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Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy

Authors

  • Ryosuke Uchibori,

    1. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
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  • Takashi Okada,

    1. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
    Current affiliation:
    1. Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
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  • Takayuki Ito,

    1. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
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  • Masashi Urabe,

    1. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
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  • Hiroaki Mizukami,

    1. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
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  • Akihiro Kume,

    1. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
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  • Keiya Ozawa

    Corresponding author
    1. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
    • Division of Genetic Therapeutics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
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Abstract

Background

Mesenchymal stem cells (MSCs) are a promising vehicle for targeted cancer gene therapy because of their potential of tumor tropism. For efficient therapeutic application, we developed retroviral vector-producing MSCs that enhance tumor transduction via progeny vector production.

Methods

Rat bone marrow-derived MSCs were nucleofected with the proviral plasmids (vesicular stomatitis virus-G protein-pseudotyped retroviral vector components) (VP-MSCs) or pLTR plasmid alone (non-VP-MSCs). The luciferase-based in vivo imaging system was used to assess gene expression periodically. To evaluate the anticancer effects, we administered MSCs expressing herpes simplex virus-thymidine kinase (HSV-tk) into the left ventricular cavity of nude mice engrafted with 9L glioma cells subcutaneously.

Results

In vivo imaging revealed that administration of luciferase-expressing non-VP-MSCs enhanced the bioluminescence signal at the inoculation sites of 9L cells, whereas no accumulation was observed in mice at the site of the control Rat-1 fibroblasts. Compared to non-VP-MSCs, the administration of VP-MSCs resulted in significant augmentation of the signal with an increase in transgene copy number. Immunohistochemical analysis showed marked luciferase expression at the tumor periphery in mice injected with VP-MSCs, whereas little expression was detected in those injected with non-VP-MSCs. Under the continuous infusion of ganciclovir, systemic administration of VP-MSCs expressing HSV-tk suppressed tumor growth more effectively than non-VP-MSC administration, whereas no anticancer effect was observed without ganciclovir treatment. Furthermore, VP-MSC administration caused no transgene transduction in the normal tissues and organs.

Conclusions

VP-MSCs accumulated at the site of tumors after intravascular injection in tumor-bearing mice, followed by in situ gene transfer to tumors without transduction of normal organs. When applied to the HSV-tk/ganciclovir suicide gene therapy, more efficient tumor growth suppression was observed using VP-MSCs compared to non-VP-MSCs. This VP-MSC-based system has great potential for improved cancer gene therapy. Copyright © 2009 John Wiley & Sons, Ltd.

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