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The use of hypoxic cultured mesenchymal stem cell for oncolytic virus therapy

Cancer Gene Therapy volume 20, pages 308–316 (2013)Cite this article

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Abstract

The safety of oncolytic viruses, such as conditionally replicative adenoviruses (CRAds), has been validated in clinical trials for cancer therapy. Their antitumor efficacy is limited by the presence of preexisting neutralizing antibodies (NAbs). Mesenchymal stem cells (MSCs) are attractive as a cellular vehicle to carry antitumor agents, not only because they are easily obtained and expanded to great numbers in vitro, but also because of their ability to migrate and engraft to tumors. MSCs expanded under hypoxic conditions decrease in replicative senescence and increase in proliferation capacity and differentiation potentials. However it remains to be clarified whether these hypoxic MSCs also are good carriers for the delivery of CRAds to tumor cells in the presence of NAbs. This study firstly demonstrated hypoxic MSCs with an increased ability to migrate toward tumors through the upregulation of chemokine receptors, such as CXCR4 and CX3CR1. It is then demonstrated that hypoxic MSCs has the capacity to carry CRAds, without inducing apoptosis, for up to one week. Using an in vitro coculture with human colon cancer cells and with intraperitoneally (i.p.) and subcutaneously (s.c.) developed human colon cancer xenografts, it is demonstrated that hypoxic MSCs are able to protect CRAds from attack by NAbs, thereby successfully delivering them to the target tumor cells. These results show that hypoxic MSCs can serve as cell carriers for CRAds and may help to develop new strategies against cancer.

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Acknowledgements

This study received grants supported by the Veterans General Hospital-Taipei (V99E1-011), National Science Council (101-2321-B-010-012-; 101-2314-B-010-028-MY3) and National Yang-Ming University, Ministry of Education.

Author contributions

This study was concepted and designed by YFH, MJC and SCH. YFH performed collection and/or assembly of data. YFH, MJC and SCH performed data analysis and interpretation. YFH and SCH wrote the manuscript. YFH and MJC approved the final manuscript.

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Authors and Affiliations

  1. Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Y-F Huang, M-H Wu & S-C Hung

  2. Mackay Memorial Hospital, Taipei, Taiwan

    M-J Chen

  3. Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan

    S-C Hung

  4. Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

    S-C Hung

  5. Department of Medical Research and Education, Stem Cell Laboratory, Taipei Veterans General Hospital, Taipei, Taiwan

    S-C Hung

  6. Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan

    S-C Hung

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  1. Y-F Huang
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  4. S-C Hung
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Correspondence to S-C Hung.

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Huang, YF., Chen, MJ., Wu, MH. et al. The use of hypoxic cultured mesenchymal stem cell for oncolytic virus therapy. Cancer Gene Ther 20, 308–316 (2013). https://doi.org/10.1038/cgt.2013.22

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