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Sustained production of a soluble IGF-I receptor by gutless adenovirus-transduced host cells protects from tumor growth in the liver

Cancer Gene Therapy volume 20, pages 229–236 (2013)Cite this article

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Abstract

The IGF-I receptor (IGF-IR) has an important role in malignant disease and is the target of several drugs presently in clinical trials. Gene therapy has been explored as cancer treatment, mainly for delivery of genes that induce cell death or enhance the immunological response to cancer. Previously, we have shown that the implantation of autologous bone-marrow stromal cells producing a soluble form of IGF-IR (sIGFIR) inhibited experimental liver metastasis of several tumor types in mice. Here, we evaluated the utility of adenovirus-based gene delivery for generating therapeutically effective plasma levels of this decoy. We constructed a third generation gutless adenovirus expressing sIGFIR and found that HEK-293 cells transduced by this, but not control adenoviruses, secreted soluble receptor protein that blocked IGF-I-induced tumor cell migration, proliferation and survival in vitro. Following virus injection in vivo, viral DNA was detectable by PCR in several host organs, particularly the liver, and this resulted in the production of measurable sIGFIR plasma levels for up to 21 days post injection. In mice producing virus-encoded sIGFIR, experimental liver metastasis was inhibited, indicating that sIGFIR levels were therapeutically effective. The results show that adenovirus-based delivery of inhibitory soluble proteins can provide an effective anticancer strategy.

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Acknowledgements

This study was supported by Canadian Institute for Health Research grants MOP-77677 and MOP-81201 (to PB).

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Author notes

  1. Y Lu and M Pinard: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec, Canada

    N Wang, Y Lu, M Pinard & P Brodt

  2. Biotechnology Research Institute, National Research Council Canada, Montreal, Quebec, Canada

    A Pilotte, R Gilbert & B Massie

  3. Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

    R Gilbert

  4. Department of Microbiology and Immunology, Université de Montréal, Quebec, Canada

    B Massie

  5. Department of Medicine, McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec, Canada

    P Brodt

  6. Department of Oncology, McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec, Canada

    P Brodt

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Correspondence to P Brodt.

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Wang, N., Lu, Y., Pinard, M. et al. Sustained production of a soluble IGF-I receptor by gutless adenovirus-transduced host cells protects from tumor growth in the liver. Cancer Gene Ther 20, 229–236 (2013). https://doi.org/10.1038/cgt.2013.10

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  • DOI: https://doi.org/10.1038/cgt.2013.10

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