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Apoptosis-Inducing Cellular Vehicles for Cancer Gene Therapy

Endothelial and Neural Progenitors

  • Chapter
Book cover Apoptosis, Cell Signaling, and Human Diseases

Summary

Endothelial progenitor cells (EPCs) and neural progenitor cells (NPCs) are promising for cancer therapy because they specifically target tumors. They have the capacity to home to, invade, migrate within, and incorporate into tumor structures. They are easily expanded and can be armed with therapeutic payloads protected within the progenitor cells. Once in the tumor, armed progenitors can be triggered to induce apoptosis in surrounding tumor cells. Pro-and antiapoptotic mechanisms are pivotal to effectively kill tumor cells while simultaneously protecting the cellular vehicles from premature demise. Increasing the ratio of tumor cell apoptosis to progenitor apoptosis will be crucial among other efforts to enhance the efficacy of endothelial and neural progenitor cells to a level sufficient for clinical application.

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References

  1. Kasid A, Morecki S, Aebersold P, et al. Human gene transfer: characterization of human tumor-infiltrating lymphocytes as vehicles for retroviral-mediated gene transfer in man. Proc Natl Acad Sci USA 1990;87:473–477.

    Article  PubMed  CAS  Google Scholar 

  2. Lang FF, Bruner JM, Fuller GN, et al. Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol 2003;21:2508–2518.

    Article  PubMed  CAS  Google Scholar 

  3. Packer RJ, Raffel C, Villablanca JG, et al. Treatment of progressive or recurrent pediatric malignant supratentorial brain tumors with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration. J Neurosurg 2000;92:249–254.

    Article  PubMed  CAS  Google Scholar 

  4. Ram Z, Culver KW, Oshiro EM, et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med 1997;3:1354–1361.

    Article  PubMed  CAS  Google Scholar 

  5. Prados MD, McDermott M, Chang SM, et al. Treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vectorproducer cells followed by intravenous ganciclovir administration: a phase I/II multiinstitutional trial. J Neurooncol 2003;65:269–278.

    Article  PubMed  Google Scholar 

  6. Valery CA, Seilhean D, Boyer O, et al. Long-term survival after gene therapy for a recurrent glioblastoma. Neurology 2002;58:1109–1112.

    PubMed  CAS  Google Scholar 

  7. Griffiths L, Binley K, Iqball S, et al. The macrophage-a novel system to deliver gene therapy to pathological hypoxia. Gene Ther 2000;7:255–262.

    Article  PubMed  CAS  Google Scholar 

  8. Ojeifo JO, Lee HR, Rezza P, Su N, Zwiebel JA. Endothelial cell-based systemic gene therapy of metastatic melanoma. Cancer Gene Ther 2001;8:636–648.

    Article  PubMed  CAS  Google Scholar 

  9. Fabre JW. The allogeneic response and tumor immunity. Nat Med 2001;7:649–652.

    Article  PubMed  CAS  Google Scholar 

  10. Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. A common precursor for hematopoietic and endothelial cells. Development 1998;125:725–732.

    PubMed  CAS  Google Scholar 

  11. Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995;376:62–66.

    Article  PubMed  CAS  Google Scholar 

  12. Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996;380:439–442.

    Article  PubMed  CAS  Google Scholar 

  13. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–967.

    Article  PubMed  CAS  Google Scholar 

  14. Gunsilius E, Petzer AL, Duba HC, Kahler CM, Gastl G. Circulating endothelial cells after transplantation. Lancet 2001;357:1449–1450.

    Article  PubMed  CAS  Google Scholar 

  15. Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 2003;9:702–712.

    Article  PubMed  CAS  Google Scholar 

  16. Peichev M, Naiyer AJ, Pereira D, et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 2000;95:952–958.

    PubMed  CAS  Google Scholar 

  17. Gehling UM, Ergun S, Schumacher U, et al. In vitro differentiation of endothelial cells from AC133-positive progenitor cells. Blood 2000;95:3106–3112.

    PubMed  CAS  Google Scholar 

  18. Shi Q, Rafii S, Wu MH, et al. Evidence for circulating bone marrow-derived endothelial cells. Blood 1998;92:362–367.

    PubMed  CAS  Google Scholar 

  19. Harraz M, Jiao C, Hanlon HD, Hartley RS, Schatteman GC. CD34-blood-derived human endothelial cell progenitors. Stem Cells 2001;19:304–312.

    Article  PubMed  CAS  Google Scholar 

  20. Bertolini F, Paul S, Mancuso P, et al. Maximum Tolerable Dose and Low-Dose Metronomic Chemotherapy Have Opposite Effects on the Mobilization and Viability of Circulating Endothelial Progenitor Cells. Cancer Res 2003;63:4342–4346.

    PubMed  CAS  Google Scholar 

  21. Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999;85:221–228.

    PubMed  CAS  Google Scholar 

  22. Davidoff AM, Ng CY, Brown P, et al. Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice. Clin Cancer Res 2001;7:2870–2879.

    PubMed  CAS  Google Scholar 

  23. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 2003;300:1155–1159.

    Article  PubMed  CAS  Google Scholar 

  24. Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001;7:1194–1201.

    Article  PubMed  CAS  Google Scholar 

  25. Gothert JR, Gustin SE, van Eekelen JA, et al. Genetically tagging endothelial cells in vivo: bone marrow-derived cells do not contribute to tumor endothelium. Blood 2004;104: 1769–1777.

    Article  PubMed  CAS  Google Scholar 

  26. De Palma M, Venneri MA, Roca C, Naldini L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 2003;9:789–795.

    Article  PubMed  CAS  Google Scholar 

  27. Rajantie I, Ilmonen M, Alminaite A, Ozerdem U, Alitalo K, Salven P. Adult bone marrowderived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood 2004;104:2084–2086.

    Article  PubMed  CAS  Google Scholar 

  28. Gill M, Dias S, Hattori K, et al. Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ Res 2001;88:167–174.

    PubMed  CAS  Google Scholar 

  29. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841–844.

    Article  PubMed  CAS  Google Scholar 

  30. Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002;109:625–637.

    Article  PubMed  CAS  Google Scholar 

  31. Carmeliet P, Moons L, Luttun A, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 2001;7:5575–5583.

    Google Scholar 

  32. Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 1994;367:576–579.

    Article  PubMed  CAS  Google Scholar 

  33. Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001;7:1194–1201.

    Article  PubMed  CAS  Google Scholar 

  34. Luttun A, Tjwa M, Moons L, et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 2002;8:831–840.

    PubMed  CAS  Google Scholar 

  35. Kryczek I, Lange A, Mottram P, et al. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res 2005;65:465–472.

    PubMed  CAS  Google Scholar 

  36. Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996;380:435–439.

    Article  PubMed  CAS  Google Scholar 

  37. Shalaby F, Ho J, Stanford WL, et al. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 1997;89:981–990.

    Article  PubMed  CAS  Google Scholar 

  38. Gerber HP, McMurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 1998;273: 30,336–30,343.

    Article  PubMed  CAS  Google Scholar 

  39. Kim I, Kim HG, So JN, Kim JH, Kwak HJ, Koh GY. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3’-Kinase/Akt signal transduction pathway. Circ Res 2000;86:24–29.

    PubMed  CAS  Google Scholar 

  40. Datta SR, Katsov A, Hu L, et al. 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. Mol Cell 2000;6:41–51.

    Article  PubMed  CAS  Google Scholar 

  41. Dimmeler S, Haendeler J, Nehls M, Zeiher AM. Suppression of apoptosis by nitric oxide via inhibition of interleukin-1beta-converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like proteases. J Exp Med 1997;185:601–607.

    Article  PubMed  CAS  Google Scholar 

  42. Butzal M, Loges S, Schweizer M,et al. Rapamycin inhibits proliferation and differentiation of human endothelial progenitor cells in vitro. Exp Cell Res 2004;300:65–71.

    Article  PubMed  CAS  Google Scholar 

  43. Gerber HP, Dixit V, Ferrara N. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 1998;273: 13,313–13,316.

    Article  PubMed  CAS  Google Scholar 

  44. O’Connor DS, Schechner JS, Adida C, et al. Control of apoptosis during angiogenesis by survivin expression in endothelial cells. Am J Pathol 2000;156:393–398.

    PubMed  CAS  Google Scholar 

  45. Tran J, Rak J, Sheehan C, et al. Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem Biophys Res Commun 1999;264:781–788.

    Article  PubMed  CAS  Google Scholar 

  46. Wang S, Sorenson CM, Sheibani N. Attenuation of retinal vascular development and neovascularization during oxygen-induced ischemic retinopathy in Bcl-2-/-mice. Dev Biol 2005;279:205–219.

    Article  PubMed  CAS  Google Scholar 

  47. Gratton JP, Morales-Ruiz M, Kureishi Y, Fulton D, Walsh K, Sessa WC. Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factormediated cytoprotection in endothelial cells. J Biol Chem 2001;276:30,359–30,365.

    Article  PubMed  CAS  Google Scholar 

  48. Carmeliet P, Lampugnani MG, Moons L, et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 1999;98:147–157.

    Article  PubMed  CAS  Google Scholar 

  49. Gao C, Sun W, Christofidou-Solomidou M, et al. PECAM-1 functions as a specific and potent inhibitor of mitochondrial-dependent apoptosis. Blood 2003;102:169–179.

    Article  PubMed  CAS  Google Scholar 

  50. Malyankar UM, Scatena M, Suchland KL, Yun TJ, Clark EA, Giachelli CM. Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. J Biol Chem 2000;275:20,959–20,962.

    Article  PubMed  CAS  Google Scholar 

  51. Stupack DG, Cheresh DA. Apoptotic cues from the extracellular matrix: regulators of angiogenesis. Oncogene 2003;22:9022–9029.

    Article  PubMed  CAS  Google Scholar 

  52. Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998;125:1591–1598.

    PubMed  CAS  Google Scholar 

  53. Murasawa S, Llevadot J, Silver M, Isner JM, Losordo DW, Asahara T. Constitutive human telomerase reverse transcriptase expression enhances regenerative properties of endothelial progenitor cells. Circulation 2002;106:1133–1139.

    Article  PubMed  CAS  Google Scholar 

  54. Dernbach E, Urbich C, Brandes RP, Hofmann WK, Zeiher AM, Dimmeler S. Antioxidative stress-associated genes in circulating progenitor cells: evidence for enhanced resistance against oxidative stress. Blood 2004;104:3591–3597.

    Article  PubMed  CAS  Google Scholar 

  55. Munshi N, Fernandis AZ, Cherla RP, Park IW, Ganju RK. Lipopolysaccharide-induced apoptosis of endothelial cells and its inhibition by vascular endothelial growth factor. J Immunol 2002;168:5860–5866.

    PubMed  CAS  Google Scholar 

  56. Dhanabal M, Ramchandran R, Waterman MJ, et al. Endostatin induces endothelial cell apoptosis. J Biol Chem 1999;274:11,721–11,776.

    Article  PubMed  CAS  Google Scholar 

  57. Bannerman DD, Tupper JC, Ricketts WA, Bennett CF, Winn RK, Harlan JM. A constitutive cytoprotective pathway protects endothelial cells from lipopolysaccharide-induced apoptosis. J Biol Chem 2001;276:14,924–14,932.

    Article  PubMed  CAS  Google Scholar 

  58. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353–364.

    Article  PubMed  CAS  Google Scholar 

  59. Levenberg S, Golub JS, Amit M, Itskovitz-Eldor J, Langer R. Endothelial cells derived from human embryonic stem cells. Proc Natl Acad Sci USA 2002;99:4391–4396.

    Article  PubMed  CAS  Google Scholar 

  60. Wei J, Blum S, Unger M, et al. Embryonic endothelial progenitor cells armed with a suicide gene target hypoxic lung metastases after intravenous delivery. Cancer Cell 2004;5:477–488.

    Article  PubMed  CAS  Google Scholar 

  61. Ingram DA, Mead LE, Moore DB, Woodard W, Fenoglio A, Yoder MC. Vessel wall derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. Blood 2004;104:2752–2760.

    Article  PubMed  CAS  Google Scholar 

  62. Murohara T, Ikeda H, Duan J, et al. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest 2000;105:1527–1536.

    Article  PubMed  CAS  Google Scholar 

  63. Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, Verfaillie CM. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 2002;109:337–346.

    Article  PubMed  CAS  Google Scholar 

  64. Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 1999;18:3964–3972.

    Article  PubMed  CAS  Google Scholar 

  65. Dimmeler S, Aicher A, Vasa M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 2001;108: 391–397.

    Article  PubMed  CAS  Google Scholar 

  66. Lin Y, Weisdorf DJ, Solovey A, Hebbel RP. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 2000;105:71–77.

    PubMed  CAS  Google Scholar 

  67. Ferrari N, Glod J, Lee J, Kobiler D, Fine HA. Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors. Gene Ther 2003;10: 647–656.

    Article  PubMed  CAS  Google Scholar 

  68. Freeman SM, Abboud CN, Whartenby KA, et al. The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993;53: 5274–5283.

    PubMed  CAS  Google Scholar 

  69. Gomez-Navarro J, Contreras JL, Arafat W, et al. Genetically modified CD34+ cells as cellular vehicles for gene delivery into areas of angiogenesis in a rhesus model. Gene Ther 2000;7:43–52.

    Article  PubMed  CAS  Google Scholar 

  70. Arafat WO, Casado E, Wang M, et al. Genetically modified CD34+ cells exert a cytotoxic bystander effect on human endothelial and cancer cells. Clin Cancer Res 2000;6: 4442–4448.

    PubMed  CAS  Google Scholar 

  71. Scappaticci FA. Mechanisms and future directions for angiogenesis-based cancer therapies. J Clin Oncol 2002;20:3906–3927.

    Article  PubMed  CAS  Google Scholar 

  72. Chester J, Ruchatz A, Gough M, et al. Tumor antigen-specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor-modified T cells. Nat Biotechnol 2002;20:256–263.

    Article  PubMed  CAS  Google Scholar 

  73. Jevremovic D, Gulati R, Hennig I, et al. Use of blood outgrowth endothelial cells as virusproducing vectors for gene delivery to tumors. Am J Physiol Heart Circ Physiol 2004;287: H494–H500.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  75. Richards LJ, Kilpatrick TJ, Bartlett PF. De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci USA 1992;89:8591–8595.

    Article  PubMed  CAS  Google Scholar 

  76. Lois C, Alvarez-Buylla A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci USA 1993;90: 2074–2077.

    Article  PubMed  CAS  Google Scholar 

  77. Gage FH, Coates PW, Palmer TD, et al. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci USA 1995;92: 11,879–11,883.

    Article  PubMed  CAS  Google Scholar 

  78. Palmer TD, Ray J, Gage FH. FGF-2-responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995;6:474–486.

    Article  PubMed  CAS  Google Scholar 

  79. Shihabuddin LS, Horner PJ, Ray J, Gage FH. Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. J Neurosci 2000;20:8727–8735.

    PubMed  CAS  Google Scholar 

  80. Palmer TD, Markakis EA, Willhoite AR, Safar F, Gage FH. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J Neurosci 1999;19:8487–8497.

    PubMed  CAS  Google Scholar 

  81. Kornack DR, Rakic P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci USA 1999;96:5768–5773.

    Article  PubMed  CAS  Google Scholar 

  82. Nunes MC, Roy NS, Keyoung HM, et al. Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med 2003; 9:439–447.

    Article  PubMed  CAS  Google Scholar 

  83. Kornack DR, Rakic P. The generation, migration, and differentiation of olfactory neurons in the adult primate brain. Proc Natl Acad Sci USA 2001;98:4752–4757.

    Article  PubMed  CAS  Google Scholar 

  84. Uchida N, Buck DW, He D, et al. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 2000;97:14,720–14,725.

    Article  PubMed  CAS  Google Scholar 

  85. Kelly S, Bliss TM, Shah AK, et al. Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proc Natl Acad Sci USA 2004;101:11,839–11,844.

    Article  PubMed  CAS  Google Scholar 

  86. Aboody KS, Brown A, Rainov NG, et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 2000;97:12,846–12,851.

    Article  PubMed  CAS  Google Scholar 

  87. Ehtesham M, Kabos P, Gutierrez MA, et al. Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 2002;62:7170–7174.

    PubMed  CAS  Google Scholar 

  88. Arnhold S, Hilgers M, Lenartz D, et al. Neural precursor cells as carriers for a gene therapeutical approach in tumor therapy. Cell Transplant 2003;12:827–837.

    PubMed  CAS  Google Scholar 

  89. Lee J, Elkahloun AG, Messina SA, et al. Cellular and genetic characterization of human adult bone marrow-derived neural stem-like cells: a potential antiglioma cellular vector. Cancer Res 2003;63:8877–8889.

    PubMed  CAS  Google Scholar 

  90. Brown AB, Yang W, Schmidt NO, et al. Intravascular delivery of neural stem cell lines to target intracranial and extracranial tumors of neural and non-neural origin. Hum Gene Ther 2003;14:1777–1785.

    Article  PubMed  CAS  Google Scholar 

  91. Tang Y, Shah K, Messerli SM, Snyder E, Breakefield X, Weissleder R. In vivo tracking of neural progenitor cell migration to glioblastomas. Hum Gene Ther 2003;14:1247–1254.

    Article  PubMed  CAS  Google Scholar 

  92. Anderson SA, Glod J, Arbab AS, et al. Noninvasive MR imaging of magnetically labeled stem cells to directly identify neovasculature in a glioma model. Blood 2005;105:420–425.

    Article  PubMed  CAS  Google Scholar 

  93. Imitola J, Raddassi K, Park KI, et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci USA 2004;101:18,117–18,122.

    Article  PubMed  CAS  Google Scholar 

  94. 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.

    PubMed  CAS  Google Scholar 

  95. Brustle O, Choudhary K, Karram K, et al. Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats. Nat Biotechnol 1998; 16:1040–1044.

    Article  PubMed  CAS  Google Scholar 

  96. Flax JD, Aurora S, Yang C, et al. Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat Biotechnol 1998;16: 1033–1039.

    Article  PubMed  CAS  Google Scholar 

  97. Chu K, Kim M, Jeong SW, Kim SU, Yoon BW. Human neural stem cells can migrate, differentiate, and integrate after intravenous transplantation in adult rats with transient forebrain ischemia. Neurosci Lett 2003;343:129–133.

    Article  PubMed  CAS  Google Scholar 

  98. Roy NS, Wang S, Jiang L, et al. In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med 2000;6:271–277.

    Article  PubMed  CAS  Google Scholar 

  99. Brustle O, Spiro AC, Karram K, Choudhary K, Okabe S, McKay RD. In vitro-generated neural precursors participate in mammalian brain development. Proc Natl Acad Sci USA 1997;94:14,809–14,814.

    Article  PubMed  CAS  Google Scholar 

  100. Kim JH, Auerbach JM, Rodriguez-Gomez JA, et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 2002; 418:50–56.

    Article  PubMed  CAS  Google Scholar 

  101. Kuo HC, Pau KY, Yeoman RR, Mitalipov SM, Okano H, Wolf DP. Differentiation of monkey embryonic stem cells into neural lineages. Biol Reprod 2003;68:1727–1735.

    Article  PubMed  CAS  Google Scholar 

  102. Kawasaki H, Suemori H, Mizuseki K, et al. Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity. Proc Natl Acad Sci USA 2002;99:1580–1585.

    Article  PubMed  CAS  Google Scholar 

  103. Ben-Hur T, Idelson M, Khaner H, et al. Transplantation of human embryonic stem cellderived neural progenitors improves behavioral deficit in Parkinsonian rats. Stem Cells 2004;22:1246–1255.

    Article  PubMed  Google Scholar 

  104. Snyder EY, Deitcher DL, Walsh C, Arnold-Aldea S, Hartwieg EA, Cepko CL. Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 1992;68:33–51.

    Article  PubMed  CAS  Google Scholar 

  105. Renfranz PJ, Cunningham MG, McKay RD. Region-specific differentiation of the hippocampal stem cell line HiB5 upon implantation into the developing mammalian brain. Cell 1991;66:713–729.

    Article  PubMed  CAS  Google Scholar 

  106. 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.

    Article  PubMed  CAS  Google Scholar 

  107. Villa A, Navarro-Galve B, Bueno C, Franco S, Blasco MA, Martinez-Serrano A. Long-term molecular and cellular stability of human neural stem cell lines. Exp Cell Res 2004;294: 559–570.

    Article  PubMed  CAS  Google Scholar 

  108. Roy NS, Nakano T, Keyoung HM, et al. Telomerase immortalization of neuronally restricted progenitor cells derived from the human fetal spinal cord. Nat Biotechnol 2004;22:297–305.

    Article  PubMed  CAS  Google Scholar 

  109. Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 2000;290:1775–1779.

    Article  PubMed  CAS  Google Scholar 

  110. 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.

    Article  PubMed  CAS  Google Scholar 

  111. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000;164:247–256.

    Article  PubMed  CAS  Google Scholar 

  112. Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002;297:2256–2259.

    Article  PubMed  CAS  Google Scholar 

  113. Soares S, Sotelo C. Adult neural stem cells from the mouse subventricular zone are limited in migratory ability compared to progenitor cells of similar origin. Neuroscience 2004;128: 807–817.

    Article  PubMed  CAS  Google Scholar 

  114. Kuida K, Zheng TS, Na S, et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 1996;384:368–372.

    Article  PubMed  CAS  Google Scholar 

  115. Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 1998;94:727–737.

    Article  PubMed  CAS  Google Scholar 

  116. Kuida K, Haydar TF, Kuan CY, et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 1998;94:325–337.

    Article  PubMed  CAS  Google Scholar 

  117. Yoshida H, Kong YY, Yoshida R, et al. Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 1998;94:739–750.

    Article  PubMed  CAS  Google Scholar 

  118. Roth KA, Kuan C, Haydar TF, et al. Epistatic and independent functions of caspase-3 and Bcl-X(L) in developmental programmed cell death. Proc Natl Acad Sci USA 2000;97: 466–471.

    Article  PubMed  CAS  Google Scholar 

  119. Yang X, Klein R, Tian X, Cheng HT, Kopan R, Shen J. Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway. Dev Biol 2004;269:81–94.

    Article  PubMed  CAS  Google Scholar 

  120. Grandbarbe L, Bouissac J, Rand M, Hrabe de Angelis M, Artavanis-Tsakonas S, Mohier E. Delta-Notch signaling controls the generation of neurons/glia from neural stem cells in a stepwise process. Development 2003;130:1391–1402.

    Article  PubMed  CAS  Google Scholar 

  121. Lutolf S, Radtke F, Aguet M, Suter U, Taylor V. Notch1 is required for neuronal and glial differentiation in the cerebellum. Development 2002;129:373–385.

    PubMed  CAS  Google Scholar 

  122. Ricci-Vitiani L, Pedini F, Mollinari C, et al. Absence of caspase 8 and high expression of PED protect primitive neural cells from cell death. J Exp Med 2004;200:1257–1266.

    Article  PubMed  CAS  Google Scholar 

  123. Bieberich E, MacKinnon S, Silva J, Noggle S, Condie BG. Regulation of cell death in mitotic neural progenitor cells by asymmetric distribution of prostate apoptosis response 4 (PAR-4) and simultaneous elevation of endogenous ceramide. J Cell Biol 2003;162:469–479.

    Article  PubMed  CAS  Google Scholar 

  124. Bieberich E, Silva J, Wang G, Krishnamurthy K, Condie BG. Selective apoptosis of pluripotent mouse and human stem cells by novel ceramide analogues prevents teratoma formation and enriches for neural precursors in ES cell-derived neural transplants. J Cell Biol 2004;167:723–734.

    Article  PubMed  CAS  Google Scholar 

  125. D’Sa-Eipper C, Leonard JR, Putcha G, et al. DNA damage-induced neural precursor cell apoptosis requires p53 and caspase 9 but neither Bax nor caspase 3. Development 2001;128:137–146.

    CAS  Google Scholar 

  126. Sun W, Winseck A, Vinsant S, Park OH, Kim H, Oppenheim RW. Programmed cell death of adult-generated hippocampal neurons is mediated by the proapoptotic gene Bax. J Neurosci 2004;24:11,205–11,213.

    Article  PubMed  CAS  Google Scholar 

  127. Lindsten T, Golden JA, Zong WX, Minarcik J, Harris MH, Thompson CB. The proapoptotic activities of Bax and Bak limit the size of the neural stem cell pool. J Neurosci 2003;23:11,112–11,119.

    PubMed  CAS  Google Scholar 

  128. Li L, Liu F, Salmonsen RA, et al. PTEN in neural precursor cells: regulation of migration, apoptosis, and proliferation. Mol Cell Neurosci 2002;20:21–29.

    Article  PubMed  CAS  Google Scholar 

  129. Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res 2003;63:4021–4027.

    PubMed  CAS  Google Scholar 

  130. Limoli CL, Giedzinski E, Rola R, Otsuka S, Palmer TD, Fike JR. Radiation response of neural precursor cells: linking cellular sensitivity to cell cycle checkpoints, apoptosis and oxidative stress. Radiat Res 2004;161:17–27.

    Article  PubMed  CAS  Google Scholar 

  131. Hori J, Ng TF, Shatos M, Klassen H, Streilein JW, Young MJ. Neural progenitor cells lack immunogenicity and resist destruction as allografts. Stem Cells 2003;21:405–416.

    Article  PubMed  Google Scholar 

  132. Reid R, Mar EC, Huang ES, Topal MD. Insertion and extension of acyclic, dideoxy, and ara nucleotides by herpesviridae, human alpha and human beta polymerases. A unique inhibition mechanism for 9-(1,3-dihydroxy-2-propoxymethyl)guanine triphosphate. J Biol Chem 1988;263:3898–3904.

    PubMed  CAS  Google Scholar 

  133. Beltinger C, Fulda S, Kammertoens T, Meyer E, Uckert W, Debatin KM. Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. Proc Natl Acad Sci USA 1999;96: 8699–8704.

    Article  PubMed  CAS  Google Scholar 

  134. Beltinger C, Fulda S, Kammertoens T, Uckert W, Debatin KM. Mitochondrial amplification of death signals determines thymidine kinase/ganciclovir-triggered activation of apoptosis. Cancer Res 2000;60:3212–3217.

    PubMed  CAS  Google Scholar 

  135. Beltinger C, Fulda S, Walczak H, Debatin KM. TRAIL enhances thymidine kinase/ ganciclovir gene therapy of neuroblastoma cells. Cancer Gene Ther 2002;9:372–381.

    Article  PubMed  CAS  Google Scholar 

  136. Immonen A, Vapalahti M, Tyynela K, et al. AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther 2004;10:967–972.

    Article  PubMed  CAS  Google Scholar 

  137. Ram Z, Culver KW, Oshiro EM, et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med 1997;3:1354–1361.

    Article  PubMed  CAS  Google Scholar 

  138. Uhl M, Weiler M, Wick W, Jacobs AH, Weller M, Herrlinger U. Migratory neural stem cells for improved thymidine kinase-based gene therapy of malignant gliomas. Biochem Biophys Res Commun 2005;328:125–129.

    Article  PubMed  CAS  Google Scholar 

  139. Huber BE, Austin EA, Richards CA, Davis ST, Good SS. Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci USA 1994;91:8302–8306.

    Article  PubMed  CAS  Google Scholar 

  140. Barresi V, Belluardo N, Sipione S, Mudo G, Cattaneo E, Condorelli DF. Transplantation of prodrug-converting neural progenitor cells for brain tumor therapy. Cancer Gene Ther 2003;10:396–402.

    Article  PubMed  CAS  Google Scholar 

  141. Benedetti S, Pirola B, Pollo B, et al. Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 2000;6:447–450.

    Article  PubMed  CAS  Google Scholar 

  142. 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  CAS  Google Scholar 

  143. Niranjan A, Wolfe D, Fellows W, et al. Gene transfer to glial tumors using herpes simplex virus. Methods Mol Biol 2004;246:323–337.

    PubMed  CAS  Google Scholar 

  144. Herrlinger U, Woiciechowski C, Sena-Esteves M, et al. Neural precursor cells for delivery of replication-conditional HSV-1 vectors to intracerebral gliomas. Mol Ther 2000;1: 347–357.

    Article  PubMed  CAS  Google Scholar 

  145. Staflin K, Honeth G, Kalliomaki S, Kjellman C, Edvardsen K, Lindvall M. Neural progenitor cell lines inhibit rat tumor growth in vivo. Cancer Res 2004;64:5347–5354.

    Article  PubMed  CAS  Google Scholar 

  146. 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.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. University Children’s Hospital, Ulm, Germany

    Gergely Jarmy, Jiwu Wei, Klaus-Michael Debatin & Christian Beltinger

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  1. Gergely Jarmy
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  2. Jiwu Wei
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  3. Klaus-Michael Debatin
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  4. Christian Beltinger
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  1. Department of Biochemistry, University of Texas Health Center at Tyler, Tyler, TX

    Rakesh Srivastava

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Jarmy, G., Wei, J., Debatin, KM., Beltinger, C. (2007). Apoptosis-Inducing Cellular Vehicles for Cancer Gene Therapy. In: Srivastava, R. (eds) Apoptosis, Cell Signaling, and Human Diseases. Humana Press. https://doi.org/10.1007/978-1-59745-200-7_12

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