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:

The anti-glioma effect of suicide gene therapy using BMSC expressing HSV/TK combined with overexpression of Cx43 in glioma cells

Cancer Gene Therapy volume 17, pages 192–202 (2010)Cite this article

Abstract

The disseminated neoplastic foci of malignant gliomas are essentially responsible for the limited efficacy of current available therapeutic modalities. Bone marrow-derived stem cells (BMSCs) have the ability to migrate into these tumors and even track infiltrating tumor cells, making them to be promising cellular vehicles for delivering therapeutic agents to glioma cells. The herpes simplex virus thymidine kinase (HSV–TK)/ganciclovir (GCV) suicide gene therapy with a potent bystander effect has been considered as one of the most promising therapeutic strategies for malignant gliomas. In this study, we evaluate the anti-glioma effect of suicide gene therapy using BMSCs expressing HSV–TK combined with overexpression of connexin 43 (Cx43), which can restore the gap junction of intercellular communication and may enhance the bystander effect of suicide gene therapy. To assess the potential of BMSCs to track glioma cells, a spheroid co-culture system in matrigel was used to show that some BMSCs migrated to C6 glioma cell microspheres. Transwell assay showed the tumor tropic property of BMSCs. In addition, BrdU-labeled BMSCs injected directly into the cerebral hemisphere opposite to the established C6 rat gliomas were capable of migrating into the xenograft gliomas. C6 cell growth was more intensively inhibited by HSV–TK/GCV treatment mediated by BMSCs, and could be further enhanced by combination with Cx43 transfection into glioma cells. The same result was observed in vivo by the growth of C6 gliomas and the survival analysis of rats bearing C6 glioma. In conclusion, Cx43 combined with HSV–TK/GCV gene therapy using BMSCs as vehicles was highly effective in a rat glioma model and therefore hold great potential as a novel approach for the gene therapy of human malignant gliomas.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. 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  Google Scholar 

  2. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Bianco P, Riminucci M, Gronthos S, Robey PG . Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 2001; 19: 180–192.

    Article  CAS  Google Scholar 

  5. Colter DC, Class R, DiGirolamo CM, Prockop DJ . Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. Proc Natl Acad Sci USA 2000; 97: 3213–3218.

    Article  CAS  Google Scholar 

  6. Koc ON, Lazarus HM . Mesenchymal stem cells: heading into the clinic. Bone Marrow Transplant 2001; 27: 235–239.

    Article  CAS  Google Scholar 

  7. Vincent AJ, Vogels R, Someren GV, Esandi MC, Noteboom JL, Avezaat CJ et al. Herpes simplex virus thymidine kinase gene therapy for rat malignant brain tumors. Hum Gene Ther 1996; 7: 197–205.

    Article  CAS  Google Scholar 

  8. Rosolen A, Frascella E, di Francesco C, Todesco A, Petrone M, Mehtali M et al. In vitro and in vivo antitumor effect of retrovirus-mediated herpes simplex thymidine kinase gene-transfer in human medulloblastoma. Gene Ther 1998; 5: 113–120.

    Article  CAS  Google Scholar 

  9. Peister A, Mellad J, Larson B, Hall B, Gobson L, Prockop D . Adult stem cells from bone marrow (MSCs) isolated from different strains of in bred mice vary in surface epitopes, rates of proliferation, and differential potential. Blood 2004; 103: 1662–1668.

    Article  CAS  Google Scholar 

  10. Wang SL, Li F, Pu PY, Wang GX, Peng Q, Wang CY . The establishment and characterization of human glioblastoma cell lines TJ899 and TJ905. Tianjin Med J 1996; 24: 416–418. (in Chinese).

    Google Scholar 

  11. Pu PY, Liu XW, Liu AX, Cui J, Zhang Y . Inhibitory effect of antisense epidermal growth factor receptor RNA on the proliferation of rat C6 glioma cells in vitro and in vivo. J. Neurosurg 2000; 92: 132–139.

    Article  CAS  Google Scholar 

  12. Conget PA, Minguell JJ . Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. J Cell Physiol 1999; 181: 67–73.

    Article  CAS  Google Scholar 

  13. Heese O, Disko A, Zirkel D, Westphal M, Lamszus K . Migration of human neural stem cells toward an intracranial glioma. Neuro Oncol 2005; 7: 476–484.

    Article  CAS  Google Scholar 

  14. Jeon JY, An JH, Kim SU, Park HG, Lee MA . Migration of human neural stem cells toward an intracranial glioma. Exp Mol Med 2008; 40: 84–91.

    Article  CAS  Google Scholar 

  15. 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  Google Scholar 

  16. Touraine RL, Ishii-Morita H, Ramsey WJ, Blaese RM . The bystander effect in the HSVtk/ganciclovir system and its relation to gap junctional communication. Gene Ther 1998; 5: 1705–1711.

    Article  CAS  Google Scholar 

  17. Touraine RL, Vahanian N, Ramsey WJ, Blaese RM . Enhancement of the herpes simplex virus thymidine kinase/ ganciclovir bystander effect and its antitumor efficacy in vivo by pharmacologic manipulation of gap junctions. Hum Gene Ther 1998; 9: 2385–2391.

    Article  CAS  Google Scholar 

  18. Bi WL, Parysek LM, Warnick R, Stambrook PJ . In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV-TK retroviral gene therapy. Hum Gene Ther 1993; 4: 725–731.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Rainov NGA . Phase III clinical evaluation of herpes simplex virus 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 2000; 11: 2389–2401.

    Article  CAS  Google Scholar 

  21. Trask TW, Trask RP, Aguilar-Cordova E, Shine HD, Wyde PR, Goodman JC et al. Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. Mol Ther 2000; 1: 195–203.

    Article  CAS  Google Scholar 

  22. Li S, Tokuyama T, Yamamoto J, Koide M, Yokota N, Namba H . Bystander effect-mediated gene therapy of gliomas using genetically engineered neural stem cells. Cancer Gene Ther 2005; 12: 600–607.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. 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  Google Scholar 

  25. 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  Google Scholar 

  26. 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  Google Scholar 

  27. Pu PY, Xia ZB, Huang Q, Wang CY, Wang GX . The effect of transfected Cx43 gene on the GJIC and proliferation of glioma cells. Chin J Cancer Res 2002; 14: 100–104. (in English).

    Article  CAS  Google Scholar 

  28. Xia ZB, Pu PY, Huang Q, Zhang YT, Jiang WY, You YP . Connexin 43 gene for the treatment of rat C6 cerebral gliomas in vivo. Chin J Oncol 2002; 24: 212–214. (in Chinese).

    CAS  Google Scholar 

  29. Huang RP, Fan Y, Mohammad Z, Peng A, Zeng ZL, Boynton AL . Reversion of the neoplastic phenotype of human glioblastoma cells by Connexin43 (Cx43). Cancer Res 1998; 58: 5089–5096.

    CAS  Google Scholar 

  30. Naus CC, Elisevich K, Zhu D, Belliveau DJ, Del Maestro RF . In vivo growth of C6 glioma cells transfected with connexin43 cDNA. Cancer Res 1992; 52: 4208–4213.

    CAS  PubMed  Google Scholar 

  31. Chen SC, Pelletier DB, Ao P, Boynton Al . Connexin 43 reverses the phenotype of transformed cells and alters their expression of cyclin/cyclin-dependent kinases. Cell Growth Differ 1995; 6: 681–690.

    CAS  PubMed  Google Scholar 

  32. Pu P, Xia Z, Yu S, Huang Q . Altered expression of Cx43 in astrocytic tumors. Clin Neurol Neurosurg 2004; 107: 49–54.

    Article  Google Scholar 

  33. Shinoura N, Chen L, Wani MA, Kim YG, Larson JJ, Warnick RE et al. Protein and messenger RNA expression of connexin 43 in astrocytomas: implications in brain tumor gene therapy. J Neurosurg 1996; 84: 839–846.

    Article  CAS  Google Scholar 

  34. Huang RP, Hossain MZ, Sehgal A . Reduced connexin 43 expression in high grade human brain glioma cells. J Surg Oncol 1999; 70: 21–24.

    Article  CAS  Google Scholar 

  35. Soroceanu L, Manning Jr TJ, Sontheimer H . Reduced expression of connexin-43 and functional gap junction coupling in human gliomas. Glia 2001; 33: 107–117.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Tianjin Education Committee (Grant No. 20050227) and Tianjin Science and Technology Committee (Grant No. 09JCZDJC20500).

Author information

Author notes

  1. Q Huang and X-Z Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, People's Republic of China

    Q Huang, C-S Kang, Y Zhong & P-Y Pu

  2. Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, People's Republic of China

    X-Z Liu, C-S Kang & G-X Wang

Authors
  1. Q Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X-Z Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C-S Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G-X Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P-Y Pu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Y Zhong or P-Y Pu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, Q., Liu, XZ., Kang, CS. et al. The anti-glioma effect of suicide gene therapy using BMSC expressing HSV/TK combined with overexpression of Cx43 in glioma cells. Cancer Gene Ther 17, 192–202 (2010). https://doi.org/10.1038/cgt.2009.64

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2009.64

Keywords

This article is cited by

Search

Advanced search

Quick links