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HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice

Cancer Gene Therapy volume 19, pages 888–898 (2012)Cite this article

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Abstract

Despite the tremendous potential of adenovirus (Ad) as a delivery vector for cancer gene therapy, its use in clinical settings has been limited, mainly as a result of the limited infectivity in many tumors and the wide tissue tropism associated with Ad. To modify the tropism of the virus, we have inserted the epidermal growth factor-like domain of the human heregulin-α (HRG) into the HI loop of Ad5 fiber. This insertion had no adverse effect on fiber trimerization nor did it affect incorporation of the modified fiber into infectious viral particles. Virions bearing modified fiber displayed growth characteristics and viral yields indistinguishable from those of wild-type (wt) virus. Most importantly, HRG-tagged virions showed enhanced infection of cells expressing the cognate receptors HER3/ErbB3 and HER4/ErbB4. This was significantly reduced in the presence of soluble HRG. Furthermore, HER3-expressing Chinese hamster ovary (CHO) cells were transduced by the HRG-modified virus, but not by wt virus. In contrast, CHO cells expressing the coxsackie-Ad receptor were transduced with both viruses. However, infection of an in vivo breast cancer xenograft model after intratumoral injection was similar with both viruses, suggesting that the tumor microenvironment and/or the route of delivery have important roles in infection of target cells with fiber-modified Ads.

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Acknowledgements

We thank Dr J Bergelson and Dr Z Wang for providing cell lines. ME was recipient of a post-doctoral fellowship from the Canadian Institutes of Health Research. SM was supported by the Dr Herbert Meltzer Fellowship, the Alberta Cancer Legacy Graduate Studentship and the Queen Elizabeth II Graduate Scholarship—Master’s Level. GB was recipient of a post-doctoral fellowship from Fondazione Italiana per la Ricerca sul Cancro. AP was supported by the Alberta Cancer Research Institute. FG was supported by grants from the National Cancer Institute of Canada, Merck Research Laboratories and the Canadian Vaccine Network. MH was supported by funding from the Canadian Breast Cancer Research Alliance, the Canadian Breast Cancer Foundation and the Canadian Institutes for Health Research.

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  1. M M Elgadi

    Present address: 4Current address: Boehringer Ingelheim (Canada) Ltd., Burlington, Ontario, Canada.,

  2. G Bossi

    Present address: 5Current address: Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Via delle Messi D’Oro, 156, Rome 00158, Italy.,

Authors and Affiliations

  1. Department of Oncology, University of Alberta, Edmonton, Alberta, Canada

    S H MacLeod, A Pisio, K Agopsowicz, D Sharon & M M Hitt

  2. Department of Biology, McMaster University, Hamilton, Ontario, Canada

    M M Elgadi, G Bossi, U Sankar & F L Graham

  3. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    F L Graham & M M Hitt

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MacLeod, S., Elgadi, M., Bossi, G. et al. HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice. Cancer Gene Ther 19, 888–898 (2012). https://doi.org/10.1038/cgt.2012.79

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