Journal of Molecular Medicine

, 87:1087 | Cite as

Brain cancer stem cells

Review

Abstract

Cancers comprise heterogeneous cells, ranging from highly proliferative immature precursors to more differentiated cell lineages. In the last decade, several groups have demonstrated the existence of cancer stem cells in both nonsolid solid tumors, including some of the brain: glioblastoma multiforme (GBM), medulloblastoma, and ependymoma. These cells, like their normal counterpart in homologous tissues, are multipotent, undifferentiated, self-sustaining, yet transformed cells. In particular, glioblastoma-stem like cells (GBSCs) self-renew under clonal conditions and differentiate into neuron- and glia-like cells, with aberrant, mixed neuronal/astroglial phenotypes. Remarkably, upon subcutaneous and intracerebral transplantation in immunosuppressed mice, GBSCs are able to form secondary tumors that closely resemble the human pathology, a property retained also throughout serial transplantation. The search is up for the identification of the markers and the molecular mechanisms that underpin the tumorigenic potential of these cells. This is critical if we aim at defining new therapeutic approaches for the treatment of malignant brain tumors. Lately, it has been shown that some key regulatory system that plays pivotal roles in neural stem cell physiology can also regulate the tumorigenic ability of cancer stem cells in GBMs. This suggests that the study of cancer stem cells in brain tumors might help to identify new and more specific therapeutic molecular effectors, with the cancer stem cells themselves representing one of the main targets, in fact the Holy Grail, in cancer cell therapy. This review includes a summary review on brain cancer cells and their usefulness as emerging targets in cancer cell therapy.

Keywords

Neural stem cells Cancer stem cells Glioblastoma multiforme Tumorigenicity Brain tumor Glioblastoma Cancer therapy 

References

  1. 1.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefPubMedGoogle Scholar
  2. 2.
    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 367:645–648CrossRefPubMedGoogle Scholar
  3. 3.
    Piccirillo SG, Vescovi AL (2007) Brain tumour stem cells: possibilities of new therapeutic strategies. Expert Opin Biol Ther 7:1129–1135CrossRefPubMedGoogle Scholar
  4. 4.
    Taipale J, Beachy PA (2001) The hedgehog and Wnt signalling pathways in cancer. Nature 411:349–354CrossRefPubMedGoogle Scholar
  5. 5.
    Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111CrossRefPubMedGoogle Scholar
  6. 6.
    Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902CrossRefPubMedGoogle Scholar
  7. 7.
    Beachy PA, Karhadkar SS, Berman DM (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature 432:324–331CrossRefPubMedGoogle Scholar
  8. 8.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737CrossRefPubMedGoogle Scholar
  9. 9.
    Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, Perry SR, Tonon G, Chu GC, Ding Z, Stommel JM, Dunn KL, Wiedemeyer R, You MJ, Brennan C, Wang YA, Ligon KL, Wong WH, Chin L, DePinho RA (2008) p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 455:1129–1133CrossRefPubMedGoogle Scholar
  10. 10.
    Alcantara 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 15:45–56CrossRefPubMedGoogle Scholar
  11. 11.
    Barth RF (1998) Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J Neurooncol 36:91–102CrossRefPubMedGoogle Scholar
  12. 12.
    Huse JT, Holland EC (2009) Genetically engineered mouse models of brain cancer and the promise of preclinical testing. Brain Pathol 19:132–143CrossRefPubMedGoogle Scholar
  13. 13.
    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 28:1807–1811CrossRefPubMedGoogle Scholar
  14. 14.
    Rosen JM, Jordan CT (2009) The increasing complexity of the cancer stem cell paradigm. Science 324:1670–1673CrossRefPubMedGoogle Scholar
  15. 15.
    Potten CS, Booth C, Pritchard DM (1997) The intestinal epithelial stem cell: the mucosal governor. Int J Exp Pathol 78:219–243CrossRefPubMedGoogle Scholar
  16. 16.
    Guo W, Lasky JL, Chang CJ, Mosessian S, Lewis X, Xiao Y, Yeh JE, Chen JY, Iruela-Arispe ML, Varella-Garcia M, Wu H (2008) Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature 453:529–533CrossRefPubMedGoogle Scholar
  17. 17.
    Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456:593–598CrossRefPubMedGoogle Scholar
  18. 18.
    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 39:193–206CrossRefPubMedGoogle Scholar
  19. 19.
    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 100:15178–15183CrossRefPubMedGoogle Scholar
  20. 20.
    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
  21. 21.
    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 64:7011–7021CrossRefPubMedGoogle Scholar
  22. 22.
    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 432:396–401CrossRefPubMedGoogle Scholar
  23. 23.
    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 9:391–403CrossRefPubMedGoogle Scholar
  24. 24.
    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 444:761–765CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang QB, Ji XY, Huang Q, Dong J, Zhu YD, Lan Q (2006) Differentiation profile of brain tumor stem cells: a comparative study with neural stem cells. Cell Res 16:909–915CrossRefPubMedGoogle Scholar
  26. 26.
    Soeda A, Inagaki A, Oka N, Ikegame Y, Aoki H, Yoshimura S, Nakashima S, Kunisada T, Iwama T (2008) Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells. J Biol Chem 283:10958–10966CrossRefPubMedGoogle Scholar
  27. 27.
    Bidlingmaier S, Zhu X, Liu B (2008) The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. J Mol Med 86:1025–1032CrossRefPubMedGoogle Scholar
  28. 28.
    Ganguly R, Puri IK (2006) Mathematical model for the cancer stem cell hypothesis. Cell Prolif 39:3–14CrossRefPubMedGoogle Scholar
  29. 29.
    Berger F, Gay E, Pelletier L, Tropel P, Wion D (2004) Development of gliomas: potential role of asymmetrical cell division of neural stem cells. Lancet Oncol 5:511–514CrossRefPubMedGoogle Scholar
  30. 30.
    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 156:71–83CrossRefPubMedGoogle Scholar
  31. 31.
    De Filippis L, Lamorte G, Snyder EY, Malgaroli A, Vescovi AL (2007) A novel, immortal, and multipotent human neural stem cell line generating functional neurons and oligodendrocytes. Stem Cells 25:2312–2321CrossRefPubMedGoogle Scholar
  32. 32.
    Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, Pilozzi E, Larocca LM, Peschle C, De Maria R (2006) Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ 13:1238–1241CrossRefPubMedGoogle Scholar
  33. 33.
    Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67CrossRefPubMedGoogle Scholar
  34. 34.
    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 444:756–760CrossRefPubMedGoogle Scholar
  35. 35.
    Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT, Bray RA, Waller EK, Buck DW (1997) A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 90:5013–5021PubMedGoogle Scholar
  36. 36.
    Corbeil D, Roper K, Weigmann A, Huttner WB (1998) AC133 hematopoietic stem cell antigen: human homologue of mouse kidney prominin or distinct member of a novel protein family? Blood 91:2625–2626PubMedGoogle Scholar
  37. 37.
    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 67:4010–4015CrossRefPubMedGoogle Scholar
  38. 38.
    Joo KM, Kim SY, Jin X, Song SY, Kong DS, Lee JI, Jeon JW, Kim MH, Kang BG, Jung Y, Jin J, Hong SC, Park WY, Lee DS, Kim H, Nam DH (2008) Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas. Lab Invest 88:808–815CrossRefPubMedGoogle Scholar
  39. 39.
    Ogden AT, Waziri AE, Lochhead RA, Fusco D, Lopez K, Ellis JA, Kang J, Assanah M, McKhann GM, Sisti MB, McCormick PC, Canoll P, Bruce JN (2008) Identification of A2B5+CD133—tumor-initiating cells in adult human gliomas. Neurosurgery 62:505–514 discussion 514-505CrossRefPubMedGoogle Scholar
  40. 40.
    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 122:761–768CrossRefPubMedGoogle Scholar
  41. 41.
    Son MJ, Woolard K, Nam DH, Lee J, Fine HA (2009) SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell 4:440–452CrossRefPubMedGoogle Scholar
  42. 42.
    Capela A, Temple S (2002) LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 35:865–875CrossRefPubMedGoogle Scholar
  43. 43.
    Capela A, Temple S (2006) LeX is expressed by principle progenitor cells in the embryonic nervous system, is secreted into their environment and binds Wnt-1. Dev Biol 291:300–313CrossRefPubMedGoogle Scholar
  44. 44.
    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 352:987–996CrossRefPubMedGoogle Scholar
  45. 45.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003CrossRefPubMedGoogle Scholar
  46. 46.
    Salmaggi A, Boiardi A, Gelati M, Russo A, Calatozzolo C, Ciusani E, Sciacca FL, Ottolina A, Parati EA, La Porta C, Alessandri G, Marras C, Croci D, De Rossi M (2006) Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. Glia 54:850–860CrossRefPubMedGoogle Scholar
  47. 47.
    Beier D, Rohrl S, Pillai DR, Schwarz S, Kunz-Schughart LA, Leukel P, Proescholdt M, Brawanski A, Bogdahn U, Trampe-Kieslich A, Giebel B, Wischhusen J, Reifenberger G, Hau P, Beier CP (2008) Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Res 68:5706–5715CrossRefPubMedGoogle Scholar
  48. 48.
    Aghi M, Martuza RL (2005) Oncolytic viral therapies—the clinical experience. Oncogene 24:7802–7816CrossRefPubMedGoogle Scholar
  49. 49.
    Hoffmann D, Wildner O (2007) Comparison of herpes simplex virus- and conditionally replicative adenovirus-based vectors for glioblastoma treatment. Cancer Gene Ther 14:627–639CrossRefPubMedGoogle Scholar
  50. 50.
    Jiang H, Gomez-Manzano C, Aoki H, Alonso MM, Kondo S, McCormick F, Xu J, Kondo Y, Bekele BN, Colman H, Lang FF, Fueyo J (2007) Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death. J Natl Cancer Inst 99:1410–1414CrossRefPubMedGoogle Scholar
  51. 51.
    Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, Rich JN (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15:501–513CrossRefPubMedGoogle Scholar
  52. 52.
    Arwert E, Hingtgen S, Figueiredo JL, Bergquist H, Mahmood U, Weissleder R, Shah K (2007) Visualizing the dynamics of EGFR activity and antiglioma therapies in vivo. Cancer Res 67:7335–7342CrossRefPubMedGoogle Scholar
  53. 53.
    Griffero F, Daga A, Marubbi D, Capra MC, Melotti A, Pattarozzi A, Gatti M, Bajetto A, Porcile C, Barbieri F, Favoni RE, Lo Casto M, Zona G, Spaziante R, Florio T, Corte G (2009) Different response of human glioma tumor-initiating cells to epidermal growth factor receptor kinase inhibitors. J Biol Chem 284:7138–7148CrossRefPubMedGoogle Scholar
  54. 54.
    Dahmane N, Sanchez P, Gitton Y, Palma V, Sun T, Beyna M, Weiner H, Ruiz i Altaba A (2001) The sonic hedgehog-GLI pathway regulates dorsal brain growth and tumorigenesis. Development 128:5201–5212PubMedGoogle Scholar
  55. 55.
    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 17:165–172CrossRefPubMedGoogle Scholar
  56. 56.
    Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A, Eberhart CG (2007) Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 25:2524–2533CrossRefPubMedGoogle Scholar
  57. 57.
    Park S, Hatanpaa KJ, Xie Y, Mickey BE, Madden CJ, Raisanen JM, Ramnarain DB, Xiao G, Saha D, Boothman DA, Zhao D, Bachoo RM, Pieper RO, Habib AA (2009) The receptor interacting protein 1 inhibits p53 induction through NF-kappaB activation and confers a worse prognosis in glioblastoma. Cancer Res 69:2809–2816CrossRefPubMedGoogle Scholar
  58. 58.
    Gallia GL, Tyler BM, Hann CL, Siu IM, Giranda VL, Vescovi AL, Brem H, Riggins GJ (2009) Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. Mol Cancer Ther 8:386–393CrossRefPubMedGoogle Scholar
  59. 59.
    Chearwae W, Bright JJ (2008) PPARgamma agonists inhibit growth and expansion of CD133+ brain tumour stem cells. Br J Cancer 99:2044–2053CrossRefPubMedGoogle Scholar
  60. 60.
    Corsten MF, Shah K (2008) Therapeutic stem-cells for cancer treatment: hopes and hurdles in tactical warfare. Lancet Oncol 9:376–384CrossRefPubMedGoogle Scholar
  61. 61.
    Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT (1997) TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. Embo J 16:5386–5397CrossRefPubMedGoogle Scholar
  62. 62.
    Shah K, Tung CH, Yang K, Weissleder R, Breakefield XO (2004) Inducible release of TRAIL fusion proteins from a proapoptotic form for tumor therapy. Cancer Res 64:3236–3242CrossRefPubMedGoogle Scholar
  63. 63.
    Shah K, Tung CH, Breakefield XO, Weissleder R (2005) In vivo imaging of S-TRAIL-mediated tumor regression and apoptosis. Mol Ther 11:926–931CrossRefPubMedGoogle Scholar
  64. 64.
    Sasportas LS, Kasmieh R, Wakimoto H, Hingtgen S, van de Water JA, Mohapatra G, Figueiredo JL, Martuza RL, Weissleder R, Shah K (2009) Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. Proc Natl Acad Sci USA 106:4822–4827CrossRefPubMedGoogle Scholar
  65. 65.
    Vlashi E, Kim K, Lagadec C, Donna LD, McDonald JT, Eghbali M, Sayre JW, Stefani E, McBride W, Pajonk F (2009) In vivo imaging, tracking, and targeting of cancer stem cells. J Natl Cancer Inst 101:350–359CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of Biosciences and BiotechnologyUniversity of Milan BicoccaMilanItaly
  2. 2.StemGen SpAMilanItaly
  3. 3.Massachusetts General HospitalHarvard Medical SchoolCharlestownUSA

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