Stem cells in neuro-oncology — development, regeneration and treatment

  • M. Kirsch
  • O. Heese
  • M. Westphal
  • G. Schackert
Conference paper
Part of the Acta Neurochirurgica Supplements book series (NEUROCHIRURGICA, volume 88)


The major obstacles to successful eradication of central nervous system (CNS) tumors are, firstly, the extensive invasive and migratory capacity of malignant cells and, secondly, the devastating effects of injury to the brain due to tumor growth and unwanted side effects caused by conventional therapy.


Stem Cell Traumatic Brain Injury Neural Stem Cell Bone Marrow Stromal Cell Neural Progenitor Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    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(23): 12846–12851PubMedCrossRefGoogle Scholar
  2. 2.
    Archibald YM, Lunn D, Ruttan LA, Macdonald DR, Del Maestro RF, Barr HW, Pexman JH, Fisher BJ, Gaspar LE, Cairncross JG (1994) Cognitive functioning in long-term survivors of high-grade glioma. J Neurosurg 80(2): 247–253PubMedCrossRefGoogle Scholar
  3. 3.
    Belka C, Budach W, Kortmann RD, Bamberg M (2001) Radiation induced CNS toxicity — molecular and cellular mechanisms. Br J Cancer 85(9): 1233–1239PubMedCrossRefGoogle Scholar
  4. 4.
    Bellinzona M, Gobbel GT, Shinohara C, Fike JR (1996) Apoptosis is induced in the subependyma of young adult rats by ionizing irradiation. Neurosci Lett 208(3): 163–166PubMedCrossRefGoogle Scholar
  5. 5.
    Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF (2000) Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 18(14): 2695–2701PubMedGoogle Scholar
  6. 6.
    Chen J, Li Y, Wang L, Lu M, Zhang X, Chopp M (2001) Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci 189(1–2): 1–2PubMedCrossRefGoogle Scholar
  7. 7.
    Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M (2001) Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32(4): 1005–1011PubMedCrossRefGoogle Scholar
  8. 8.
    Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE, Sanchez-Ramos J, Chopp M (2001) Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32(11): 2682–2688PubMedCrossRefGoogle Scholar
  9. 9.
    Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, Lu M, Zhu Z, Chopp M (2003) Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Cire Res 92: 692–699CrossRefGoogle Scholar
  10. 10.
    Chen X, Katakowski M, Li Y, Lu D, Wang L, Zhang L, Chen J, Xu Y, Gautam S, Mahmood A, Chopp M (2002) Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: growth factor production. J Neurosci Res 69(5): 687–691PubMedCrossRefGoogle Scholar
  11. 11.
    Clyde Z, Chataway SJ, Signorini D, Gregor A, Grant R (1998) Significant change in tests of neurological impairment in patients with brain tumours. J Neurooncol 39(1): 81–90PubMedCrossRefGoogle Scholar
  12. 12.
    Craig CG, Tropepe V, Morshead CM, Reynolds BA, Weiss S, van der KD (1996) In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci 16(8): 2649–2658PubMedGoogle Scholar
  13. 13.
    Dirks PB (2001) Glioma migration: clues from the biology of neural progenitor cells and embryonic CNS cell migration. J Neurooncol 53(2): 203–212PubMedCrossRefGoogle Scholar
  14. 14.
    Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A (1997) Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci 17(13): 5046–5061Google Scholar
  15. 15.
    Ehtesham M, Kabos P, Gutierrez MA, Chung NH, Griffith TS, Black KL, Yu JS (2002) Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 62(24): 7170–7174PubMedGoogle Scholar
  16. 16.
    Ehtesham M, Kabos P, Kabosova A, Neuman T, Black KL, Yu JS (2002) The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res 62(20): 5657–5663PubMedGoogle Scholar
  17. 17.
    Folkerth RD, Durso R (1996) Survival and proliferation of nonneural tissues, with obstruction of cerebral ventricles, in a parkinsonian patient treated with fetal allografts. Comments: Neurology (1997) 48: 1737–1739; Neurology 46(5): 1737–1739Google Scholar
  18. 18.
    Glauser TA, Packer RJ (1991) Cognitive deficits in long-term survivors of childhood brain tumors. Childs Nerv Syst 7(1): 2–12PubMedCrossRefGoogle Scholar
  19. 19.
    Gross CG (2000) Neurogenesis in the adult brain: death of a dogma. Nat Rev Neurosci 1(1): 67–73PubMedCrossRefGoogle Scholar
  20. 20.
    Hagell P, Brundin P (2001) Cell survival and clinical outcome following intrastriatal transplantation in Parkinson disease. J Neuropathol Exp Neurol 60(8): 741–752Google Scholar
  21. 21.
    Hao HN, Zhao J, Thomas RL, Parker GC, Lyman WD (2003) Fetal human hematopoietic stem cells can differentiate sequentially into neural stem cells and then astrocytes in vitro. J Hematother Stem Cell Res 12(1): 23–32PubMedCrossRefGoogle Scholar
  22. 22.
    Hatten ME (2002) New directions in neuronal migration. Science 297(5587): 1660–1663PubMedCrossRefGoogle Scholar
  23. 23.
    Herrlinger U, Woiciechowski C, Sena-Esteves M, Aboody KS, Jacobs AH, Rainov NG, Snyder EY, Breakefield XO (2000) Neural precursor cells for delivery of replication-conditional HSV-1 vectors to intracerebral gliomas. Mol Ther 1(4): 347–357PubMedCrossRefGoogle Scholar
  24. 24.
    Kabos P, Ehtesham M, Kabosova A, Black KL, Yu JS (2002) Generation of neural progenitor cells from whole adult bone marrow. Exp Neurol 178(2): 288–293PubMedCrossRefGoogle Scholar
  25. 25.
    Kitchens DL, Snyder EY, Gottlieb DI (1994) FGF and EGF are mitogens for immortalized neural progenitors. J Neurobiol 25(7): 797–807PubMedCrossRefGoogle Scholar
  26. 26.
    Kondziolka D, Wechsler L, Tyler-Kabara E, Achim C (2003) The role of cell therapy for stroke. Neurosurg Focus 13[5], 1–6. Ref Type: genericGoogle Scholar
  27. 27.
    Kuhn HG, Winkler J, Kempermann G, Thal LJ, Gage FH (1997) Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci 17(15): 5820–5829PubMedGoogle Scholar
  28. 28.
    Kurita H, Kawahara N, Asai A, Ueki K, Shin M, Kirino T (2001) Radiation-induced apoptosis of oligodendrocytes in the adult rat brain. Neurol Res 23(8): 869–874PubMedCrossRefGoogle Scholar
  29. 29.
    Lamszus K, Laterra J, Westphal M, Rosen EM (1999) Scatter factor/hepatocyte growth factor (SF/HGF) content and function in human gliomas. Int J Dev Neurosci 17(5–6): 5–6PubMedCrossRefGoogle Scholar
  30. 30.
    Lamszus K, Schmidt NO, Jin L, Laterra J, Zagzag D, Way D, Witte M, Weinand M, Goldberg ID, Westphal M, Rosen EM (1998) Scatter factor promotes motility of human glioma and neuromicrovascular endothelial cells. Int J Cancer 75(1): 19–28PubMedCrossRefGoogle Scholar
  31. 31.
    Li Y, Chen J, Chopp M (2001) Adult bone marrow transplantation after stroke in adult rats. Cell Transplant 10(1): 31–40PubMedGoogle Scholar
  32. 32.
    Lois C, Alvarez-Buylla A (1994) Long-distance neuronal migration in the adult mammalian brain. Science 264(5162): 1145–1148Google Scholar
  33. 33.
    Lu D, Li Y, Wang L, Chen J, Mahmood A, Chopp M (2001) Intraarterial administration of marrow stromal cells in a rat model of traumatic brain injury 18(8): 813–819PubMedCrossRefGoogle Scholar
  34. 34.
    Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M (2001) Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport 12(3): 559–563PubMedCrossRefGoogle Scholar
  35. 35.
    Lu D, Li Y, Mahmood A, Wang L, Rafiq T, Chopp M (2002) Neural and marrow-derived stromal cell sphere transplantation in a rat model of traumatic brain injury. J Neurosurg 97(4): 935–940PubMedCrossRefGoogle Scholar
  36. 36.
    Lu D, Sanberg PR, Mahmood A, Li Y, Wang L, Sanchez-Ramos J, Chopp M (2002) Intravenous administration of human umbilical cord blood reduces neurological deficit in the rat after traumatic brain injury. Cell Transplant 11(3): 275–281PubMedGoogle Scholar
  37. 37.
    Mahmood A, Lu D, Wang L, Li Y, Lu M, Chopp M (2001) Treatment of traumatic brain injury in female rats with intravenous administration of bone marrow stromal cells. Neurosurgery 49(5): 1196–1203PubMedGoogle Scholar
  38. 38.
    Mahmood A, Lu D, Yi L, Chen JL, Chopp M (2001) Intracranial bone marrow transplantation after traumatic brain injury improving functional outcome in adult rats. J Neurosurg 94(4): 589–595PubMedCrossRefGoogle Scholar
  39. 39.
    Mahmood A, Lu D, Wang L, Chopp M (2002) Intracerebral transplantation of marrow stromal cells cultured with neurotrophic factors promotes functional recovery in adult rats subjected to traumatic brain injury. J Neurotrauma 19(12): 1609–1617CrossRefGoogle Scholar
  40. 40.
    Mamelak AN, Eggerding FA, Oh DS, Wilson E, Davis RL, Spitzer R, Hay JA, Caton WL, III (1998) Fatal cyst formation after fetal mesencephalic allograft transplant for Parkinson’s disease. Comments: J Neurosurg (1999) 90: 1148–1150; J Neurosurg 89(4): 1148–1150Google Scholar
  41. 41.
    Mavilio F, Simeone A, Boncinelli E, Andrews PW (1988) Activation of four homeobox gene clusters in human embryonal carcinoma cells induced to differentiate by retinoic acid. Differentiation 37(1): 73–79PubMedCrossRefGoogle Scholar
  42. 42.
    Mezey E, Chandross KJ (2000) Bone marrow: a possible alternative source of cells in the adult nervous system. Eur J Pharmacol 405(1–3): 1–3PubMedCrossRefGoogle Scholar
  43. 43.
    Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B (2003) Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci USA 100(3): 1364–1369PubMedCrossRefGoogle Scholar
  44. 44.
    Monje ML, Mizumatsu S, Fike JR, Palmer TD (2002) Irradiation induces neural precursor-cell dysfunction. Nat Med 8(9): 955–962PubMedCrossRefGoogle Scholar
  45. 45.
    Mulhern RK, Palmer SL, Reddick WE, Glass JO, Kun LE, Taylor J, Langston J, Gajjar A (2001) Risks of young age for selected neurocognitive deficits in medulloblastoma are associated with white matter loss. J Clin Oncol 19(2): 472–479PubMedGoogle Scholar
  46. 46.
    Nelson PT, Kondziolka D, Wechsler L, Goldstein S, Gebel J, DeCesare S, Elder EM, Zhang PJ, Jacobs A, McGrogan M, Lee VM, Trojanowski JQ (2002) Clonal human (hNT) neuron grafts for stroke therapy: neuropathology in a patient 27 months after implantation. Am J Pathol 160(4): 1201–1206PubMedCrossRefGoogle Scholar
  47. 47.
    Okabe S, Forsberg-Nilsson K, Spiro AC, Segal M, McKay RD (1996) Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev 59(1): 89–102Google Scholar
  48. 48.
    Ourednik J, Ourednik V, Lynch WP, Schachner M, Snyder EY (2002) Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol 20(11): 1103–1110PubMedCrossRefGoogle Scholar
  49. 49.
    Peissner W, Kocher M, Treuer H, Gillardon F (1999) Ionizing radiation-induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus. Brain Res Mol Brain Res 71(1): 61–68PubMedCrossRefGoogle Scholar
  50. 50.
    Pera MF, Herszfeld D (1998) Differentiation of human pluripotent teratocarcinoma stem cells induced by bone morphogenetic protein-2. Reprod Fertil Dev 10(7–8): 7–8PubMedCrossRefGoogle Scholar
  51. 51.
    Philips MF, Mattiasson G, Wieloch T, Bjorklund A, Johansson BB, Tomasevic G, Martinez-Serrano A, Lenzlinger PM, Sin-son G, Grady MS, McIntosh TK (2001) Neuroprotective and behavioral efficacy of nerve growth factor-transfected hippo-campal progenitor cell transplants after experimental traumatic brain injury. J Neurosurg 94(5): 765–774PubMedCrossRefGoogle Scholar
  52. 52.
    Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernandez-Klett F, Prass K, Bechmann I, de Boer BA, Frotscher M, Kreutzberg GW, Persons DA, Dirnagl U (2001) Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 7(12): 1356–1361PubMedCrossRefGoogle Scholar
  53. 53.
    Radcliffe J, Bunin GR, Sutton LN, Goldwein JW, Phillips PC (1994) Cognitive deficits in long-term survivors of childhood medulloblastoma and other noncortical tumors: age-dependent effects of whole brain radiation. Int J Dev Neurosci 12(4): 327–334PubMedCrossRefGoogle Scholar
  54. 54.
    Reimers D, Lopez-Toledano MA, Mason I, Cuevas P, Redondo C, Herranz AS, Lobo MV, Bazan E (2001) Developmental expression of fibroblast growth factor (FGF) receptors in neural stem cell progeny. Modulation of neuronal and glial lineages by basic FGF treatment. Neurol Res 23(6): 612–621PubMedCrossRefGoogle Scholar
  55. 55.
    Renfranz PJ, Cunningham MG, McKay RD (1991) Region-specific differentiation of the hippocampal stem cell line HiB5 upon implantation into the developing mammalian brain. Cell 66(4): 713–729PubMedCrossRefGoogle Scholar
  56. 56.
    Riess P, Zhang C, Saatman KE, Laurer HL, Longhi LG, Raghupathi R, Lenzlinger PM, Lifshitz J, Boockvar J, Neugebauer E, Snyder EY, McIntosh TK (2002) Transplanted neural stem cells survive, differentiate, and improve neurological motor function after experimental traumatic brain injury. Neurosurgery 51(4): 1043–1052PubMedGoogle Scholar
  57. 57.
    Riva D, Giorgi C, Nichelli F, Bulgheroni S, Massimino M, Cefalo G, Gandola L, Giannotta M, Bagnasco I, Saletti V, Pantaleoni C (2002) Intrathecal methotrexate affects cognitive function in children with medulloblastoma. Neurology 59(1): 48–53PubMedGoogle Scholar
  58. 58.
    Rubio F, Kokaia Z, Arco A, Garcia-Simon M, Snyder E, Lindvall O, Satrustegui J, Martinez-Serrano A (1999) BDNF gene transfer to the mammalian brain using CNS-derived neural precursors. Gene Ther 6(11): 1851–1866PubMedCrossRefGoogle Scholar
  59. 59.
    Salander P, Karlsson T, Bergenheim T, Henriksson R (1995) Long-term memory deficits in patients with malignant gliomas. J Neurooncol 25(3): 227–238PubMedCrossRefGoogle Scholar
  60. 60.
    Schagen SB, Hamburger HL, Muller MJ, Boogerd W, Van Dam FS (2001) Neurophysiological evaluation of late effects of adjuvant high-dose chemotherapy on cognitive function. J Neurooncol 51(2): 159–165PubMedCrossRefGoogle Scholar
  61. 61.
    Snyder EY, Deitcher DL, Walsh C, Arnold-Aldea S, Hartwieg EA, Cepko CL (1992) Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 68(1): 33–51PubMedCrossRefGoogle Scholar
  62. 62.
    Snyder EY, Vescovi AL (2000) The possibilities/perplexities of stem cells. Nat Biotechnol 18(8): 827–828PubMedCrossRefGoogle Scholar
  63. 63.
    Soloviev AI, Tishkin SM, Parshikov AV, Ivanova IV, Goncharov EV, Gurney AM (2003) Mechanisms of endothelial dysfunction after ionized radiation: selective impairment of the nitric oxide component of endothelium-dependent vasodilation. Br J Pharmacol 138(5): 837–844PubMedCrossRefGoogle Scholar
  64. 64.
    Steen RG, Koury BSM, Granja CI, Xiong X, Wu S, Glass JO, Mulhern RK, Kun LE, Merchant TE (2001) Effect of ionizing radiation on the human brain: white matter and gray matter Tl in pediatric brain tumor patients treated with conformal radiation therapy. Int J Radiat Oncol Biol Phys 49(1): 79–91PubMedCrossRefGoogle Scholar
  65. 65.
    Tada E, Parent JM, Lowenstein DH, Fike JR (2000) X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats. Neuroscience 99(1): 33–41PubMedCrossRefGoogle Scholar
  66. 66.
    Thompson S, Stern PL, Webb M, Walsh FS, Engstrom W, Evans EP, Shi WK, Hopkins B, Graham CF (1984) Cloned human teratoma cells differentiate into neuron-like cells and other cell types in retinoic acid. J Cell Sci 72: 37–64PubMedGoogle Scholar
  67. 67.
    Trainor PA, Ariza-McNaughton L, Krumlauf R (2002) Role of the isthmus and FGFs in resolving the paradox of neural crest plasticity and prepatterning. Science 295(5558): 1288–1291PubMedCrossRefGoogle Scholar
  68. 68.
    Vescovi AL, Snyder EY (1999) Establishment and properties of neural stem cell clones: plasticity in vitro and in vivo. Brain Pathol 9(3): 569–598PubMedCrossRefGoogle Scholar
  69. 69.
    Waber DP, Tarbell NJ, Fairclough D, Atmore K, Castro R, Isquith P, Lussier F, Romero I, Carpenter PJ, Schiller M (1995) Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice. J Clin Oncol 13(10): 2490–2496PubMedGoogle Scholar

Copyright information

© Springer-Verlag/Wien 2003

Authors and Affiliations

  • M. Kirsch
    • 1
  • O. Heese
    • 2
  • M. Westphal
    • 2
  • G. Schackert
    • 1
  1. 1.Klinik und Poliklinik für NeurochirurgieUniversitätsklinikum Dresden der Technischen Universität DresdenDresdenGermany
  2. 2.Klinik und Poliklinik für NeurochirurgieUniversitätsklinikum Hamburg-EppendorfHamburgGermany

Personalised recommendations