Skip to main content
PMC home page
Cytotechnology logoLink to Cytotechnology
. 2003 Mar;41(2-3):93–101. doi: 10.1023/A:1024818621377

The potential of stem cells for the treatment of brain tumors and globoid cell leukodystrophy

Patrizia Tunici 1, Serena Pellegatta 1, Gaetano Finocchiaro 1
PMCID: PMC3466696  PMID: 19002946

Abstract

Stem cells of different origin are under careful scrutiny as potential new tools for the treatment of several neurological diseases. The major focus of these reaserches have been neurodegenerative disorders, such as Huntington Chorea or Parkinson Disease (Shihabuddin et al., 1999). More recently attention has been devoted to their use for brain repair after stroke (Savitz et al., 2002). In this review we will focus on the potential of stem cell treatments for glioblastoma multiforme (Holland, 2000), the most aggressive primary brain tumor, and globoid cell leukodystrophy (Krabbe disease), a metabolic disorder of the white matter (Berger et al., 2001). These two diseases may offer a paradigm of what the stem cell approach may offer in term of treatment, alone or in combination with other therapeutic approaches. Two kinds of stem cells will be consideredhere: neural stem cells and hematopoietic stem cells, both obtained after birth. The review will focus on experimental models, with an eye on clinical perspectives.

Keywords: neurodegenerative disorders, neurological diseases, stem cells

Full Text

The Full Text of this article is available as a PDF (101.4 KB).

References

  1. Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, et al. From the cover: neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. Proc Natl Acad Sci USA. 2000;97:12846–12851. doi: 10.1073/pnas.97.23.12846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Albarosa R, Colombo BM, Roz L, Magnani I, Pollo B, Cirenei N, Giani C, Conti AM, DiDonato S, Finocchiaro G. Deletion mapping of gliomas suggest the presence of two small regions for candidate tumor-suppressor genes in a 17-cM interval on chromosome 10q. Am J Hum Genet. 1996;58:1260–1267. [PMC free article] [PubMed] [Google Scholar]
  3. Alvarez-Buylla A, Garcia-Verdugo JM. Neurogenesis in adult subventricular zone. J Neurosci. 2002;22:629–634. doi: 10.1523/JNEUROSCI.22-03-00629.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Arsenijevic Y, Villemure JG, Brunet JF, Bloch JJ, Deglon N, Kostic C, Zurn A, Aebischer P. Isolation of multipotent neural precursors residing in the cortex of the adult human brain. Exp Neurol. 2001;170:48–62. doi: 10.1006/exnr.2001.7691. [DOI] [PubMed] [Google Scholar]
  5. Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D, Galli R, Selleri S, Di Meco F, De Fraja C, et al. Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med. 2000;6:447–450. doi: 10.1038/74710. [DOI] [PubMed] [Google Scholar]
  6. Berger J, Moser HW, Forss-Petter S. Leukodystrophies: Recent developments in genetics, molecular biology, pathogenesis and treatment. Curr Opin Neurol. 2001;14:305–312. doi: 10.1097/00019052-200106000-00007. [DOI] [PubMed] [Google Scholar]
  7. Bjorklund A, Lindvall O. Cell replacement therapies for central nervous system disorders. Nat Neurosci. 2000;3:537–544. doi: 10.1038/75705. [DOI] [PubMed] [Google Scholar]
  8. Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: expression of neuronal phenotypes in adult mice. Science. 2000;290:1775–1779. doi: 10.1126/science.290.5497.1775. [DOI] [PubMed] [Google Scholar]
  9. Carpenter MK, Cui X, Hu ZY, Jackson J, Sherman S, Seiger A, Wahlberg LU. In vitro expansion of a multipotent population of human neural progenitor cells. Exp Neurol. 1999;158:265–278. doi: 10.1006/exnr.1999.7098. [DOI] [PubMed] [Google Scholar]
  10. Carson MJ, Sutcliffe JG. Balancing function vs. self defense: The CNS as an active regulator of immune responses. J Neurosci Res. 1999;55:1–8. doi: 10.1002/(SICI)1097-4547(19990101)55:1<1::AID-JNR1>3.0.CO;2-9. [DOI] [PubMed] [Google Scholar]
  11. Chiariello E, Roz L, Albarosa R, Magnani I, Finocchiaro G. PTEN/MMAC1 mutations in primary glioblastomas and shortterm cultures of malignant gliomas. Oncogene. 1998;16:541–545. doi: 10.1038/sj.onc.1201689. [DOI] [PubMed] [Google Scholar]
  12. Desbaillets I, Tada M, De Tribolet N, Diserens AC, Hamou MF, Van Meir EG. Human astrocytomas and glioblastomas express monocyte chemoattractant protein-1 (MCP-1) in vivo and in vitro. Int J Cancer. 1994;58:240–247. doi: 10.1002/ijc.2910580216. [DOI] [PubMed] [Google Scholar]
  13. Duchen LW, Eicher EM, Jacobs JM, Scaravilli F, Teixeira F. Hereditary leucodystrophy in the mouse: The new mutant twitcher. Brain. 1980;103:695–710. doi: 10.1093/brain/103.3.695. [DOI] [PubMed] [Google Scholar]
  14. Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA. 1997;94:4080–4085. doi: 10.1073/pnas.94.8.4080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ehtesham M, Kabos P, Kabosova A, Neuman T, Black KL, Yu JS. The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res. 2002;62:5657–5663. [PubMed] [Google Scholar]
  16. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313–1317. doi: 10.1038/3305. [DOI] [PubMed] [Google Scholar]
  17. Flugel A, Hager G, Horvat A, Spitzer C, Singer GM, Graeber MB, Kreutzberg GW, Schwaiger FW. Neuronal MCP-1 expression in response to remote nerve injury. J Cereb Blood Flow Metab. 2001;21:69–76. doi: 10.1097/00004647-200101000-00009. [DOI] [PubMed] [Google Scholar]
  18. Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res. 2000;60:1383–1387. [PubMed] [Google Scholar]
  19. Fricker RA, Carpenter MK, Winkler C, Greco C, Gates MA, Bjorklund A. Site-specific migration and neuronal differentiation of human neural progenitor cells after transplantation in the adult rat brain. J Neurosci. 1999;19:5990–6005. doi: 10.1523/JNEUROSCI.19-14-05990.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fulci G, Labuhn M, Maier D, Lachat Y, Hausmann O, Hegi ME, Janzer RC, Merlo A, Van Meir EG. p53 gene mutation and ink4a-arf deletion appear to be twomutually exclusive events in human glioblastoma. Oncogene. 2000;19:3816–3822. doi: 10.1038/sj.onc.1203700. [DOI] [PubMed] [Google Scholar]
  21. Hayashi Y, Ueki K, Waha A, Wiestler OD, Louis DN, Von Deimling A. Association of EGFR gene amplification and CDKN2 (p16/MTS1) gene deletion in glioblastoma multiforme. Brain Pathol. 1997;7:871–875. doi: 10.1111/j.1750-3639.1997.tb00890.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, Nister M. Platelet-derived growth factor and its receptors in human glioma tissue: Expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res. 1992;52:3213–3219. [PubMed] [Google Scholar]
  23. Holland EC. Glioblastoma multiforme: The terminator. Proc Natl Acad Sci USA. 2000;97:6242–6244. doi: 10.1073/pnas.97.12.6242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet. 2000;25:55–57. doi: 10.1038/75596. [DOI] [PubMed] [Google Scholar]
  25. Holland EC, Hively WP, DePinho RA, Varmus HE. A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev. 1998;12:3675–3685. doi: 10.1101/gad.12.23.3675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hoogerbrugge PM, Suzuki K, Poorthuis BJ, Kobayashi T, Wagemaker G, Van Bekkum DW. Donor-derived cells in the central nervous system of twitcher mice after bone marrow transplantation. Science. 1988;239:1035–1038. doi: 10.1126/science.3278379. [DOI] [PubMed] [Google Scholar]
  27. Ichioka T, Kishimoto Y, Brennan S, Santos GW, Yeager AM. Hematopoietic cell transplantation in murine globoid cell leukodystrophy (the twitcher mouse): effects on levels of galactosylceramidase, psychosine, and galactocerebrosides. Proc Natl Acad Sci USA. 1987;84:4259–4263. doi: 10.1073/pnas.84.12.4259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kobayashi T, Yamanaka T, Jacobs JM, Teixeira F, Suzuki K. The Twitcher mouse: an enzymatically authentic model of human globoid cell leukodystrophy (Krabbe disease) Brain Res. 1980;202:479–483. doi: 10.1016/0006-8993(80)90159-6. [DOI] [PubMed] [Google Scholar]
  29. Krivit W, Shapiro EG, Peters C, Wagner JE, Cornu G, Kurtzberg J, Wenger DA, Kolodny EH, Vanier MT, Loes DJ, et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med. 1998;338:1119–1126. doi: 10.1056/NEJM199804163381605. [DOI] [PubMed] [Google Scholar]
  30. Kukekov VG, Laywell ED, Suslov O, Davies K, Scheffler B, Thomas LB, O'Brien TF, Kusakabe M, Steindler DA. Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain. Exp Neurol. 1999;156:333–344. doi: 10.1006/exnr.1999.7028. [DOI] [PubMed] [Google Scholar]
  31. Kuratsu J, Yoshizato K, Yoshimura T, Leonard EJ, Takeshima H, Ushio Y. Quantitative study of monocyte chemoattractant protein-1 (MCP-1) in cerebrospinal fluid and cyst fluid from patients with malignant glioma. J Natl Cancer Inst. 1993;85:1836–1839. doi: 10.1093/jnci/85.22.1836. [DOI] [PubMed] [Google Scholar]
  32. Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA. Malignant glioma: Genetics and biology of a grave matter. Genes Dev. 2001;15:1311–1333. doi: 10.1101/gad.891601. [DOI] [PubMed] [Google Scholar]
  33. Matsushima GK, Taniike M, Glimcher LH, Grusby MJ, Frelinger JA, Suzuki K, Ting JP. Absence of MHC class II molecules reduces CNS demyelination, microglial/macrophage infiltration, and twitching in murine globoid cell leukodystrophy. Cell. 1994;78:645–656. doi: 10.1016/0092-8674(94)90529-0. [DOI] [PubMed] [Google Scholar]
  34. Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: Cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000;290:1779–1782. doi: 10.1126/science.290.5497.1779. [DOI] [PubMed] [Google Scholar]
  35. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci USA. 1998;95:13513–13518. doi: 10.1073/pnas.95.23.13513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, Huang HJ. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci USA. 1994;91:7727–7731. doi: 10.1073/pnas.91.16.7727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernandez-Klett F, Prass K, Bechmann I, De Boer BA, et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med. 2001;7:1356–1361. doi: 10.1038/nm1201-1356. [DOI] [PubMed] [Google Scholar]
  38. Qu T, Brannen CL, Kim HM, Sugaya K. Human neural stem cells improve cognitive function of aged brain. Neuroreport. 2001;12:1127–1132. doi: 10.1097/00001756-200105080-00016. [DOI] [PubMed] [Google Scholar]
  39. Reilly KM, Loisel DA, Bronson RT, McLaughlin ME, Jacks T. Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet. 2000;26:109–113. doi: 10.1038/79075. [DOI] [PubMed] [Google Scholar]
  40. Roy NS, Benraiss A, Wang S, Fraser RA, Goodman R, Couldwell WT, Nedergaard M, Kawaguchi A, Okano H, Goldman SA. Promoter-targeted selection and isolation of neural progenitor cells from the adult human ventricular zone. J Neurosci Res. 2000;59:321–331. doi: 10.1002/(SICI)1097-4547(20000201)59:3<321::AID-JNR5>3.0.CO;2-9. [DOI] [PubMed] [Google Scholar]
  41. Savitz SI, Rosenbaum DM, Dinsmore JH, Wechsler LR, Caplan LR. Cell transplantation for stroke. Ann Neurol. 2002;52:266–275. doi: 10.1002/ana.60000. [DOI] [PubMed] [Google Scholar]
  42. Schlegel J, Merdes A, Stumm G, Albert FK, Forsting M, Hynes N, Kiessling M. Amplification of the epidermal-growthfactor-receptor gene correlates with different growth behaviour in human glioblastoma. Int J Cancer. 1994;56:72–77. doi: 10.1002/ijc.2910560114. [DOI] [PubMed] [Google Scholar]
  43. Selleri S, Torchiana E, Pareyson D, Lulli L, Bertagnolio B, Savoiardo M, Farina L, Carrara F, Filocamo M, Gatti R, et al. Deletion of exons 11–17 and novel mutations of the galactocerebrosidase gene in adult-and early-onset patients with Krabbe disease. J Neurol. 2000;247:875–877. doi: 10.1007/s004150070076. [DOI] [PubMed] [Google Scholar]
  44. Shihabuddin LS, Palmer TD, Gage FH. The search for neural progenitor cells: Prospects for the therapy of neurodegenerative disease. Mol Med Today. 1999;5:474–480. doi: 10.1016/S1357-4310(99)01596-8. [DOI] [PubMed] [Google Scholar]
  45. Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature. 2002;417:39–44. doi: 10.1038/417039a. [DOI] [PubMed] [Google Scholar]
  46. Suzuki K, Suzuki Y. Globoid cell leucodystrophy Krabbe's disease: Deficiency of galactocerebroside beta-galactosidase. Proc Natl Acad Sci USA. 1970;66:302–309. doi: 10.1073/pnas.66.2.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Suzuki Y, Suzuki K. Krabbe's globoid cell leukodystrophy: Deficiency of glactocerebrosidase in serum, leukocytes, and fibroblasts. Science. 1971;171:73–75. doi: 10.1126/science.171.3966.73. [DOI] [PubMed] [Google Scholar]
  48. Svendsen CN, Caldwell MA, Ostenfeld T. Human neural stem cells: isolation, expansion and transplantation. Brain Pathol. 1999;9:499–513. doi: 10.1111/j.1750-3639.1999.tb00538.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, Kleihues P, Ohgaki H. PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol. 1998;57:684–689. doi: 10.1097/00005072-199807000-00005. [DOI] [PubMed] [Google Scholar]
  50. Torchiana E, Lulli L, Cattaneo E, Invernizzi F, Orefice R, Bertagnolio B, Di Donato S, Finocchiaro G. Retroviralmediated transfer of the galactocerebrosidase gene in neural progenitor cells. Neuroreport. 1998;9:3823–3827. doi: 10.1097/00001756-199812010-00011. [DOI] [PubMed] [Google Scholar]
  51. Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA. 2000;97:14720–14725. doi: 10.1073/pnas.97.26.14720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Ueki K, Ono Y, Henson JW, Efird JT, Von Deimling A, Louis DN. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res. 1996;56:150–153. [PubMed] [Google Scholar]
  53. Uhrbom L, Dai C, Celestino JC, Rosenblum MK, Fuller GN, Holland EC. Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res. 2002;62:5551–5558. [PubMed] [Google Scholar]
  54. Vescovi AL, Parati EA, Gritti A, Poulin P, Ferrario M, Wanke E, Frolichsthal-Schoeller P, Cova L, Arcellana-Panlilio M, Colombo A, Galli R. 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. 1999;156:71–83. doi: 10.1006/exnr.1998.6998. [DOI] [PubMed] [Google Scholar]
  55. Villa A, Snyder EY, Vescovi A, Martinez-Serrano A. Establishment and properties of a growth factor-dependent, perpetual neural stem cell line from the human CNS. Exp Neurol. 2000;161:67–84. doi: 10.1006/exnr.1999.7237. [DOI] [PubMed] [Google Scholar]
  56. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–310. doi: 10.1038/35042675. [DOI] [PubMed] [Google Scholar]
  57. Wenger DA, Rafi MA, Luzi P, Datto J, Costantino-Ceccarini E. Krabbe disease: Genetic aspects and progress toward therapy. Mol Genet Metab. 2000;70:1–9. doi: 10.1006/mgme.2000.2990. [DOI] [PubMed] [Google Scholar]
  58. Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA. 1998;95:15587–15591. doi: 10.1073/pnas.95.26.15587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Wu YP, McMahon E, Kraine MR, Tisch R, Meyers A, Frelinger J, Matsushima GK, Suzuki K. Distribution and characterization of GFP(+) donor hematogenous cells in Twitcher mice after bone marrow transplantation. Am J Pathol. 2000;156:1849–1854. doi: 10.1016/S0002-9440(10)65058-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Young E, Wilson J, Patrick AD, Crome L. Galactocerebrosidase deficiency in globoid cell leucodystrophy of late onset. Arch Dis Child. 1972;47:449–450. doi: 10.1136/adc.47.253.449. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Cytotechnology are provided here courtesy of Springer Science+Business Media B.V.

RESOURCES