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Modeling oncolytic virus dynamics in the tumor microenvironment using zebrafish

Cancer Gene Therapy volume 28, pages 769–784 (2021)Cite this article

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Abstract

We have adapted a zebrafish (Danio rerio) tumor xenograft model for use in the study of oncolytic virotherapy. Following implantation of mammalian cancer cells into the perivitelline space of developing zebrafish embryos, both local and intravenous oncolytic virus treatments produce a tumor-specific infection with measurable antitumor effects. Tumor cells are injected at 48 h post fertilization, with oncolytic virus treatment then being administered 24 h later to allow for an initial period of tumor development and angiogenesis. Confocal fluorescent imaging is used to quantify dynamics within the tumor environment. The natural translucency of zebrafish at the embryo stage, coupled with the availability of strains with fluorescent immune and endothelial cell reporter lines, gives the model broad potential to allow for real time, in vivo investigation of important events within tumors throughout the course of virotherapy. Zebrafish xenografts offer a system with biologic fidelity to processes in human cancer development that influence oncolytic virus efficacy, and to our knowledge this is the first demonstration of the model’s use in the context of virotherapy. Compared with other models, our protocol offers a powerful, inexpensive approach to evaluating novel oncolytic viruses and oncolytic virus-based combination therapies, with potential application to investigating the impacts of virotherapy on immune response, tumor vasculature, and metastatic disease.

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Fig. 1: Fluorescent confocal imaging of Zebrafish tumor xenograft model.
Fig. 2: Tumor growth in the xenograft model.
Fig. 3: Tumor-stimulated angiogenesis.
Fig. 4: Innate immune cell visualization.
Fig. 5: Oncolytic Vaccinia virus (vvDD) treatment.
Fig. 6: Antitumor effect following treatment with vvDD.
Fig. 7: Anti-vascular effects following treatment with vvDD.
Fig. 8: Off-target infection and macrophage uptake.

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Acknowledgements

The authors would like to acknowledge the financial support of The Terry Fox Foundation, PSI Foundation, Hold ‘em For Life Charity, and the Surgeon Scientist Training Program at the University of Toronto, without which the work would not have been possible. We would also like to acknowledge Dr. Claire Lewis and Dr. Simon Tazzyman from the University of Sheffield, who provided the zebrafish strains used in this work as well as initial expertise in zebrafish methodologies.

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  1. David Mealiea, Lili Okamoto & J. Andrea McCart

    Present address: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

Authors and Affiliations

  1. Department of Surgery, University of Toronto, Toronto, Ontario, Canada

    David Mealiea & J. Andrea McCart

  2. Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

    David Mealiea, Emilie Boudreau, Naomi De Silva, Lili Okamoto, Tiffany Ho, Jason E. Fish & J. Andrea McCart

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Jason E. Fish

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DM and AM were responsible for developing the zebrafish model, designing the experiments, and writing this paper. ND contributed to early optimization and initial testing. EB and JF were responsible for all zebrafish husbandry and breeding, as well as providing assistance and expertise with zebrafish care. LL and TH were responsible for technical support during each experiment and preparation of reagents and materials.

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Mealiea, D., Boudreau, E., De Silva, N. et al. Modeling oncolytic virus dynamics in the tumor microenvironment using zebrafish. Cancer Gene Ther 28, 769–784 (2021). https://doi.org/10.1038/s41417-020-0194-7

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