Recent progress in the research of suicide gene therapy for malignant glioma

  • Ryota Tamura
  • Hiroyuki Miyoshi
  • Kazunari Yoshida
  • Hideyuki Okano
  • Masahiro TodaEmail author


Malignant glioma, which is characterized by diffuse infiltration into the normal brain parenchyma, is the most aggressive primary brain tumor with dismal prognosis. Over the past 40 years, the median survival has only slightly improved. Therefore, new therapeutic modalities must be developed. In the 1990s, suicide gene therapy began attracting attention for the treatment of malignant glioma. Some clinical trials used a viral vector for suicide gene transduction; however, it was found that viral vectors cannot cover the large invaded area of glioma cells. Interest in this therapy was recently revived because some types of stem cells possess a tumor-tropic migratory capacity, which can be used as cellular delivery vehicles. Immortalized, clonal neural stem cell (NSC) line has been used for patients with recurrent high-grade glioma, which showed safety and efficacy. Embryonic and induced pluripotent stem cells may be considered as sources of NSC because NSC is difficult to harvest, and ethical issues have been raised. Mesenchymal stem cells are alternative candidates for cellular vehicle and are easily harvested from the bone marrow. In addition, a new type of nonlytic, amphotropic retroviral replicating vector encoding suicide gene has shown efficacy in patients with recurrent high-grade glioma in a clinical trial. This replicating viral capacity is another possible candidate as delivery vehicle to tackle gliomas. Herein, we review the concept of suicide gene therapy, as well as recent progress in preclinical and clinical studies in this field.


Suicide gene therapy HSVtk CD GCV 5FC Neural stem cells 



This work was financially supported in part by grants from the Japan Society for the Promotion of Science (JSPS) (16K20026 to R.T., 17H04306 and 18K19622 to M.T.) and by the Research Center Network for the Realization of Regenerative Medicine from the Japan Agency for Medical Research and Development (18bm0204001h0006 to H.O.).

Compliance with ethical standards

Conflict of interest

H.O. is a compensated scientific consultant of San Bio, Co., Ltd. and K Pharma Inc. The other authors declare no potential conflicts of interest.

Ethical approval

No human participants are directly involved in this manuscript.


  1. 1.
    Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K, Delattre JY (2012) Primary brain tumours in adults. Lancet 379:1984–1996PubMedCrossRefGoogle Scholar
  2. 2.
    Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466CrossRefGoogle Scholar
  3. 3.
    Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for new diagnosed glioblastoma. N Engl J Med 370:709–722CrossRefGoogle Scholar
  4. 4.
    Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T, Voloschin A, Ramkissoon SH, Ligon KL, Latek R, Zwirtes R, Strauss L, Paliwal P, Harbison CT, Reardon DA, Sampson JH (2018) Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol 20:674–686PubMedCrossRefGoogle Scholar
  6. 6.
    Tamura R, Miyoshi H, Sampetrean O, Shinozaki M, Morimoto Y, Iwasawa C, Fukaya R, Mine Y, Masuda H, Maruyama T (2019) Visualization of spatiotemporal dynamics of human glioma stem cell invasion. Mol Brain 12:45PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Adachi N (1999) The HSV-tk/ganciclovir gene therapy for brain tumor (review). Gene Ther Mol Biol 4:249–260Google Scholar
  8. 8.
    Amessou M, Kandouz M (2013) Targeting intercellular communication in cancer gene therapy. INTECH 13:327–351Google Scholar
  9. 9.
    Alavi JB, Eck SL (2001) Gene therapy for high grade gliomas. Expert Opin Biol Ther 1:239–252PubMedCrossRefGoogle Scholar
  10. 10.
    Iwami K, Natsume A, Wakabayashi T (2010) Gene therapy for high-grade glioma. Neurol Med Chir (Tokyo) 50:727–736CrossRefGoogle Scholar
  11. 11.
    Oldfield EH (1993) Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and venous ganciclovir. Hum gene Ther 4:39–69PubMedCrossRefGoogle Scholar
  12. 12.
    Pulkkanen KJ, Yla-Herttuala S (2005) Gene therapy for malignant glioma: current clinical status. Mol Ther 12:585–598PubMedCrossRefGoogle Scholar
  13. 13.
    Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, Ponzoni M, Rossini S, Mavilio F, Traversari C, Bordignon C (1997) HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276:1719–1724PubMedCrossRefGoogle Scholar
  14. 14.
    Tiberghien P, Ferrand C, Lioure B, Milpied N, Angonin R, Deconinck E, Certoux JM, Robinet E, Saas P, Petracca B, Juttner C, Reynolds CW, Longo DL, Hervé P, Cahn JY (2001) Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood 97:63–72PubMedCrossRefGoogle Scholar
  15. 15.
    Chen CH (1995) Effect of herpes simplex virus thymidine kinase expression levels on ganciclovir mediated cytotoxicity and the bystander effect. Hum Gene Ther 6:1467–1476PubMedCrossRefGoogle Scholar
  16. 16.
    Rigg A, Sikora K (1997) Genetic prodrug activation therapy. Mol Med Today 3:359–366PubMedCrossRefGoogle Scholar
  17. 17.
    Rainov NG (2000) A phase lll clinical evaluation of herpes simplex type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 11:2389–2401PubMedCrossRefGoogle Scholar
  18. 18.
    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 U S A 97:12846–12851PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Koizumi S, Gu C, Amano S, Yamamoto S, Ihara H, Tokuyama T, Namba H (2011) Migration of mouse-induced pluripotent stem cells to glioma-conditioned medium is mediated by tumor-associated specific growth factors. Oncol Lett 2:283–288PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F (2008) Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther 15:730–738PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Yamazoe T, Koizumi S, Yamasaki T, Amano S, Tokuyama T, Namba H (2015) Potent tumor tropism of induced pluripotent stem cells and induced pluripotent stem cell-derived neural stem cells in the mouse intracerebral glioma model. Int J Oncol 46:147–152PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Aboody KS, Najbauer J, Metz MZ, D’Apuzzo M, Gutova M, Annala AJ, Synold TW, Couture LA, Blanchard S, Moats RA, Garcia E, Aramburo S, Valenzuela VV, Frank RT, Barish ME, Brown CE, Kim SU, Badie B, Portnow J (2013) Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies. Sci Transl Med 5:184CrossRefGoogle Scholar
  23. 23.
    Ostertag D, Amundson KK, Lopez Espinoza F, Martin B, Buckley T, Galvão da Silva AP, Lin AH, Valenta DT, Perez OD, Ibañez CE, Chen CI, Pettersson PL, Burnett R, Daublebsky V, Hlavaty J, Gunzburg W, Kasahara N, Gruber HE, Jolly DJ, Robbins JM (2012) Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. Neuro Oncol 14:145–159PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Amano S, Gu C, Koizumi S, Tokuyama T, Namba H (2011) Tumoricidal bystander effect in the suicide gene therapy using mesenchymal stem cells does not injure normal brain tissues. Cancer Lett 306:99105CrossRefGoogle Scholar
  25. 25.
    Kojima K, Miyoshi H, Nagoshi N, Kohyama J, Itakura G, Kawabata S, Ozaki M, Iida T, Sugai K, Ito S, Fukuzawa R, Yasutake K, Renault-Mihara F, Shibata S, Matsumoto M, Nakamura M, Okano H (2019) Selective ablation of tumorigenic cells following human induced pluripotent stem cell-derived neural stem/progenitor cell transplantation in spinal cord injury. Stem Cells Transl Med 8:260–270PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Bi WL, Parysek LM, Warnick R, Stambrook PJ (1993) In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy. Hum Gene Ther 4:725–731PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Cottin S, Gould PV, Cantin L, Caruso M (2011) Gap junctions in human glioblastomas: implications for suicide gene therapy. Cancer Gene Ther 18:674–681PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Freeman SM, Ramesh R, Marrogi AJ (1997) Immune system in suicide-gene therapy. Lancet 349:2–3PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Jahan N, Talat H, Curry WT (2018) Agonist OX40 immunotherapy improves survival in glioma-bearing mice and is complementary with vaccination with irradiated GM-CSF-expressing tumor cells. Neuro Oncol 20:44–54PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Toda M, Martuza RL, Rabkin SD (2000) Tumor growth inhibition by intratumoral inoculation of defective herpes simplex virus vectors expressing granulocyte-macrophage colony-stimulating factor. Mol Ther 2:324–329PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Agard C, Ligeza C, Dupas B, Izembart A, El Kouri C, Moullier P, Ferry N (2001) Immune-dependent distant bystander effect after adenovirus-mediated suicide gene transfer in a rat model of liver colorectal metastasis. Cancer Gene Ther 8:128–136PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Barresi V, Belluardo N, Sipione S, Mudo G, Cattaneo E, Condorelli D (2003) Transplantation of prodrug-converting neural progenitor cells for brain tumor therapy. Cancer Gene Ther 10:396–402PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Kosaka H, Ichikawa T, Kurozumi K, Kambara H, Inoue S, Maruo T, Nakamura K, Hamada H, Date I (2012) Therapeutic effect of suicide gene-transferred mesenchymal stem cells in a rat model of glioma. Cancer Gene Ther 19:572–578PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Altanerova V, Cihova M, Babic M, Rychly B, Ondicova K, Mravec B (2012) Human adipose tissue-derived mesenchymal stem cells expressing yeast cytosinedeaminase: uracil phosphoribosyltransferase inhibit intracerebral rat glioblastoma. Int J Cancer 130:2455–2463PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Bourbeau D, Lavoie G, Nalbantoglu J, Massie B (2004) Suicide gene therapy with an adenovirus expressing the fusion gene CD::UPRT in human glioblastomas: different sensitivities correlate with p53 status. J Gene Med 6:1320–1332PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Johnson AJ, Ardiani A, Sanchez-Bonilla M, Black ME (2011) Comparative analysis of enzyme and pathway engineering strategies for 5FC-mediated suicide gene therapy applications. Cancer Gene Ther 18:533–542PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Kambara H, Tamiya T, Ono Y, Ohtsuka S, Terada K, Adachi Y, Ichikawa T, Hamada H, Ohmoto T (2002) Combined radiation and gene therapy for brain tumors with adenovirus-mediated transfer of cytosine deaminase and uracil phosphoribosyltransferase genes. Cancer Gene Ther 9:840–845PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Kawamura K, Bahar R, Namba H, Seimiya M, Takenaga K, Hamada H, Sakiyama S, Tagawa M (2001) Bystander effect in uracil phosphoribosyltransferase/5-fluorouracil-mediated suicide gene therapy is correlated with the level of intercellular communication. Int J Oncol 18:117120Google Scholar
  39. 39.
    Shi DZ, Hu WX, Li LX, Chen G, Wei D, Gu PY (2009) Pharmacokinetics and the bystander effect in CD::UPRT/5-FC bi-gene therapy of glioma. Chin Med J (Engl) 122:1267–1272Google Scholar
  40. 40.
    Choi S, Lee J, Wang K, Phi J, Song S, Song J, Kim S (2012) Human adipose tissue-derived mesenchymal stem cells: characteristics and therapeutic potential as cellular vehicles for prodrug gene therapy against brainstem gliomas. Eur J Cancer 48:129–137PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Danks M, Yoon K, Bush R, Remack J, Wierdl M, Tsurkan L, Kim S, Garcia E, Metz M, Najbauer J, Potter P, Aboody K (2007) Tumor-targeted enzyme/ prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma. Cancer Res 67:22–25PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Kawamura K, Namba H, Bahar R, Miyauchi M, Maeda T, Hamada H, Sakiyama S, Tagawa M (2000) Transduction of the human deoxycytidine kinase gene in rodent tumor cells induces in vivo growth retardation in syngeneic hosts. Cancer Lett 156:151–157PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH, Blaese RM (1992) In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 256:1550–1552PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Boviatsis EJ, Park JS, Sena-Esteves M, Kramm CM, Chase M, Efird JT, Wei MX, Breakefield XO, Chiocca EA (1994) Long-term survival of rats harboring brain neoplasms treated with ganciclovir and a herpes simplex virus vector that retains an intact thymidine kinase gene. Cancer Res 54:5745–5751PubMedPubMedCentralGoogle Scholar
  45. 45.
    Ram Z, Culver KW, Walbridge S, Frank JA, Blaese RM, Oldfield EH (1993) Toxicity studies of retroviral-mediated gene transfer for the treatment of brain tumors. J Neurosurg 79:400–407PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Takamiya Y, Short MP, Ezzeddine ZD, Moolten FL, Breakefield XO, Martuza RL (1992) Gene therapy of malignant brain tumors: a rat glioma line bearing the herpes simplex virus type 1-thymidine kinase gene and wild type retrovirus kills other tumor cells. J Neurosci Res 33:493–503PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Vincent AJ, Vogels R, Someren GV, Esandi MC, Noteboom JL, Avezaat CJ, Vecht C, Bekkum DW, Valerio D, Bout A, Hoogerbrugge PM (1996) Herpes simplex virus thymidine kinase gene therapy for rat malignant brain tumors. Hum Gene Ther 7:197–205PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Li S, Tokuyama T, Yamamoto J, Koide M, Yokota N, Namba H (2005) Potent bystander effect in suicide gene therapy using neural stem cells transduced with herpes simplex virus thymidine kinase gene. Oncology 69:503–538PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Moolten FL (1986) Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res 46:5276–5281PubMedPubMedCentralGoogle Scholar
  50. 50.
    Moolten FL (1990) Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst 82:297–300PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Adachi N (1998) HSV-tk/ganciclovir gene therapy in relapsed glioblastoma multiformeresults of an international multicenter study. Gene Ther Mol Biol 2:380–381Google Scholar
  52. 52.
    Tamura M, Ikenaka K, Tamura K, Yoshimatsu T, Miyao Y, Kishima H, Mabuchi E, Shimizu K (1998) Transduction of glioma cells using a high-titer retroviral vector system and their subsequent migration in brain tumors. Gene Ther 5:1698–1704PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Estin D, Li M, Spray D, Wu JK (1999) Connexins are expressed in primary brain tumors and enhance the bystander effect in gene therapy. Neurosurgery 44:361–368PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Kane JR, Miska J, Young JS, Kanojia D, Kim JW, Lesniak MS (2015) Sui generis: gene therapy and delivery systems for the treatment of glioblastoma. Neuro Oncol 17:ii24–ii36PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Okura H, Smith CA, Rutka JT (2014) Gene therapy for malignant glioma. Mol Cell Ther 2:21PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Ram Z (1995) Summary of results and conclusions of the gene therapy of malignant brain tumors: Clinical study. J Neurosurg 82:343AGoogle Scholar
  57. 57.
    Ram Z, Culver KW, Oshiro EM, Viola JJ, DeVroom HL, Otto E, Long Z, Chiang Y, McGarrity GJ, Muul LM, Katz D, Blaese RM, Oldfield EH (1997) Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med 3:1354–1361PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Germano IM, Fable J, Gultekin SH, Silvers A (2003) Adenovirus/herpes simplex-thymidine kinase/ganciclovir complex: preliminary results of a phase I trial in patients with recurrent malignant gliomas. J Neurooncol 65:279–289PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Harsh GR, Deisboeck TS, Louis DN, Hilton J, Colvin M, Silver JS, Qureshi NH, Kracher J, Finkelstein D, Chiocca EA, Hochberg FH (2000) Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropathological study. J Neurosurg 92:804–811PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Izquierdo M, Cortés ML, Martín V, de Felipe P, Izquierdo JM, Pérez-Higueras A, Paz JF, Isla A, Blázquez MG (1997) Gene therapy in brain tumours: implications of the size of glioblastoma on its curability. Acta Neurochir 68:111–117Google Scholar
  61. 61.
    Klatzmann D, Valéry CA, Bensimon G, Marro B, Boyer O, Mokhtari K, Diquet B, Salzmann JL, Philippon J (1998) A phase I/II study of herpes simplex virus type 1 thymidine kinase “suicide” gene therapy for recurrent glioblastoma. Study Group on Gene Therapy for Glioblastoma. Hum Gene Ther 9:25952–25604Google Scholar
  62. 62.
    Packer RJ, Raffel C, Villablanca JG, Tonn JC, Burdach SE, Burger K, LaFond D, McComb JG, Cogen PH, Vezina G, Kapcala LP (2000) 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 92:249–254PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Palù G, Cavaggioni A, Calvi P, Franchin E, Pizzato M, Boschetto R, Parolin C, Chilosi M, Ferrini S, Zanusso A, Colombo F (1999) Gene therapy of glioblastoma multiforme via combined expression of suicide and cytokine genes: a pilot study in humans. Gene Ther 6:330–337PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Prados MD, McDermott M, Chang SM, Wilson CB, Fick J, Culver KW, Van Gilder J, Keles GE, Spence A, Berger M (2003) Treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration: a phase I/II multi-institutional trial. J Neurooncol 65:269–278PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Sandmair AM, Loimas S, Puranen P, Immonen A, Kossila M, Puranen M, Hurskainen H, Tyynelä K, Turunen M, Vanninen R, Lehtolainen P, Paljärvi L, Johansson R, Vapalahti M, Ylä-Herttuala S (2000) Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. Hum Gene Ther 11:2197–2205PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Trask TW, Trask RP, Aguilar-Cordova E, Shine HD, Wyde PR, Goodman JC, Hamilton WJ, Rojas-Martinez A, Chen SH, Woo SL, Grossman RG (2000) Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. Mol Ther 1:195–203PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Chen SH, Shine HD, Goodman JC, Grossman RG, Woo SL (1994) Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci USA 91:3054–3507PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Immonen A, Vapalahti M, Tyynelä K, Hurskainen H, Sandmair A, Vanninen R, Langford G, Murray N, Ylä-Herttuala S (2004) AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther 10:967–972PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Westphal M, Ylä-Herttuala S, Martin J, Warnke P, Menei P, Eckland D, Kinley J, Kay R, Ram Z (2013) Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3trial. Lancet Oncol 14:823-33.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Colombo F, Barzon L, Franchin E, Pacenti M, Pinna V, Danieli D, Zanusso M, Palù G (2005) Combined HSV-TK/IL-2 gene therapy in patients with recurrent glioblastoma multiforme: biological and clinical results. Cancer Gene Ther 12:835–848PubMedCrossRefGoogle Scholar
  71. 71.
    Chiocca EA, Aguilar LK, Bell SD, Kaur B, Hardcastle J, Cavaliere R, McGregor J, Lo S, Ray-Chaudhuri A, Chakravarti A, Grecula J, Newton H, Harris KS, Grossman RG, Trask TW, Baskin DS, Monterroso C, Manzanera AG, Aguilar-Cordova E, New PZ (2011) Phase IB study of gene-mediated cytotoxic immunotherapy adjuvant to up-front surgery and intensive timing radiation for malignant glioma. J Clin Oncol 29:3611–3619PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Hossain JA, Latif MA, Ystaas LAR, Ninzima S, Riecken K, Muller A, Azuaje F, Joseph JV, Talasila KM, Ghimire J, Fehse B, Bjerkvig R, Miletic H (2019) Long-term treatment with valganciclovir improves lentiviral suicide gene therapy of glioblastoma. Neuro Oncol 8Google Scholar
  73. 73.
    Hossain JA, Ystaas LR, Mrdalj J, Välk K, Riecken K, Fehse B, Bjerkvig R, Grønli J, Miletic H (2016) Lentiviral HSV-Tk.007-mediated suicide gene therapy is not toxic for normal brain cells. J Gene Med 18:234–243PubMedCrossRefGoogle Scholar
  74. 74.
    Kim GS, Heo JR, Kim SU, Choi KC (2018) Cancer-specific inhibitory effects of genetically engineered stem cells expressing cytosine deaminase and interferon-β against choriocarcinoma in xenografted metastatic mouse models. Transl Oncol 11:74–85PubMedCrossRefGoogle Scholar
  75. 75.
    Wheeler LA, Manzanera AG, Bell SD, Cavaliere R, McGregor JM, Grecula JC, Newton HB, Lo SS, Badie B, Portnow J, Teh BS, Trask TW, Baskin DS, New PZ, Aguilar LK, Aguilar-Cordova E, Chiocca EA (2016) Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma. Neuro Oncol 18:1137–1145PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Kieran MW, Goumnerova L, Manley P, Chi SN, Marcus KJ, Manzanera AG, Polanco MLS, Guzik BW, Aguilar-Cordova E, Diaz-Montero CM, DiPatri AJ, Tomita T, Lulla R, Greenspan L, Aguilar LK, Goldman S (2019) Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma. Neuro Oncol 21:537–546PubMedCrossRefGoogle Scholar
  77. 77.
    Bak XY, Yang J, Wang S (2010) Baculovirus-transduced bone marrow mesenchymal stem cells for systemic cancer therapy. Cancer Gene Ther 17:721–729PubMedCrossRefGoogle Scholar
  78. 78.
    Floeth FW, Shand N, Bojar H, Prisack HB, Felsberg J, Neuen-Jacob E, Aulich A, Burger KJ, Bock WJ, Weber F (2001) Local inflammation and devascularization--in vivo mechanisms of the “bystander effect” in VPC-mediated HSV-Tk/GCV gene therapy for human malignant glioma. Cancer Gene Ther 8:843–851PubMedCrossRefGoogle Scholar
  79. 79.
    Matuskova M, Hlubinova K, Pastorakova A, Hunakova L, Altanerova V, Altaner C, Kucerova L (2010) HSV-tk expressing mesenchymal stem cells exert bystander effect on human glioblastoma cells. Cancer Lett 290:58–67PubMedCrossRefGoogle Scholar
  80. 80.
    Miletic H, Fischer Y, Litwak S, Giroglou T, Waerzeggers Y, Winkeler A, Li H, Himmelreich U, Lange C, Stenzel W, Deckert M, Neumann H, Jacobs AH, von Laer D (2007) Bystander killing of malignant glioma by bone marrow-derived tumor-infiltrating progenitor cells expressing a suicide gene. Mol Ther 15:1373–1381PubMedCrossRefGoogle Scholar
  81. 81.
    Niu J, Xing C, Yan C, Liu H, Cui Y, Peng H, Chen Y, Li D, Jiang C, Li N, Yang H (2013) Lentivirus-mediated CD/TK fusion gene transfection neural stem cell therapy for C6 glioblastoma. Tumour Biol 34:3731–3741PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Uchibori R, Okada T, Ito T, Urabe M, Mizukami H, Kume A, Ozawa K (2009) Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. J Gene Med 11:373–381PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Ge K, Xu L, Zheng Z, Xu D, Sun L, Liu X (1997) Transduction of cytosine deaminase gene makes rat glioma cells highly sensitive to 5-fluorocytosine. Int J Cancer 71:675–679PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Kurozumi K, Tamiya T, Ono Y, Otsuka S, Kambara H, Adachi Y, Ichikawa T, Hamada H, Ohmoto T (2004) Apoptosis induction with 5-fluorocytosine/cytosine deaminase gene therapy for human malignant glioma cells mediated by adenovirus. J Neurooncol 66:117–127PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Chang JW, Lee H, Kim E, Lee Y, Chung SS, Kim JH (2000) Combined antitumor effects of an adenoviral cytosine deaminase/thymidine kinase fusion gene in rat C6 glioma. Neurosurgery 47:931–938PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Hiraoka K, Inagaki A, Kato Y, Huang TT, Mitchell LA, Kamijima S, Takahashi M, Matsumoto H, Hacke K, Kruse CA, Ostertag D, Robbins JM, Gruber HE, Jolly DJ, Kasahara N (2017) Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity. Neuro Oncol 19:918–929PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Hlavaty J, Jandl G, Liszt M, Petznek H, König-Schuster M, Sedlak J, Egerbacher M, Weissenberger J, Salmons B, Günzburg WH, Renner M (2011) Comparative evaluation of preclinical in vivo models for the assessment of replicating retroviral vectors for the treatment of glioblastoma. J Neurooncol 102:59–69PubMedCrossRefGoogle Scholar
  88. 88.
    Huang TT, Hlavaty J, Ostertag D, Espinoza FL, Martin B, Petznek H, Rodriguez-Aguirre M, Ibañez CE, Kasahara N, Gunzburg W, Gruber HE, Pertschuk D, Jolly DJ, Robbins JM (2013) Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model. Cancer Gene Ther 20:544–551PubMedCrossRefGoogle Scholar
  89. 89.
    Huang TT, Parab S, Burnett R, Diago O, Ostertag D, Hofman FM, Espinoza FL, Martin B, Ibañez CE, Kasahara N, Gruber HE, Pertschuk D, Jolly DJ, Robbins JM (2015) Intravenous administration of retroviral replicating vector, Toca 511, demonstrates therapeutic efficacy in orthotopic immune-competent mouse glioma model. Hum Gene Ther 26:82–93PubMedCrossRefGoogle Scholar
  90. 90.
    Mitchell LA, Lopez Espinoza F, Mendoza D, Kato Y, Inagaki A, Hiraoka K, Kasahara N, Gruber HE, Jolly DJ, Robbins JM (2017) Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model. Neuro Oncol 19:930–939PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Perez OD, Logg CR, Hiraoka K, Diago O, Burnett R, Inagaki A, Jolson D, Amundson K, Buckley T, Lohse D, Lin A, Burrascano C, Ibanez C, Kasahara N, Gruber HE, Jolly DJ (2012) Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression. Mol Ther 20:1689–1698PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Tai CK, Wang WJ, Chen TC, Kasahara N (2005) Single-shot, multicycle suicide gene therapy by replication-competent retrovirus vectors achieves long-term survival benefit in experimental glioma. Mol Ther 12:842–851PubMedCrossRefGoogle Scholar
  93. 93.
    Takahashi M, Valdes G, Hiraoka K, Inagaki A, Kamijima S, Micewicz E, Gruber HE, Robbins JM, Jolly DJ, McBride WH, Iwamoto KS, Kasahara N (2014) Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector. Cancer Gene Ther 21:405–410PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Twitty CG, Diago OR, Hogan DJ, Burrascano C, Ibanez CE, Jolly DJ, Ostertag D (2016) Retroviral replicating vectors deliver cytosine deaminase leading to targeted 5-fluorouracil-mediated cytotoxicity in multiple human cancer types. Hum Gene Ther Methods 27:17–31PubMedCrossRefGoogle Scholar
  95. 95.
    Wang WJ, Tai CK, Kasahara N, Chen TC (2003) Highly efficient and tumor-restricted gene transfer to malignant gliomas by replication-competent retroviral vectors. Hum Gene Ther 14:117–127PubMedCrossRefGoogle Scholar
  96. 96.
    Yagiz K, Huang TT, Lopez Espinoza F, Mendoza D, Ibañez CE, Gruber HE, Jolly DJ, Robbins JM (2016) Toca 511 plus 5-fluorocytosine in combination with lomustine shows chemotoxic and immunotherapeutic activity with no additive toxicity in rodent glioblastoma models. Neuro Oncol 18:1390–1401PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Cloughesy TF, Landolfi J, Hogan DJ, Bloomfield S, Carter B, Chen CC, Elder JB, Kalkanis SN, Kesari S, Lai AL, Lee IY, Liau LM, Mikkelsen T, Nghiemphu PL, Piccioni D, Walbert T, Chu A, Das A, Diago OR, Gammon D, Gruber HE, Hanna M, Jolly DJ, Kasahara N, McCarthy D, Mitchell L, Ostertag D, Robbins JM, Rodriguez-Aguirre M, Vogelbaum MA (2016) Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma. Sci Transl Med 8:341ra75PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Cloughesy TF, Landolfi J, Vogelbaum MA, Ostertag D, Elder JB, Bloomfield S, Carter B, Chen CC, Kalkanis SN, Kesari S, Lai A, Lee IY, Liau LM, Mikkelsen T, Nghiemphu P, Piccioni D, Accomando W, Diago OR, Hogan DJ, Gammon D, Kasahara N, Kheoh T, Jolly DJ, Gruber HE, Das A, Walbert T (2018) Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. Neuro Oncol 20:1383–1392PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Muller FJ, Snyder EY (2006) Loring JF (2006) Gene therapy:can neural stem cells deliver? Nat Rev Neurosci 7:75–84PubMedCrossRefGoogle Scholar
  100. 100.
    Alexiades NG, Auffinger B, Kim CK, Hasan T, Lee G, Deheeger M, Tobias AL, Kim J, Balyasnikova I, Lesniak MS, Aboody K, Ahmed AU (2015) MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells. Stem Cell Res 15:598–607PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Pincus DW, Keyoung HM, Harrison-Restelli C, Goodman RR, Fraser RA, Edgar M, Sakakibara S, Okano H, Nedergaard M, Goldman SA (1998) Fibroblast growth factor-2/brain-derived neurotrophic factor-associated maturation of new neurons generated from adult human subependymal cells. Ann Neurol 43:576–585PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Roy NS, Wang S, Jiang L, Kang J, Benraiss A, Harrison-Restelli C, Fraser RA, Couldwell WT, Kawaguchi A, Okano H, Nedergaard M, Goldman SA (2000) In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med 6:271–277PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Gutova M, Flores L, Adhikarla V, Tsaturyan L, Tirughana R, Aramburo S, Metz M, Gonzaga J, Annala A, Synold TW, Portnow J, Rockne RC, Aboody KS (2019) Quantitative evaluation of intraventricular delivery of therapeutic neural stem cells to orthotopic glioma. Front Oncol 9:68PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Heo JR, Hwang KA, Kim SU, Choi KC (2019) A potential therapy using engineered stem cells prevented malignant melanoma in cellular and xenograft mouse models. Cancer Res Treat 51:797–811PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Yi BR, Hwang KA, Aboody KS, Jeung EB, Kim SU, Choi KC (2014) Selective antitumor effect of neural stem cells expressing cytosine deaminase and interferon-beta against ductal breast cancer cells in cellular and xenograft models. Stem Cell Res 12:36–48PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Yi BR, Hwang KA, Kang NH, Kim SU, Jeung EB, Kim HC, Choi KC (2019) Synergistic effects of genetically engineered stem cells expressing cytosine deaminase and interferon-β via their tumor tropism to selectively target human hepatocarcinoma cells. Cancer Gene Ther 19:644–651CrossRefGoogle Scholar
  107. 107.
    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 1:347–357PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Li S, Tokuyama T, Yamamoto J, Koide M, Yokota N, Namba H (2005) Bystander effect-mediated gene therapy of gliomas using genetically engineered neural stem cells. Cancer Gene Ther 12:600–607PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Kim JH, Kim JY, Kim SU, Cho KG (2012) Therapeutic effect of genetically modified human neural stem cells encoding cytosine deaminase on experimental glioma. Biochem Biophys Res Commun 417:534–540PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Portnow J, Synold TW, Badie B, Tirughana R, Lacey SF, D’Apuzzo M, Metz MZ, Najbauer J, Bedell V, Vo T, Gutova M, Frankel P, Chen M, Aboody KS (2017) Neural stem cell-based anticancer gene therapy: a first-in-human study in recurrent high-grade glioma patients. Clin Cancer Res 23:2951–2960PubMedCrossRefGoogle Scholar
  111. 111.
    Lee JY, Lee DH, Kim HA, Choi SA, Lee HJ, Park CK, Phi JH, Wang KC, Kim SU, Kim SK (2014) Double suicide gene therapy using human neural stem cells against glioblastoma: double safety measures. J Neurooncol 116:49–57PubMedCrossRefGoogle Scholar
  112. 112.
    Ropper AE, Zeng X, Haragopal H, Anderson JE, Aljuboori Z, Han I, Abd-El-Barr M, Lee HJ, Sidman RL, Snyder EY, Viapiano MS, Kim SU, Chi JH, Teng YD (2016) Targeted treatment of experimental spinal cord glioma with dual gene-engineered human neural stem cells. Neurosurgery 79:481–491PubMedCrossRefGoogle Scholar
  113. 113.
    Amano S, Li S, Gu C, Gao Y, Koizumi S, Yamamoto S, Terakawa S, Namba H (2009) Use of genetically engineered bone marrow-derived mesenchymal stem cells for glioma gene therapy. Int J Oncol 35:1265–1270PubMedGoogle Scholar
  114. 114.
    de Melo SM, Bittencourt S, Ferrazoli EG, da Silva CS, da Cunha FF, da Silva FH, Stilhano RS, Denapoli PM, Zanetti BF, Martin PK, Silva LM, dos Santos AA, Baptista LS, Longo BM, Han SW (2015) The anti-tumor effects of adipose tissue mesenchymal stem cell transduced with HSV-Tk gene on U-87-driven brain tumor. PLoS One 10:e0128922PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Jung JH, Kim AA, Chang DY, Park YR, Suh-Kim H, Kim SS (2015) Three-dimensional assessment of bystander effects of mesenchymal stem cells carrying a cytosine deaminase gene on glioma cells. Am J Cancer Res 5:2686–2696PubMedPubMedCentralGoogle Scholar
  116. 116.
    Leten C, Trekker J, Struys T, Roobrouck VD, Dresselaers T, Vande Velde G, Lambrichts I, Verfaillie CM, Himmelreich U (2016) Monitoring the bystander killing effect of human multipotent stem cells for treatment of malignant brain tumors. Stem Cells Int:4095072Google Scholar
  117. 117.
    Li S, Gu C, Gao Y, Amano S, Koizumi S, Tokuyama T, Namba H (2012) Bystander effect in glioma suicide gene therapy using bone marrow stromal cells. Stem Cell Res 9:270–276PubMedCrossRefGoogle Scholar
  118. 118.
    Mori K, Iwata J, Miyazaki M, Osada H, Tange Y, Yamamoto T, Aiko Y, Tamura M, Shiroishi T (2010) Bystander killing effect of tymidine kinase genetransduced adult bone marrow stromal cells with ganciclovir on malignant glioma cells. Neurol Med Chir (Tokyo) 50:545–553CrossRefGoogle Scholar
  119. 119.
    Amano S, Gu C, Koizumi S, Tokuyama T, Namba H (2011) Timing of ganciclovir administration in glioma gene therapy using HSVtk gene-transduced mesenchymal stem cells. Cancer Genom Proteom 8:245–250Google Scholar
  120. 120.
    Rhee KJ, Lee JI, Eom YW (2015) Mesenchymal stem cell-mediated effects of tumor support or suppression. Int J Mol Sci 16:30015–30033PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Tang H, Chu Y, Huang Z, Cai J, Wang Z (2019) The metastatic phenotype shift towards myofibroblast of adipose-derived mesenchymal stem cells promotes ovarian cancer progression. Carcinogenesis. bgz083.Google Scholar
  122. 122.
    Wu YL, Li HY, Zhao XP, Jiao JY, Tang DX, Yan LJ, Wan Q, Pan CB (2017) Mesenchymal stem cell-derived CCN2 promotes the proliferation, migration and invasion of human tongue squamous cell carcinoma cells. Cancer Sci 108:897–909PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Wen S, Niu Y, Yeh S, Chang C (2015) BM-MSCs promote prostate cancer progression via the conversion of normal fibroblasts to cancer-associated fibroblasts. Int J Oncol 47:719–727PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449:557–563PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Suzuki K, Sun R, Origuchi M, Kanehira M, Takahata T, Itoh J, Umezawa A, Kijima H, Fukuda S, Saijo Y (2011) Mesenchymal stromal cells promote tumor growth through the enhancement of neovascularization. Mol Med 17:579–587PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Lin G, Yang R, Banie L, Wang G, Ning H, Li LC, Lue TF, Lin CS (2010) Effects of transplantation of adipose tissue-derived stem cells on prostate tumor. Prostate 70:1066–1073PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Yu JM, Jun ES, Bae YC, Jung JS (2008) Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo. Stem Cells Dev 17:463–473PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Dasari VR, Kaur K, Velpula KK, Gujrati M, Fassett D, Klopfenstein JD, Dinh DH, Rao JS (2010) Upregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathway. PLoS One 5:e10350PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    He N, Kong Y, Lei X, Liu Y, Wang J, Xu C, Wang Y, Du L, Ji K, Wang Q, Li Z, Liu Q (2018) MSCs inhibit tumor progression and enhance radiosensitivity of breast cancer cells by down-regulating Stat3 signaling pathway. Cell Death Dis 9:1026PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Qiao L, Xu Z, Zhao T, Zhao Z, Shi M, Zhao RC, Ye L, Zhang X (2008) Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model. Cell Res 18:500–507PubMedCrossRefGoogle Scholar
  131. 131.
    Zhu Y, Sun Z, Han Q, Liao L, Wang J, Bian C, Li J, Yan X, Liu Y, Shao C, Zhao RC (2009) Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 23:925–933PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Tabatabai G, Bähr O, Möhle R, Eyüpoglu IY, Boehmler AM, Wischhusen J, Rieger J, Blümcke I, Weller M, Wick W (2005) Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells. Brain 128:2200–2211PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Lee EX, Lam DH, Wu C, Yang J, Tham CK, Ng WH, Wang S (2011) Glioma gene therapy using induced pluripotent stem cell derived neural stem cells. Mol Pharm 8:1515–1524PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Luo Y, Zhu D, Lam DH, Huang J, Tang Y, Luo X, Wang S (2015) A Double-switch cell fusion-inducible transgene expression system for neural stem cell-based antiglioma gene therapy. Stem Cells Int 2015:649080PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Nori S, Okada Y, Yasuda A, Tsuji O, Takahashi Y, Kobayashi Y, Fujiyoshi K, Koike M, Uchiyama Y, Ikeda E (2011) Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. Proc Natl Acad SCi UCA 108:16825–16830CrossRefGoogle Scholar
  136. 136.
    Oki K, Tatarishvili J, Wood J, Koch P, Wattananit S, Mine Y, Monni E, Tornero D, Ahlenius H, Ladewig J et al (2012) Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem cells 30:1120–1133PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Okano H, Yamanaka S (2014) iPS cell technologies: significance and applications to CNS regeneration and disease. Mol Brain 31:7–22Google Scholar
  138. 138.
    Kawai H, Yamashita T, Ohta Y, Deguchi K, Nagotani S, Zhang X, Ikeda Y, Matsuura T, Abe K Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J Cereb Blood Flow Metab 30:1487–1493CrossRefGoogle Scholar
  139. 139.
    Nori S, Okada Y, Nishimura S, Sasaki T, Itakura G, Kobayashi Y, Renault-Mihara F, Shimizu A, Koya I, Yoshida R, Kudoh J, Koike M, Uchiyama Y, Ikeda E, Toyama Y, Nakamura M, Okano H (2015) Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition. Stem Cell Reports 4:360–373PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Okano H, Nakamura M, Yoshida K, Okada Y, Tsuji O, Nori S, Ikeda E, Yamanaka S, Miura K (2013) Steps toward safe cell therapy using induced pluripotent stem cells. Circ Res 112:523–533PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Cheng F, Ke Q, Chen F, Cai B, Gao Y, Ye C, Wang D, Zhang L, Lahn BT, Li W, Xiang AP (2012) Protecting against wayward human induced pluripotent stem cells with a suicide gene. Biomaterials 33:3195–3204PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Itakura G, Kawabata S, Ando M, Nishiyama Y, Sugai K, Ozaki M, Iida T, Ookubo T, Kojima K, Kashiwagi R, Yasutake K, Nakauchi H, Miyoshi H, Nagoshi N, Kohyama J, Iwanami A, Matsumoto M, Nakamura M, Okano H (2017) Fail-safe system against potential tumorigenicity after transplantation of iPSC derivatives. Stem Cell Reports 8:673–684PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Iwasawa C, Tamura R, Sugiura Y, Suzuki S, Kuzumaki N, Narita M, Suematsu M, Nakamura M, Yoshida K, Toda M (2019) Increased cytotoxicity of herpes simplex virus thymidine kinase expression in human induced pluripotent stem cells. Int J Mol Sci 20:E810PubMedCrossRefGoogle Scholar
  144. 144.
    Jeong M, Kwon YS, Park SH, Kim CY, Jeun SS, Song KW, Ko Y, Robbins PD, Billiar TR, Kim BM, Seol DW (2009) Possible novel therapy for malignant gliomas with secretable trimeric TRAIL. PLoS One 4:e4545PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Shi F, Rakhmilevich AL, Heise CP, Oshikawa K, Sondel PM, Yang NS, Mahvi DM (2002) Intratumoral injection of IL-12 plasmid DNA, either naked or in complex with cationic lipid, results in similar tumor regression in a murine model. Mol Cancer Ther 1:949–957PubMedPubMedCentralGoogle Scholar
  146. 146.
    Lee J, Elkahloun AG, Messina SA, Ferrari N, Xi D, Smith CL, Cooper R Jr, Albert PS, Fine HA (2002) Cellular and genetic characterization of human adult bone marrow derived neural stem cells: a potential Cellular vector. Cancer Res 63:8877–8889Google Scholar
  147. 147.
    Pollack IF, Erff M, Ashkenazi A (2001) Direct stimulation of apoptotic signaling by soluble Apo2/tumor necrosis-related apoptosis-inducing ligand leads to selective killing of glioma cells. Clin Cancer Res 7:1362–1369PubMedPubMedCentralGoogle Scholar
  148. 148.
    Balyasnikova IV, Ferguson SD, Han Y, Liu F, Lesniak MS (2011) Therapeutic effect of neural stem cells expressing TRAIL and bortezomib in mice with glioma xenografts. Cancer Lett 310:148–159PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D, Galli R, Selleri S, Di Meco F, De Fraja C, Vescovi A, Cattaneo E, Finocchiaro G (2000) Gene therapy of experimental brain tumors using neural progenitor cells. Nature Medicine 6:447–450PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    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 62:7170–7174PubMedPubMedCentralGoogle Scholar
  151. 151.
    Choi SA, Hwang SK, Wang KC, Cho BK, Phi JH, Lee JY, Jung HW, Lee DH, Kim SK (2011) Therapeutic efficacy and safety of TRAIL-producing human adipose tissue-derived mesenchymal stem cells against experimental brainstem glioma. Neuro Oncol 13:61–69PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Frieboes HB, Wu M, Lowengrub J, Decuzzi P, Cristini V (2013) A computational model for predicting nanoparticle accumulation in tumor vasculature. PLoS One 8:e56876PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Bagci-Onder T, Du W, Figueiredo JL, Martinez-Quintanilla J, Shah K (2015) Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells. Brain 138:1710–1721PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Malecki M (2012) Cancer suicide gene therapy: apoptosis of the ovarian cancer cells induced by EGFRvIII targeted delivery and cell nucleus targeted expression of the DNase transgenes. J Genet Syndr Gene Ther 3:4CrossRefGoogle Scholar
  155. 155.
    Albanese A, Tang PS, Chan WC (2012) The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng 14:141–116CrossRefGoogle Scholar
  156. 156.
    Mitra S, Gaur U, Ghosh PC, Maitra AN (2001) Tumour targeted delivery of encapsulated dextran-doxorubicin conjugate using chitosan nanoparticles as carrier. J Control Release 74:317–323PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Wang CH, Chiou SH, Chou CP, Chen YC, Huang YJ, Peng CA (2011) Photothermolysis of glioblastoma stem-like cells targeted by carbon nanotubes conjugated with CD133 monoclonal antibody. Nanomedicine 7:69–79PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Zhang Y, Bai Y, Yan B (2010) Functionalized carbon nanotubes for potential medicinal applications. Drug Discov Today 15:428–435PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Zhang G, Liu T, Chen YH, Chen Y, Xu M, Peng J, Yu S, Yuan J, Zhang X (2009) Tissue specific cytotoxicity of colon cancer cells mediated by nanoparticle-delivered suicide gene in vitro and in vivo. Clin Cancer Res 15:201–207PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Ananda S, Nowak AK, Cher L, Dowling A, Brown C, Simes J, Rosenthal MA (2011) Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy. J Clin Neurosci 18:1444–1448PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Eavarone DA, Yu X, Bellamkonda RV (2000) Targeted drug delivery to C6 glioma by transferrin-coupled liposomes. J Biomed Mater Res 51:10–14PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Gao JQ, Lv Q, Li LM, Tang XJ, Li FZ, Hu YL, Han M (2013) Glioma targeting and blood-brain barrier penetration by dual-targeting doxorubincin liposomes. Biomaterials 34:5628–5639PubMedCrossRefGoogle Scholar
  163. 163.
    Yang ZZ, Li JQ, Wang ZZ, Dong DW, Qi XR (2014) Tumor-targeting dual peptides-modified cationic liposomes for delivery of siRNA and docetaxel to gliomas. Biomaterials 35:5226–5239PubMedCrossRefGoogle Scholar
  164. 164.
    Huang YH, Zugates GT, Peng W, Holtz D, Dunton C, Green JJ, Hossain N, Chernick MR, Padera RF Jr, Langer R, Anderson DG, Sawicki JA (2009) Nanoparticle-delivered suicide gene therapy effectively reduces ovarian tumor burden in mice. Cancer Res 69:6184–6191PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Mangraviti A, Tzeng SY, Kozielski KL, Wang Y, Jin Y, Gullotti D, Pedone M, Buaron N, Liu A, Wilson DR, Hansen SK, Rodriguez FJ, Gao GD, DiMeco F, Brem H, Olivi A, Tyler B, Green JJ (2015) Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo. ACS Nano 9:1236–1249PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Vago R, Collico V, Zuppone S, Prosperi D, Colombo M (2016) Nanoparticle-mediated delivery of suicide genes in cancer therapy. Pharmacol Res 111:619–641PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Bauerschmitz GJ, Guse K, Kanerva A, Menzel A, Herrmann I, Desmond RA, Yamamoto M, Nettelbeck DM, Hakkarainen T, Dall P, Curiel DT, Hemminki A (2006) Triple-targeted oncolytic adenoviruses featuring the cox2 promoter, E1A transcomplementation, and serotype chimerism for enhanced selectivity for ovarian cancer cells. Mol Ther 14:164–174PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Li W, Li DM, Chen K, Chen Z, Zong Y, Yin H, Xu ZK, Zhu Y, Gong FR, Tao M (2012) Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and pgk promoter: an in vitro and in vivo study. BMC Cancer 12:547PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Rojas JJ, Cascallo M, Guedan S, Gros A, Martinez-Quintanilla J, Hemminki A, Alemany R (2009 Dec) A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses. Gene Ther 16(12):1441–1451PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Wang W, Ji W, Hu H, Ma J, Li X, Mei W, Xu Y, Hu H, Yan Y, Song Q, Li Z, Su C (2014) Survivin promoter-regulated oncolytic adenovirus with Hsp70 gene exerts effective antitumor efficacy in gastric cancer immunotherapy. Oncotarget 5:150–160PubMedPubMedCentralGoogle Scholar
  171. 171.
    Bush TG, Savidge TC, Freeman TC, Cox HJ, Campbell EA, Mucke L, Johnson MH, Sofroniew MV (1998) Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 93:189–201PubMedCrossRefPubMedCentralGoogle Scholar
  172. 172.
    Castro MG, Candolfi M, Kroeger K, King GD, Curtin JF, Yagiz K, Mineharu Y, Assi H, Wibowo M, Ghulam Muhammad AK, Foulad D, Puntel M, Lowenstein PR (2011) Gene therapy and targeted toxins for glioma. Curr Gene Ther 11:155–180PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    McKie EA, Graham DI, Brown SM (1998) Selective astrocytic transgene expression in vitro and in vivo from the GFAP promoter in a HSV RL1 null mutant vector--potential glioblastoma targeting. Gene Ther 5:440–450PubMedCrossRefPubMedCentralGoogle Scholar
  174. 174.
    Balani P, Boulaire J, Zhao Y, Zeng J, Lin J, Wang S (2009) High mobility group box2 promoter-controlled suicide gene expression enables targeted glioblastoma treatment. Mol Ther 17:1003–1011PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Pan J, Wang H, Liu X, Hu J, Song W, Luo J, Jiang S, Yan F, Zhai B (2015) Tumor restrictive suicide gene therapy for glioma controlled by the FOS promoter. PLoS One 10:e0143112PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Yawata T, Maeda Y, Okiku M, Ishida E, Ikenaka K, Shimizu K (2011) Identification and functional characterization of glioma-specific promoters and their application in suicide gene therapy. J Neurooncol 104:497–507PubMedCrossRefGoogle Scholar
  177. 177.
    Li M, Sun S, Dangelmajer S, Zhang Q, Wang J, Hu F, Dong F, Kahlert UD, Zhu M, Lei T (2019) Exploiting tumor-intrinsic signals to induce mesenchymal stem cell-mediated suicide gene therapy to fight malignant glioma. Stem Cell Res Ther10:88.Google Scholar
  178. 178.
    Barba D, Hardin J, Sadelain M, Gage FH (1994) Development of anti-tumor immunity following thymidine kinase-mediated killing of experimental brain tumors. Proc Natl Acad Sci U S A 91:4348–4352PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Shand N, Weber F, Mariani L, Bernstein M, Gianella-Borradori A, Long Z, Sorensen AG, Barbier N (1999) A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. GLI328 European-Canadian Study Group. Hum Gene Ther 10:2325–2335PubMedCrossRefGoogle Scholar
  180. 180.
    Stuckey DW, Shah K (2014) Stem cell-based therapies for cancer treatment: separating hope from hype. Nat Rev Cancer 14:683–691PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Uzzaman M, Keller G, Germano IM (2009) In vivo gene delivery by embryonic-stem-cell-derived astrocytes for malignant gliomas. Neuro Oncol 11:102–108PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurosurgeryKeio University School of MedicineTokyoJapan
  2. 2.Department of PhysiologyKeio University School of MedicineTokyoJapan

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