Scholar 

  87. 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 tumour-initiating cells. Nature 444:761–765

    PubMed  CAS  Google Scholar 

  88. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13:1253–1259

    PubMed  CAS  Google Scholar 

  89. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95

    PubMed  CAS  Google Scholar 

  90. Adams JM, Strasser A (2008) Is Tumor growth sustained by rare cancer stem cells or dominant clones? Cancer Res 68:4018–4021

    PubMed  CAS  Google Scholar 

  91. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456:593–598. doi:nature07567 [pii] 10.1038/nature07567

    PubMed  CAS  Google Scholar 

  92. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, Song H, Vandenberg S, Johnson RS, Werb Z, Bergers G (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220. doi:S1535-6108(08)00041-X [pii] 10.1016/j.ccr.2008.01.034

    PubMed  CAS  Google Scholar 

  93. Jurvansuu J, Zhao Y, Leung DSY, Boulaire J, Yu YH, Ahmed S, Wang S (2008) Transmembrane protein 18 enhances the tropism of neural stem cells for glioma cells. Cancer Res 68:4614–4622

    PubMed  CAS  Google Scholar 

  94. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr., Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476. doi:ncb1800 [pii] 10.1038/ncb1800

    PubMed  CAS  Google Scholar 

  95. Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY (2000) Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 97:12846–12851. doi:10.1073/pnas.97.23.1284697/23/12846 [pii]

    PubMed  CAS  Google Scholar 

  96. Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D, Galli R, Selleri S, Di Meco F, De Fraja C, Vescovi A, Cattaneo E, Finocchiaro G (2000) Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 6:447–450. doi:10.1038/74710

    PubMed  CAS  Google Scholar 

  97. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J (2008) Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 10:619–624. doi:ncb1725 [pii] 10.1038/ncb1725

    PubMed  CAS  Google Scholar 

  98. Hadjipanayis CG, Bonder MJ, Balakrishnan S, Wang X, Mao H, Hadjipanayis GC (2008) Metallic iron nanoparticles for MRI contrast enhancement and local hyperthermia. Small 4:1925–1929. doi:10.1002/smll.200800261

    PubMed  CAS  Google Scholar 

  99. Veiseh O, Sun C, Gunn J, Kohler N, Gabikian P, Lee D, Bhattarai N, Ellenbogen R, Sze R, Hallahan A, Olson J, Zhang M (2005) Optical and MRI multifunctional nanoprobe for targeting gliomas. Nano Lett 5:1003–1008. doi:10.1021/nl0502569

    PubMed  CAS  Google Scholar 

  100. Maier-Hauff K, Rothe R, Scholz R, Gneveckow U, Wust P, Thiesen B, Feussner A, von Deimling A, Waldoefner N, Felix R, Jordan A (2007) Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: results of a feasibility study on patients with glioblastoma multiforme. J Neurooncol 81:53–60. doi:10.1007/s11060-006-9195-0

    PubMed  CAS  Google Scholar 

  101. Jordan A, Scholz R, Maier-Hauff K, van Landeghem FK, Waldoefner N, Teichgraeber U, Pinkernelle J, Bruhn H, Neumann F, Thiesen B, von Deimling A, Felix R (2006) The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. J Neurooncol 78:7–14. doi:10.1007/s11060-005-9059-z

    PubMed  CAS  Google Scholar 

  102. Wu A, Wiesner S, Xiao J, Ericson K, Chen W, Hall WA, Low WC, Ohlfest JR (2007) Expression of MHC I and NK ligands on human CD133+glioma cells: possible targets of immunotherapy. J Neurooncol 83:121–131. doi:10.1007/s11060-006-9265-3

    PubMed  CAS  Google Scholar 

  103. Pellegatta S, Poliani PL, Corno D, Menghi F, Ghielmetti F, Suarez-Merino B, Caldera V, Nava S, Ravanini M, Facchetti F, Bruzzone MG, Finocchiaro G (2006) Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Res 66:10247–10252. doi:66/21/10247 [pii] 10.1158/0008-5472.CAN-06-2048

    PubMed  CAS  Google Scholar 

  104. Skog J, Edlund K, Bergenheim AT, Wadell G (2007) Adenoviruses 16 and CV23 efficiently transduce human low-passage brain tumor and cancer stem cells. Mol Ther 15:2140–2145. doi:6300315 [pii] 10.1038/sj.mt.6300315

    PubMed  CAS  Google Scholar 

  105. Nandi S, Ulasov IV, Tyler MA, Sugihara AQ, Molinero LYH, Zhu ZB, Lesniak MS (2008) Low-dose radiation enhances survivin-mediated virotherapy against malignant glioma stem cells. Cancer Res 68:5778–5784

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank Dr. Daniel Brat who kindly provided the microscopic sections of the brain and the immunohistochemistry staining present in Fig. 1.

Financial support

This work was supported in part by grants from the NIH (CA86335, CA116804 to EGVM, NS053454 to CGH), American Brain Tumor Association (to CGH), Brain Tumor Foundation for Children (to EGVM), Southeastern Brain Tumor Foundation (to CGN and EGVM), Goldhirsh Foundation (to EGVM), and the Georgia Cancer Coalition, Distinguished Cancer Clinicians and Scientists Program (to CGH).

Author information

Authors and Affiliations

  1. Laboratory of Molecular Neuro-Oncology, Departments of Neurosurgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 33022, USA

    Costas G. Hadjipanayis

  2. Laboratory of Molecular Neuro-Oncology, Departments of Neurosurgery, Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Erwin G. Van Meir

Authors
  1. Costas G. Hadjipanayis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erwin G. Van Meir
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Erwin G. Van Meir.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hadjipanayis, C.G., Van Meir, E.G. Tumor initiating cells in malignant gliomas: biology and implications for therapy. J Mol Med 87, 363–374 (2009). https://doi.org/10.1007/s00109-009-0440-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-009-0440-9

Keywords

Search

Navigation