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Stem and progenitor cell-mediated tumor selective gene therapy

Gene Therapy volume 15, pages 739–752 (2008)Cite this article

A Corrigendum to this article was published on 01 July 2008

Abstract

The poor prognosis for patients with aggressive or metastatic tumors and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Stem/progenitor cells display inherent tumor-tropic properties that can be exploited for targeted delivery of anticancer genes to invasive and metastatic tumors. Therapeutic genes that have been inserted into stem cells and delivered to tumors with high selectivity include prodrug-activating enzymes (cytosine deaminase, carboxylesterase, thymidine kinase), interleukins (IL-2, IL-4, IL-12, IL-23), interferon-β, apoptosis-promoting genes (tumor necrosis factor-related apoptosis-inducing ligand) and metalloproteinases (PEX). We and others have demonstrated that neural and mesenchymal stem cells can deliver therapeutic genes to elicit a significant antitumor response in animal models of intracranial glioma, medulloblastoma, melanoma brain metastasis, disseminated neuroblastoma and breast cancer lung metastasis. Most studies reported reduction in tumor volume (up to 90%) and increased survival of tumor-bearing animals. Complete cures have also been achieved (90% disease-free survival for >1 year of mice bearing disseminated neuroblastoma tumors). As we learn more about the biology of stem cells and the molecular mechanisms that mediate their tumor-tropism and we identify efficacious gene products for specific tumor types, the clinical utility of cell-based delivery strategies becomes increasingly evident.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D et al. Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 2000; 6: 447–450.

    Article  CAS  PubMed  Google Scholar 

  3. Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 2000; 97: 12846–12851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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.

    CAS  PubMed  Google Scholar 

  5. Ehtesham M, Kabos P, Gutierrez MA, Chung NH, Griffith TS, Black KL 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.

    CAS  PubMed  Google Scholar 

  6. 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  CAS  PubMed  Google Scholar 

  7. Shah K, Tung CH, Breakefield XO, Weissleder R . In vivo imaging of S-TRAIL-mediated tumor regression and apoptosis. Mol Ther 2005; 11: 926–931.

    Article  CAS  PubMed  Google Scholar 

  8. Kim SK, Cargioli TG, Machluf M, Yang W, Sun Y, Al-Hashem R et al. PEX-producing human neural stem cells inhibit tumor growth in a mouse glioma model. Clin Cancer Res 2005; 11: 5965–5970.

    Article  CAS  PubMed  Google Scholar 

  9. Yuan X, Hu J, Belladonna ML, Black KL, Yu JS . Interleukin-23-expressing bone marrow-derived neural stem-like cells exhibit antitumor activity against intracranial glioma. Cancer Res 2006; 66: 2630–2638.

    Article  CAS  PubMed  Google Scholar 

  10. Aboody KS, Najbauer J, Schmidt NO, Yang W, Wu JK, Zhuge Y et al. Targeting of melanoma brain metastases using engineered neural stem/progenitor cells. Neuro Oncol 2006; 8: 119–126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lin D, Najbauer J, Salvaterra PM, Mamelak AN, Barish ME, Garcia E et al. Novel method for visualizing and modeling the spatial distribution of neural stem cells within intracranial glioma. Neuroimage 2007; 37: S18–S26.

    Article  PubMed  Google Scholar 

  12. Li S, Gao Y, Tokuyama T, Yamamoto J, Yokota N, Yamamoto S et al. Genetically engineered neural stem cells migrate and suppress glioma cell growth at distant intracranial sites. Cancer Lett 2007; 251: 220–227.

    Article  CAS  PubMed  Google Scholar 

  13. Kim SK, Kim SU, Park IH, Bang JH, Aboody KS, Wang KC et al. Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression. Clin Cancer Res 2006; 12: 5550–5556.

    Article  CAS  PubMed  Google Scholar 

  14. Shimato S, Natsume A, Takeuchi H, Wakabayashi T, Fujii M, Ito M et al. Human neural stem cells target and deliver therapeutic gene to experimental leptomeningeal medulloblastoma. Gene Therapy 2007; 14: 1132–1142.

    Article  CAS  PubMed  Google Scholar 

  15. Aboody KS, Bush RA, Garcia E, Metz MZ, Najbauer J, Justus KA et al. Development of a tumor-selective approach to treat metastatic cancer. PLoS ONE 2006; 1: e23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Danks MK, Yoon KJ, Bush RA, Remack JS, Wierdl M, Tsurkan L et al. Tumor-targeted enzyme/prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma. Cancer Res 2007; 67: 22–25.

    Article  CAS  PubMed  Google Scholar 

  17. Dickson PV, Hamner JB, Burger RA, Garcia E, Ouma AA, Kim SU et al. Intravascular administration of tumor tropic neural progenitor cells permits targeted delivery of interferon-beta and restricts tumor growth in a murine model of disseminated neuroblastoma. J Pediatr Surg 2007; 42: 48–53.

    Article  PubMed  Google Scholar 

  18. Nakamura K, Ito Y, Kawano Y, Kurozumi K, Kobune M, Tsuda H et al. Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Therapy 2004; 11: 1155–1164.

    Article  CAS  PubMed  Google Scholar 

  19. Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 2005; 65: 3307–3318.

    Article  CAS  PubMed  Google Scholar 

  20. Miletic H, Fischer Y, Litwak S, Giroglou T, Waerzeggers Y, Winkeler A et al. Bystander killing of malignant glioma by bone marrow-derived tumor-infiltrating progenitor cells expressing a suicide gene. Mol Ther 2007; 15: 1373–1381.

    Article  CAS  PubMed  Google Scholar 

  21. Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M . Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 2002; 62: 3603–3608.

    CAS  PubMed  Google Scholar 

  22. Elzaouk L, Moelling K, Pavlovic J . Anti-tumor activity of mesenchymal stem cells producing IL-12 in a mouse melanoma model. Exp Dermatol 2006; 15: 865–874.

    Article  CAS  PubMed  Google Scholar 

  23. Potapova I, Plotnikov A, Lu Z, Danilo Jr P, Valiunas V, Qu J et al. Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ Res 2004; 94: 952–959.

    Article  CAS  PubMed  Google Scholar 

  24. Ehtesham M, Stevenson CB, Thompson RC . Stem cell therapies for malignant glioma. Neurosurg Focus 2005; 19: E5.

    Article  PubMed  Google Scholar 

  25. Klein SM, Behrstock S, McHugh J, Hoffmann K, Wallace K, Suzuki M et al. GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum Gene Ther 2005; 16: 509–521.

    Article  CAS  PubMed  Google Scholar 

  26. Hall B, Dembinski J, Sasser AK, Studeny M, Andreeff M, Marini F . Mesenchymal stem cells in cancer: tumor-associated fibroblasts and cell-based delivery vehicles. Int J Hematol 2007; 86: 8–16.

    Article  CAS  PubMed  Google Scholar 

  27. Kanehira M, Xin H, Hoshino K, Maemondo M, Mizuguchi H, Hayakawa T et al. Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells. Cancer Gene Ther 2007; 14: 894–903.

    Article  CAS  PubMed  Google Scholar 

  28. Kucerova L, Altanerova V, Matuskova M, Tyciakova S, Altaner C . Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res 2007; 67: 6304–6313.

    Article  CAS  PubMed  Google Scholar 

  29. Mapara KY, Stevenson CB, Thompson RC, Ehtesham M . Stem cells as vehicles for the treatment of brain cancer. Neurosurg Clin N Am 2007; 18: 71–80, ix.

    Article  PubMed  Google Scholar 

  30. Najbauer J, Danks MK, Schmidt NO, Kim SU, Aboody KS . Neural stem cell-mediated therapy of primary and metastatic solid tumors. In: Bertolotti R, Ozawa K (eds). Progress in Gene Therapy, Autologous and Cancer Stem Cell Gene Therapy. World Scientific: Singapore, 2007.

    Google Scholar 

  31. Xin H, Kanehira M, Mizuguchi H, Hayakawa T, Kikuchi T, Nukiwa T et al. Targeted delivery of CX3CL1 to multiple lung tumors by mesenchymal stem cells. Stem Cells 2007; 25: 1618–1626.

    Article  CAS  PubMed  Google Scholar 

  32. Ulrich AS . Biophysical aspects of using liposomes as delivery vehicles. Biosci Rep 2002; 22: 129–150.

    Article  CAS  PubMed  Google Scholar 

  33. Lee J, Elkahloun AG, Messina SA, Ferrari N, Xi D, Smith CL 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.

    CAS  PubMed  Google Scholar 

  34. Miller AD . Nonviral liposomes. Methods Mol Med 2004; 90: 107–137.

    CAS  PubMed  Google Scholar 

  35. Merdan T, Kopecek J, Kissel T . Prospects for cationic polymers in gene and oligonucleotide therapy against cancer. Adv Drug Deliv Rev 2002; 54: 715–758.

    Article  CAS  PubMed  Google Scholar 

  36. Brokx R, Gariepy J . Peptide- and polymer-based gene delivery vehicles. Methods Mol Med 2004; 90: 139–160.

    CAS  PubMed  Google Scholar 

  37. Bharali DJ, Klejbor I, Stachowiak EK, Dutta P, Roy I, Kaur N et al. Organically modified silica nanoparticles: a nonviral vector for in vivo gene delivery and expression in the brain. Proc Natl Acad Sci USA 2005; 102: 11539–11544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Waehler R, Russell SJ, Curiel DT . Engineering targeted viral vectors for gene therapy. Nat Rev Genet 2007; 8: 573–587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wagner E, Zatloukal K, Cotten M, Kirlappos H, Mechtler K, Curiel DT et al. Coupling of adenovirus to transferrin-polylysine/DNA complexes greatly enhances receptor-mediated gene delivery and expression of transfected genes. Proc Natl Acad Sci USA 1992; 89: 6099–6103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Joo SY, Kim JS . Enhancement of gene transfer to cervical cancer cells using transferrin-conjugated liposome. Drug Dev Ind Pharm 2002; 28: 1023–1031.

    Article  CAS  PubMed  Google Scholar 

  41. Zhu ZB, Makhija SK, Lu B, Wang M, Rivera AA, Preuss M et al. Transport across a polarized monolayer of Caco-2 cells by transferrin receptor-mediated adenovirus transcytosis. Virology 2004; 325: 116–128.

    Article  CAS  PubMed  Google Scholar 

  42. Daniels TR, Ng PP, Delgado T, Lynch MR, Schiller G, Helguera G et al. Conjugation of an anti transferrin receptor IgG3-avidin fusion protein with biotinylated saporin results in significant enhancement of its cytotoxicity against malignant hematopoietic cells. Mol Cancer Ther 2007; 6: 2995–3008.

    Article  CAS  PubMed  Google Scholar 

  43. Peng JL, Wu S, Zhao XP, Wang M, Li WH, Shen X et al. Downregulation of transferrin receptor surface expression by intracellular antibody. Biochem Biophys Res Commun 2007; 354: 864–871.

    Article  CAS  PubMed  Google Scholar 

  44. Tang Y, Han T, Everts M, Zhu ZB, Gillespie GY, Curiel DT et al. Directing adenovirus across the blood-brain barrier via melanotransferrin (P97) transcytosis pathway in an in vitro model. Gene Therapy 2007; 14: 523–532.

    Article  CAS  PubMed  Google Scholar 

  45. Xia CF, Zhang Y, Zhang Y, Boado RJ, Pardridge WM . Intravenous siRNA of brain cancer with receptor targeting and avidin-biotin technology. Pharm Res 2007; 24: 2309–2316.

    Article  CAS  PubMed  Google Scholar 

  46. Prutki M, Poljak-Blazi M, Jakopovic M, Tomas D, Stipancic I, Zarkovic N . Altered iron metabolism, transferrin receptor 1 and ferritin in patients with colon cancer. Cancer Lett 2006; 238: 188–196.

    Article  CAS  PubMed  Google Scholar 

  47. Kelter G, Steinbach D, Konkimalla VB, Tahara T, Taketani S, Fiebig HH et al. Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate. PLoS ONE 2007; 2: e798.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD 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: 18117–18122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Erlandsson A, Larsson J, Forsberg-Nilsson K . Stem cell factor is a chemoattractant and a survival factor for CNS stem cells. Exp Cell Res 2004; 301: 201–210.

    Article  CAS  PubMed  Google Scholar 

  50. Sun L, Lee J, Fine HA . Neuronally expressed stem cell factor induces neural stem cell migration to areas of brain injury. J Clin Invest 2004; 113: 1364–1374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Heese O, Disko A, Zirkel D, Westphal M, Lamszus K . Neural stem cell migration toward gliomas in vitro. Neuro Oncol 2005; 7: 476–484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Schmidt NO, Przylecki W, Yang W, Ziu M, Teng Y, Kim SU et al. Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor. Neoplasia 2005; 7: 623–629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Widera D, Holtkamp W, Entschladen F, Niggemann B, Zanker K, Kaltschmidt B et al. MCP-1 induces migration of adult neural stem cells. Eur J Cell Biol 2004; 83: 381–387.

    Article  CAS  PubMed  Google Scholar 

  54. Palumbo R, Bianchi ME . High mobility group box 1 protein, a cue for stem cell recruitment. Biochem Pharmacol 2004; 68: 1165–1170.

    Article  CAS  PubMed  Google Scholar 

  55. Palumbo R, Galvez BG, Pusterla T, De Marchis F, Cossu G, Marcu KB et al. Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-kappaB activation. J Cell Biol 2007; 179: 33–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Wysoczynski M, Reca R, Ratajczak J, Kucia M, Shirvaikar N, Honczarenko M et al. Incorporation of CXCR4 into membrane lipid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient. Blood 2005; 105: 40–48.

    Article  CAS  PubMed  Google Scholar 

  58. Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J et al. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 2006; 24: 1254–1264.

    Article  CAS  PubMed  Google Scholar 

  59. Ziu M, Schmidt NO, Cargioli TG, Aboody KS, Black PM, Carroll RS . Glioma-produced extracellular matrix influences brain tumor tropism of human neural stem cells. J Neurooncol 2006; 79: 125–133.

    Article  CAS  PubMed  Google Scholar 

  60. Ries C, Egea V, Karow M, Kolb H, Jochum M, Neth P . MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood 2007; 109: 4055–4063.

    Article  CAS  PubMed  Google Scholar 

  61. Aghi M, Hochberg F, Breakefield XO . Prodrug activation enzymes in cancer gene therapy. J Gene Med 2000; 2: 148–164.

    Article  CAS  PubMed  Google Scholar 

  62. Davidson BL, Breakefield XO . Viral vectors for gene delivery to the nervous system. Nat Rev Neurosci 2003; 4: 353–364.

    Article  CAS  PubMed  Google Scholar 

  63. Rooseboom M, Commandeur JN, Vermeulen NP . Enzyme-catalyzed activation of anticancer prodrugs. Pharmacol Rev 2004; 56: 53–102.

    Article  CAS  PubMed  Google Scholar 

  64. Fischer U, Steffens S, Frank S, Rainov NG, Schulze-Osthoff K, Kramm CM . Mechanisms of thymidine kinase/ganciclovir and cytosine deaminase/5-fluorocytosine suicide gene therapy-induced cell death in glioma cells. Oncogene 2005; 24: 1231–1243.

    Article  CAS  PubMed  Google Scholar 

  65. Lee KC, Hamstra DA, Bullarayasamudram S, Bhojani MS, Moffat BA, Dornfeld KJ et al. Fusion of the HSV-1 tegument protein vp22 to cytosine deaminase confers enhanced bystander effect and increased therapeutic benefit. Gene Therapy 2006; 13: 127–137.

    Article  CAS  PubMed  Google Scholar 

  66. Pommier Y . Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 2006; 6: 789–802.

    Article  CAS  PubMed  Google Scholar 

  67. Shah K, Breakefield XO . HSV amplicon vectors for cancer therapy. Curr Gene Ther 2006; 6: 361–370.

    Article  CAS  PubMed  Google Scholar 

  68. Guffey MB, Parker JN, Luckett Jr WS, Gillespie GY, Meleth S, Whitley RJ et al. Engineered herpes simplex virus expressing bacterial cytosine deaminase for experimental therapy of brain tumors. Cancer Gene Ther 2007; 14: 45–56.

    Article  CAS  PubMed  Google Scholar 

  69. Jeong SW, Chu K, Jung KH, Kim SU, Kim M, Roh JK . Human neural stem cell transplantation promotes functional recovery in rats with experimental intracerebral hemorrhage. Stroke 2003; 34: 2258–2263.

    Article  PubMed  Google Scholar 

  70. Kim SU . Human neural stem cells genetically modified for brain repair in neurological disorders. Neuropathology 2004; 24: 159–171.

    Article  PubMed  Google Scholar 

  71. Kim SU, Park IH, Kim TH, Kim KS, Choi HB, Hong SH et al. Brain transplantation of human neural stem cells transduced with tyrosine hydroxylase and GTP cyclohydrolase 1 provides functional improvement in animal models of Parkinson disease. Neuropathology 2006; 26: 129–140.

    Article  PubMed  Google Scholar 

  72. Kim SU . Genetically engineered human neural stem cells for brain repair in neurological diseases. Brain Dev 2007; 29: 193–201.

    Article  CAS  PubMed  Google Scholar 

  73. Lee HJ, Kim KS, Park IH, Kim SU . Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model. PLoS ONE 2007; 2: e156.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Dittmar T, Seidel J, Zaenker KS, Niggemann B . Carcinogenesis driven by bone marrow-derived stem cells. Contrib Microbiol 2006; 13: 156–169.

    Article  PubMed  Google Scholar 

  75. Chen EH, Grote E, Mohler W, Vignery A . Cell-cell fusion. FEBS Lett 2007; 581: 2181–2193.

    Article  CAS  PubMed  Google Scholar 

  76. Duelli D, Lazebnik Y . Cell-to-cell fusion as a link between viruses and cancer. Nat Rev Cancer 2007; 7: 968–976.

    Article  CAS  PubMed  Google Scholar 

  77. Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN et al. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004; 96: 1593–1603.

    Article  CAS  PubMed  Google Scholar 

  78. Hall B, Andreeff M, Marini F . The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles. Handb Exp Pharmacol 2007; 180: 263–283.

    Article  CAS  Google Scholar 

  79. Stoff-Khalili MA, Rivera AA, Mathis JM, Banerjee NS, Moon AS, Hess A et al. Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma. Breast Cancer Res Treat 2007; 105: 157–167.

    Article  PubMed  Google Scholar 

  80. Takahashi K, Okita K, Nakagawa M, Yamanaka S . Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc 2007; 2: 3081–3089.

    Article  CAS  PubMed  Google Scholar 

  81. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131: 861–872.

    Article  CAS  PubMed  Google Scholar 

  82. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318: 1917–1920.

    Article  CAS  PubMed  Google Scholar 

  83. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 2008; 26: 101–106.

    Article  CAS  PubMed  Google Scholar 

  84. Nosrat IV, Smith CA, Mullally P, Olson L, Nosrat CA . Dental pulp cells provide neurotrophic support for dopaminergic neurons and differentiate into neurons in vitro; implications for tissue engineering and repair in the nervous system. Eur J Neurosci 2004; 19: 2388–2398.

    Article  PubMed  Google Scholar 

  85. Chan J, O’Donoghue K, de la Fuente J, Roberts IA, Kumar S, Morgan JE et al. Human fetal mesenchymal stem cells as vehicles for gene delivery. Stem Cells 2005; 23: 93–102.

    Article  CAS  PubMed  Google Scholar 

  86. Wei J, Blum S, Unger M, Jarmy G, Lamparter M, Geishauser A 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  CAS  PubMed  Google Scholar 

  87. Kern S, Eichler H, Stoeve J, Kluter H, Bieback K . Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006; 24: 1294–1301.

    Article  CAS  PubMed  Google Scholar 

  88. Pike-Overzet K, van der Burg M, Wagemaker G, van Dongen JJ, Staal FJ . New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy. Mol Ther 2007; 15: 1910–1916.

    Article  CAS  PubMed  Google Scholar 

  89. Cacci E, Villa A, Parmar M, Cavallaro M, Mandahl N, Lindvall O et al. Generation of human cortical neurons from a new immortal fetal neural stem cell line. Exp Cell Res 2007; 313: 588–601.

    Article  CAS  PubMed  Google Scholar 

  90. De Filippis L, Lamorte G, Snyder EY, Malgaroli A, Vescovi AL . A novel, immortal, and multipotent human neural stem cell line generating functional neurons and oligodendrocytes. Stem Cells 2007; 25: 2312–2321.

    Article  CAS  PubMed  Google Scholar 

  91. Lee HJ, Kim KS, Kim EJ, Choi HB, Lee KH, Park IH et al. Brain transplantation of immortalized human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model. Stem Cells 2007; 25: 1204–1212.

    Article  CAS  PubMed  Google Scholar 

  92. Bai Y, Hu Q, Li X, Wang Y, Lin C, Shen L et al. Telomerase immortalization of human neural progenitor cells. Neuroreport 2004; 15: 245–249.

    Article  CAS  PubMed  Google Scholar 

  93. Xu C, Jiang J, Sottile V, McWhir J, Lebkowski J, Carpenter MK . Immortalized fibroblast-like cells derived from human embryonic stem cells support undifferentiated cell growth. Stem Cells 2004; 22: 972–980.

    Article  CAS  PubMed  Google Scholar 

  94. Natesan S . Telomerase extends a helping hand to progenitor cells. Trends Biotechnol 2005; 23: 1–3.

    Article  CAS  PubMed  Google Scholar 

  95. Terai M, Uyama T, Sugiki T, Li XK, Umezawa A, Kiyono T . Immortalization of human fetal cells: the life span of umbilical cord blood-derived cells can be prolonged without manipulating p16INK4a/RB braking pathway. Mol Biol Cell 2005; 16: 1491–1499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Honma T, Honmou O, Iihoshi S, Harada K, Houkin K, Hamada H et al. Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Exp Neurol 2006; 199: 56–66.

    Article  CAS  PubMed  Google Scholar 

  97. Zhang X, Soda Y, Takahashi K, Bai Y, Mitsuru A, Igura K et al. Successful immortalization of mesenchymal progenitor cells derived from human placenta and the differentiation abilities of immortalized cells. Biochem Biophys Res Commun 2006; 351: 853–859.

    Article  CAS  PubMed  Google Scholar 

  98. Huang Q, Chen M, Liang S, Acha V, Liu D, Yuan F et al. Improving cell therapy—experiments using transplanted telomerase-immortalized cells in immunodeficient mice. Mech Ageing Dev 2007; 128: 25–30.

    Article  CAS  PubMed  Google Scholar 

  99. Takeuchi M, Takeuchi K, Kohara A, Satoh M, Shioda S, Ozawa Y et al. Chromosomal instability in human mesenchymal stem cells immortalized with human papilloma virus E6, E7, and hTERT genes. In Vitro Cell Dev Biol Anim 2007; 43: 129–138.

    Article  CAS  PubMed  Google Scholar 

  100. Truckenmiller ME, Vawter MP, Zhang P, Conejero-Goldberg C, Dillon-Carter O, Morales N et al. AF5, a CNS cell line immortalized with an N-terminal fragment of SV40 large T: growth, differentiation, genetic stability, and gene expression. Exp Neurol 2002; 175: 318–337.

    Article  CAS  PubMed  Google Scholar 

  101. Yeager TR, Reddel RR . Constructing immortalized human cell lines. Curr Opin Biotechnol 1999; 10: 465–469.

    Article  CAS  PubMed  Google Scholar 

  102. Serakinci N, Christensen R, Graakjaer J, Cairney CJ, Keith WN, Alsner J et al. Ectopically hTERT expressing adult human mesenchymal stem cells are less radiosensitive than their telomerase negative counterpart. Exp Cell Res 2007; 313: 1056–1067.

    Article  CAS  PubMed  Google Scholar 

  103. Richardson RM, Nguyen B, Holt SE, Broaddus WC, Fillmore HL . Ectopic telomerase expression inhibits neuronal differentiation of NT2 neural progenitor cells. Neurosci Lett 2007; 421: 168–172.

    Article  CAS  PubMed  Google Scholar 

  104. Foroni C, Galli R, Cipelletti B, Caumo A, Alberti S, Fiocco R et al. Resilience to transformation and inherent genetic and functional stability of adult neural stem cells ex vivo. Cancer Res 2007; 67: 3725–3733.

    Article  CAS  PubMed  Google Scholar 

  105. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002; 416: 542–545.

    Article  CAS  PubMed  Google Scholar 

  106. Ying QL, Nichols J, Evans EP, Smith AG . Changing potency by spontaneous fusion. Nature 2002; 416: 545–548.

    Article  CAS  PubMed  Google Scholar 

  107. Ianus A, Holz GG, Theise ND, Hussain MA . In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 2003; 111: 843–850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wurmser AE, Nakashima K, Summers RG, Toni N, D’Amour KA, Lie DC et al. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature 2004; 430: 350–356.

    Article  CAS  PubMed  Google Scholar 

  109. Brittan M, Braun KM, Reynolds LE, Conti FJ, Reynolds AR, Poulsom R et al. Bone marrow cells engraft within the epidermis and proliferate in vivo with no evidence of cell fusion. J Pathol 2005; 205: 1–13.

    Article  PubMed  Google Scholar 

  110. Sato Y, Araki H, Kato J, Nakamura K, Kawano Y, Kobune M et al. Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood 2005; 106: 756–763.

    Article  CAS  PubMed  Google Scholar 

  111. Schulze M, Belema-Bedada F, Technau A, Braun T . Mesenchymal stem cells are recruited to striated muscle by NFAT/IL-4-mediated cell fusion. Genes Dev 2005; 19: 1787–1798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ishikawa F, Shimazu H, Shultz LD, Fukata M, Nakamura R, Lyons B et al. Purified human hematopoietic stem cells contribute to the generation of cardiomyocytes through cell fusion. FASEB J 2006; 20: 950–952.

    Article  CAS  PubMed  Google Scholar 

  113. Hori J, Ng TF, Shatos M, Klassen H, Streilein JW, Young MJ . Neural progenitor cells lack immunogenicity and resist destruction as allografts. 2003. Ocul Immunol Inflamm 2007; 15: 261–273.

    Article  CAS  PubMed  Google Scholar 

  114. Wierdl M, Tsurkan L, Hyatt JL, Edwards CC, Hatfield MJ, Morton CL et al. An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11. Cancer Gene Ther 2008; 15: 183–192.

    Article  CAS  PubMed  Google Scholar 

  115. Ozawa CR, Springer ML, Blau HM . A novel means of drug delivery: myoblast-mediated gene therapy and regulatable retroviral vectors. Annu Rev Pharmacol Toxicol 2000; 40: 295–317.

    Article  CAS  PubMed  Google Scholar 

  116. Okada T, Ozawa K . Vector-producing tumor-tracking multipotent mesenchymal stromal cells for suicide cancer gene therapy. Front Biosci 2008; 13: 1887–1891.

    Article  CAS  PubMed  Google Scholar 

  117. Stender S, Murphy M, O’Brien T, Stengaard C, Ulrich-Vinther M, Soballe K et al. Adeno-associated viral vector transduction of human mesenchymal stem cells. Eur Cell Mater 2007; 13: 93–99; discussion 99.

    Article  CAS  PubMed  Google Scholar 

  118. Herrlinger U, Jacobs A, Quinones A, Woiciechowsky C, Sena-Esteves M, Rainov NG et al. Helper virus-free herpes simplex virus type 1 amplicon vectors for granulocyte-macrophage colony-stimulating factor-enhanced vaccination therapy for experimental glioma. Hum Gene Ther 2000; 11: 1429–1438.

    Article  CAS  PubMed  Google Scholar 

  119. Ramezani A, Hawley TS, Hawley RG . Performance- and safety-enhanced lentiviral vectors containing the human interferon-beta scaffold attachment region and the chicken beta-globin insulator. Blood 2003; 101: 4717–4724.

    Article  CAS  PubMed  Google Scholar 

  120. Komarova S, Kawakami Y, Stoff-Khalili MA, Curiel DT, Pereboeva L . Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses. Mol Cancer Ther 2006; 5: 755–766.

    Article  CAS  PubMed  Google Scholar 

  121. Springer CJ . Introduction to vectors for suicide gene therapy. Methods Mol Med 2004; 90: 29–45.

    CAS  PubMed  Google Scholar 

  122. Niculescu-Duvaz I, Springer CJ . Introduction to the background, principles, and state of the art in suicide gene therapy. Mol Biotechnol 2005; 30: 71–88.

    Article  CAS  PubMed  Google Scholar 

  123. 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  CAS  PubMed  PubMed Central  Google Scholar 

  124. Danks MK, Morton CL, Pawlik CA, Potter PM . Overexpression of a rabbit liver carboxylesterase sensitizes human tumor cells to CPT-11. Cancer Res 1998; 58: 20–22.

    CAS  PubMed  Google Scholar 

  125. Potter PM, Pawlik CA, Morton CL, Naeve CW, Danks MK . Isolation and partial characterization of a cDNA encoding a rabbit liver carboxylesterase that activates the prodrug irinotecan (CPT-11). Cancer Res 1998; 58: 2646–2651.

    CAS  PubMed  Google Scholar 

  126. Houghton PJ, Santana VM . Clinical trials using irinotecan. J Pediatr Hematol Oncol 2002; 24: 84–85.

    Article  PubMed  Google Scholar 

  127. Faber C, Terao E, Morga E, Heuschling P . Interleukin-4 enhances the in vitro precursor cell recruitment for tumor-specific T lymphocytes in patients with glioblastoma. J Immunother (1997) 2000; 23: 11–16.

    Article  CAS  Google Scholar 

  128. Jean WC, Spellman SR, Wallenfriedman MA, Hall WA, Low WC . Interleukin-12-based immunotherapy against rat 9L glioma. Neurosurgery 1998; 42: 850–856; discussion 856–857.

    Article  CAS  PubMed  Google Scholar 

  129. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A . Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996; 271: 12687–12690.

    Article  CAS  PubMed  Google Scholar 

  130. Pollack IF, Erff M, Ashkenazi A . Direct stimulation of apoptotic signaling by soluble Apo2l/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. Clin Cancer Res 2001; 7: 1362–1369.

    CAS  PubMed  Google Scholar 

  131. Shah K, Tang Y, Breakefield X, Weissleder R . Real-time imaging of TRAIL-induced apoptosis of glioma tumors in vivo. Oncogene 2003; 22: 6865–6872.

    Article  CAS  PubMed  Google Scholar 

  132. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999; 104: 155–162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Brooks PC, Silletti S, von Schalscha TL, Friedlander M, Cheresh DA . Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 1998; 92: 391–400.

    Article  CAS  PubMed  Google Scholar 

  134. Bello L, Lucini V, Carrabba G, Giussani C, Machluf M, Pluderi M et al. Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2. Cancer Res 2001; 61: 8730–8736.

    CAS  PubMed  Google Scholar 

  135. Davidoff AM, Ng CY, Brown P, Leary MA, Spurbeck WW, Zhou J 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.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by National Institutes of Health/National Cancer Institute (CA113446, CA79763, CA76202, and CA21765); Stop Cancer Foundation, The Rosalinde and Arthur Gilbert Foundation, Neidorf Family Foundation, HL Snyder Foundation, Jeanne Schnitzer-Reynolds Foundation, Joseph Drown Foundation, and American Lebanese Syrian Associated Charities (ALSAC).

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Authors and Affiliations

  1. Division of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA

    K S Aboody & J Najbauer

  2. Division of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA

    K S Aboody

  3. Department of Molecular Pharmacology, St Jude Children's Research Hospital, Memphis, TN, USA

    M K Danks

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  1. K S Aboody
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  2. J Najbauer
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  3. M K Danks
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Correspondence to K S Aboody or M K Danks.

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Aboody, K., Najbauer, J. & Danks, M. Stem and progenitor cell-mediated tumor selective gene therapy. Gene Ther 15, 739–752 (2008). https://doi.org/10.1038/gt.2008.41

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