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The viral tropism of two distinct oncolytic viruses, reovirus and myxoma virus, is modulated by cellular tumor suppressor gene status

Oncogene volume 29, pages 3990–3996 (2010)Cite this article

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Abstract

Replication-competent oncolytic viruses hold great potential for the clinical treatment of many cancers. Importantly, many oncolytic virus candidates, such as reovirus and myxoma virus, preferentially infect cancer cells bearing abnormal cellular signaling pathways. Reovirus and myxoma virus are highly responsive to activated Ras and Akt signaling pathways, respectively, for their specificity for viral oncolysis. However, considering the complexity of cancer cell populations, it is possible that other tumor-specific signaling pathways may also contribute to viral discrimination between normal versus cancer cells. Because carcinogenesis is a multistep process involving the accumulation of both oncogene activations and the inactivation of tumor suppressor genes, we speculated that not only oncogenes but also tumor suppressor genes may have an important role in determining the tropism of these viruses for cancer cells. It has been previously shown that many cellular tumor suppressor genes, such as p53, ATM and Rb, are important for maintaining genomic stability; dysfunction of these tumor suppressors may disrupt intact cellular antiviral activity due to the accumulation of genomic instability or due to interference with apoptotic signaling. Therefore, we speculated that cells with dysfunctional tumor suppressors may display enhanced susceptibility to challenge with these oncolytic viruses, as previously seen with adenovirus. We report here that both reovirus and myxoma virus preferentially infect cancer cells bearing dysfunctional or deleted p53, ATM and Rb tumor suppressor genes compared to cells retaining normal counterparts of these genes. Thus, oncolysis by these viruses may be influenced by both oncogenic activation and tumor suppressor status.

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Abbreviations

WT reovirus:

wild-type reovirus

AV reovirus:

S1 attenuated reovirus

Myx:

myxoma virus

Myx-GFP:

GFP-expressing myxoma virus

MOI:

multiplicity of infection

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Acknowledgements

This work was supported by funding from the Canadian Institutes of Health Research and the Canadian Breast Cancer Foundation (to RNJ) and a start-up grant from the University of Florida College of Medicine and NIH grant R01 CA138541 (to GM). GM is an International Scholar of the Howard Hughes Medical Institute.

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Author notes

  1. M Kim

    Present address: 5Current address: Department of Medicine, Yonsei Cancer Center, College of Medicine, Yonsei University, Seoul, South Korea.,

  2. G McFadden and R N Johnston: Shared senior author.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada

    M Kim, C T Williamson, J Prudhomme, K Riabowol, S P Lees-Miller, Y Mori & R N Johnston

  2. Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA

    M Kim, M M Rahman & G McFadden

  3. Department of Oncology, University of Calgary, Calgary, Alberta, Canada

    D G Bebb

  4. Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada

    P W K Lee

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Correspondence to R N Johnston.

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Kim, M., Williamson, C., Prudhomme, J. et al. The viral tropism of two distinct oncolytic viruses, reovirus and myxoma virus, is modulated by cellular tumor suppressor gene status. Oncogene 29, 3990–3996 (2010). https://doi.org/10.1038/onc.2010.137

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