Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Neural stem cells target intracranial glioma to deliver an oncolytic adenovirus in vivo

Abstract

Adenoviral oncolytic virotherapy represents an attractive treatment modality for central nervous system (CNS) neoplasms. However, successful application of virotherapy in clinical trials has been hampered by inadequate distribution of oncolytic vectors. Neural stem cells (NSCs) have been shown as suitable vehicles for gene delivery because they track tumor foci. In this study, we evaluated the capability of NSCs to deliver a conditionally replicating adenovirus (CRAd) to glioma. We examined NSC specificity with respect to viral transduction, migration and capacity to deliver a CRAd to tumor cells. Fluorescence-activated cell sorter (FACS) analysis of NSC shows that these cells express a variety of surface receptors that make them amenable to entry by recombinant adenoviruses. Luciferase assays with replication-deficient vectors possessing a variety of transductional modifications targeted to these receptors confirm these results. Real-time PCR analysis of the replication profiles of different CRAds in NSCs and a representative glioma cell line, U87MG, identified the CRAd-Survivin (S)-pk7 virus as optimal vector for further delivery studies. Using in vitro and in vivo migration studies, we show that NSCs infected with CRAd-S-pk7 virus migrate and preferentially deliver CRAd to U87MG glioma. These results suggest that NSCs mediate an enhanced intratumoral distribution of an oncolytic vector in malignant glioma when compared with virus injection alone.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Tyler MA, Sonabend AM, Ulasov IV, Lesniak MS . Vector therapies for malignant glioma: shifting the clinical paradigm. Expert Opin Drug Deliv 2008; 5: 445–458.

    Article  CAS  PubMed  Google Scholar 

  2. Borovjagin AV, Krendelchtchikov A, Ramesh N, Yu DC, Douglas JT, Curiel DT . Complex mosaicism is a novel approach to infectivity enhancement of adenovirus type 5-based vectors. Cancer Gene Ther 2005; 12: 475–486.

    Article  CAS  PubMed  Google Scholar 

  3. Brouwer E, Havenga MJ, Ophorst O, de Leeuw B, Gijsbers L, Gillissen G et al. Human adenovirus type 35 vector for gene therapy of brain cancer: improved transduction and bypass of pre-existing anti-vector immunity in cancer patients. Cancer Gene Ther 2007; 14: 211–219.

    Article  CAS  PubMed  Google Scholar 

  4. Miura Y, Yoshida K, Nishimoto T, Hatanaka K, Ohnami S, Asaka M et al. Direct selection of targeted adenovirus vectors by random peptide display on the fiber knob. Gene Therapy 2007; 14: 1448–1460.

    Article  CAS  PubMed  Google Scholar 

  5. Paul CP, Everts M, Dent P, Fisher PB, Ulasov IV, Lesniak MS et al. Characterization of infectivity of Knob-modified adenoviral vectors in glioma. Cancer Biol Ther 2008; 7: 786–793.

    Article  CAS  PubMed  Google Scholar 

  6. Tyler MA, Ulasov IV, Borovjagin A, Sonabend AM, Khramtsov A, Han Y et al. Enhanced transduction of malignant glioma with a double targeted Ad5/3-RGD fiber-modified adenovirus. Mol Cancer Ther 2006; 5: 2408–2416.

    Article  CAS  PubMed  Google Scholar 

  7. Ulasov IV, Tyler MA, Han Y, Glasgow JN, Lesniak MS . Novel recombinant adenoviral vector that targets the interleukin-13 receptor alpha2 chain permits effective gene transfer to malignant glioma. Hum Gene Ther 2007; 18: 118–129.

    Article  CAS  PubMed  Google Scholar 

  8. Ulasov IV, Tyler MA, Zheng S, Han Y, Lesniak MS . CD46 represents a target for adenoviral gene therapy of malignant glioma. Hum Gene Ther 2006; 17: 556–564.

    Article  CAS  PubMed  Google Scholar 

  9. Ulasov IV, Zhu ZB, Tyler MA, Han Y, Rivera AA, Khramtsov A et al. Survivin-driven and fiber-modified oncolytic adenovirus exhibits potent antitumor activity in established intracranial glioma. Hum Gene Ther 2007; 18: 589–602.

    Article  CAS  PubMed  Google Scholar 

  10. Aboody KS, Najbauer J, Danks MK . Stem and progenitor cell-mediated tumor selective gene therapy. Gene Therapy 2008; 15: 739–752.

    Article  CAS  PubMed  Google Scholar 

  11. Sonabend AM, Ulasov IV, Tyler MA, Rivera AA, Mathis JM, Lesniak MS . Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma. Stem Cells 2008; 26: 831–841.

    Article  CAS  PubMed  Google Scholar 

  12. Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 1997; 275: 1320–1323.

    Article  CAS  PubMed  Google Scholar 

  13. Gaggar A, Shayakhmetov DM, Lieber A . CD46 is a cellular receptor for group B adenoviruses. Nat Med 2003; 9: 1408–1412.

    Article  CAS  PubMed  Google Scholar 

  14. Wickham TJ, Tzeng E, Shears II LL, Roelvink PW, Li Y, Lee GM et al. Increased in vitro and in vivo gene transfer by adenovirus vectors containing chimeric fiber proteins. J Virol 1997; 71: 8221–8229.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ulasov IV, Rivera AA, Sonabend AM, Rivera LB, Wang M, Zhu ZB et al. Comparative evaluation of survivin, midkine and CXCR4 promoters for transcriptional targeting of glioma gene therapy. Cancer Biol Ther 2007; 6: 679–685.

    Article  CAS  PubMed  Google Scholar 

  16. Lesniak MS . Targeted therapy for malignant glioma: neural stem cells. Expert Rev Neurother 2006; 6: 1–3.

    Article  PubMed  Google Scholar 

  17. 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 

  18. Brown AB, Yang W, Schmidt NO, Carroll R, Leishear KK, Rainov NG 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  CAS  PubMed  Google Scholar 

  19. 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 

  20. Ourednik V, Ourednik J, Park KI, Teng YD, Aboody KA, Auguste KI et al. Neural stem cells are uniquely suited for cell replacement and gene therapy in the CNS. Novartis Found Symp 2000; 231: 242–262; discussion 262–269, 302–306.

    CAS  PubMed  Google Scholar 

  21. 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 

  22. Modo M, Rezaie P, Heuschling P, Patel S, Male DK, Hodges H . Transplantation of neural stem cells in a rat model of stroke: assessment of short-term graft survival and acute host immunological response. Brain Res 2002; 958: 70–82.

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. 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 

  25. 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 

  26. 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 

  27. 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 

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

    Article  PubMed  Google Scholar 

  29. Ehtesham M, Yuan X, Kabos P, Chung NH, Liu G, Akasaki Y et al. Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 2004; 6: 287–293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kabos P, Ehtesham M, Black KL, Yu JS . Neural stem cells as delivery vehicles. Expert Opin Biol Ther 2003; 3: 759–770.

    Article  CAS  PubMed  Google Scholar 

  31. Kabos P, Ehtesham M, Kabosova A, Black KL, Yu JS . Generation of neural progenitor cells from whole adult bone marrow. Exp Neurol 2002; 178: 288–293.

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. Shah K, Hingtgen S, Kasmieh R, Figueiredo JL, Garcia-Garcia E, Martinez-Serrano A et al. Bimodal viral vectors and in vivo imaging reveal the fate of human neural stem cells in experimental glioma model. J Neurosci 2008; 28: 4406–4413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chu K, Kim M, Park KI, Jeong SW, Park HK, Jung KH et al. Human neural stem cells improve sensorimotor deficits in the adult rat brain with experimental focal ischemia. Brain Res 2004; 1016: 145–153.

    Article  CAS  PubMed  Google Scholar 

  35. 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 

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

    Article  PubMed  Google Scholar 

  37. Meng XL, Shen JS, Ohashi T, Maeda H, Kim SU, Eto Y . Brain transplantation of genetically engineered human neural stem cells globally corrects brain lesions in the mucopolysaccharidosis type VII mouse. J Neurosci Res 2003; 74: 266–277.

    Article  CAS  PubMed  Google Scholar 

  38. Coskun V, Wu H, Blanchi B, Tsao S, Kim K, Zhao J et al. CD133+ neural stem cells in the ependyma of mammalian postnatal forebrain. Proc Natl Acad Sci USA 2008; 105: 1026–1031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Duan X, Kang E, Liu CY, Ming GL, Song H . Development of neural stem cell in the adult brain. Curr Opin Neurobiol 2008; 18: 108–115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sims Jr TL, Hamner JB, Bush RA, Williams RF, Zhou J, Kim SU et al. Neural progenitor cell-mediated delivery of interferon beta improves neuroblastoma response to cyclophosphamide. Ann Surg Oncol 2008; 15: 3259–3267.

    Article  PubMed  PubMed Central  Google Scholar 

  41. 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  CAS  PubMed  Google Scholar 

  42. Shaner NC, Campbell RE, Steinbach PA, Giepmans BN, Palmer AE, Tsien RY . Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat Biotechnol 2004; 22: 1567–1572.

    Article  CAS  PubMed  Google Scholar 

  43. Deregowski V, Canalis E . Gene delivery by retroviruses. Methods Mol Biol 2008; 455: 157–162.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Cancer Institute (R01-CA122930), the National Institute of Neurological Disorders and Stroke (K08-NS046430), The Alliance for Cancer Gene Therapy Young Investigator Award and the American Cancer Society (RSG-07-276-01-MGO). We are grateful for the assistance of Dr Dingcai Cao, a biostatistician at the University of Chicago, in preparing this article. We also acknowledge Dr Vytas Bindokas and Shirley Bond (University of Chicago Integrated Microscopy Research Facility) for their help in obtaining the fluorescent microscope images presented in this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M S Lesniak.

Additional information

Conflict of interest

The authors state no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tyler, M., Ulasov, I., Sonabend, A. et al. Neural stem cells target intracranial glioma to deliver an oncolytic adenovirus in vivo. Gene Ther 16, 262–278 (2009). https://doi.org/10.1038/gt.2008.165

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2008.165

Keywords

This article is cited by

Search

Quick links