Down-regulation of type I interferon receptor sensitizes bladder cancer cells to vesicular stomatitis virus-induced cell death

The Vancouver Prostate Centre, Vancouver, BC, Canada.
International Journal of Cancer (Impact Factor: 5.09). 08/2010; 127(4):830-8. DOI: 10.1002/ijc.25088
Source: PubMed


The intrinsic oncolytic specificity of vesicular stomatitis virus (VSV) is currently being exploited to develop alternative therapeutic strategies for bladder cancer and other cancers. Previously we reported that oncolytic VSV is a potent agent for intravesical treatment of high risk bladder cancer. We observed that VSV preferentially targeted bladder cancer cells resistant to type I interferon (IFN) treatment. The goal of the current study was to further elucidate the nature of the molecular defect of IFN signaling by which bladder cancer cells become susceptible to VSV infection. Using a tissue microarray composed of human bladder cancer cores, we observed that expression of type I IFN receptor (IFNAR) was decreased relative to normal bladder tissue. Advanced bladder cancers had even lower expression of IFNAR. We found that bladder cancer cells susceptible to VSV-induced lysis had low expression of IFNAR as well. We hypothesized that down-regulation of IFNAR in bladder cancer cells may be a molecular mechanism responsible for resistance to type I IFN treatment and sensitivity to VSV oncolysis. SiRNA knockdown of IFNAR indeed facilitated replication of VSV in cells previously resistant to VSV treatment. Blocking IFNAR with a neutralizing antibody showed a similar effect. Hence down-regulation of IFNAR in bladder cancer may be one of the primary molecular mechanisms for clinical IFN resistance. However, this also facilitates VSV replication and oncolysis in high risk bladder cancers and provides a basis for selecting bladder cancer patients for IFN or oncolytic VSV therapy in future clinical trials.

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Available from: John Bell, Sep 01, 2014
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    • "The unexpected inhibition of antiviral signaling by p53 can be explained by dysregulation of type I IFN signaling in cancer cells. In many cancer cell types, specific genes associated with type I IFN signaling are transcriptionally downregulated or functionally inactive (Balachandran and Barber, 2004; Marozin et al., 2008, 2010; Moussavi et al., 2010; Zhang et al., 2010). Also, type I IFN mediated responses can be inhibited by MEK/ERK signaling, which is often upregulated in cancer cells (Noser et al., 2007), or by epigenetic silencing of IFN responsive transcription factors IRF7 or IRF5 (Li and Tainsky, 2011). "
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    ABSTRACT: Virus-encoded tumor suppressor p53 transgene expression has been successfully used in vesicular stomatitis virus (VSV) and other oncolytic viruses (OVs) to enhance their anticancer activities. However, p53 is also known to inhibit virus replication via enhanced type I interferon (IFN) antiviral responses. To examine whether p53 transgenes enhance antiviral signaling in human pancreatic ductal adenocarcinoma (PDAC) cells, we engineered novel VSV recombinants encoding human p53 or the previously described chimeric p53-CC, which contains the coiled-coil (CC) domain from breakpoint cluster region (BCR) protein and evades the dominant-negative activities of endogenously expressed mutant p53. Contrary to an expected enhancement of antiviral signaling by p53, our global analysis of gene expression in PDAC cells showed that both p53 and p53-CC dramatically inhibited type I IFN responses. Our data suggest that this occurs through p53-mediated inhibition of the NF-κB pathway. Importantly, VSV-encoded p53 or p53-CC did not inhibit antiviral signaling in non-malignant human pancreatic ductal cells, which retained their resistance to all tested VSV recombinants. To the best of our knowledge, this is the first report of p53-mediated inhibition of antiviral signaling, and it suggests that OV-encoded p53 can simultaneously produce anticancer activities while assisting, rather than inhibiting, virus replication in cancer cells. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 05/2015; 483:126-140. DOI:10.1016/j.virol.2015.04.017 · 3.32 Impact Factor
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    • "However, some cancers retain the ability to produce and/or respond to type I IFN (Naik and Russell, 2009; Stojdl et al., 2000). For example, PC3 prostate cancer cells (Ahmed et al., 2004; Carey et al., 2008), SW982 human sarcoma cells (Paglino and van den Pol, 2011), RT-4 and RT112 bladder cancer cells (Zhang et al., 2010), and multiple mesothelioma cells lines (Saloura et al., 2010) have been shown to be resistant to VSV infection at least in part due to IFN responsiveness and/or constitutive ISG expression. Furthermore, constitutive ISG expression was shown to be predictive of permissiveness of several PDA cell lines to adenovirus infection (Monsurro et al., 2010). "
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    ABSTRACT: Oncolytic virus (OV) therapy takes advantage of common cancer characteristics, such as defective type I interferon (IFN) signaling, to preferentially infect and kill cancer cells with viruses. Our recent study (Murphy et al., 2012. J. Virol. 86, 3073-87) found human pancreatic ductal adenocarcinoma (PDA) cells were highly heterogeneous in their permissiveness to vesicular stomatitis virus (VSV) and suggested at least some resistant cell lines retained functional type I IFN responses. Here we examine cellular responses to infection by the oncolytic VSV recombinant VSV-ΔM51-GFP by analyzing a panel of 11 human PDA cell lines for expression of 33 genes associated with type I IFN pathways. Although all cell lines sensed infection by VSV-ΔM51-GFP and most activated IFN-α and β expression, only resistant cell lines displayed constitutive high-level expression of the IFN-stimulated antiviral genes MxA and OAS. Inhibition of JAK/STAT signaling decreased levels of MxA and OAS and increased VSV infection, replication and oncolysis, further implicating IFN responses in resistance. Unlike VSV, vaccinia and herpes simplex virus infectivity and killing of PDA cells was independent of the type I IFN signaling profile, possibly because these two viruses are better equipped to evade type I IFN responses. Our study demonstrates heterogeneity in the type I IFN signaling status of PDA cells and suggests MxA and OAS as potential biomarkers for PDA resistance to VSV and other OVs sensitive to type I IFN responses.
    Virology 12/2012; 436(1). DOI:10.1016/j.virol.2012.11.014 · 3.32 Impact Factor
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    • "In many cancer cells, VSV oncoselectivity is based largely on defective or reduced type I IFN responses (Barber, 2004; Lichty et al., 2004; Stojdl et al., 2000, 2003). In many cancer cells, specific genes associated with type I IFN responses are downregulated or functionally inactive (Balachandran & Barber, 2004; Marozin et al., 2008, 2010; Moussavi et al., 2010; Zhang et al., 2010). In addition, IFN signalling can be inhibited by MEK/ERK signalling, a cascade often upregulated in cancer cells (Noser et al., 2007). "
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    ABSTRACT: Oncolytic virus (OV) therapy is an emerging anti-cancer approach that utilizes viruses to preferentially infect and kill cancer cells, while not harming healthy cells. Vesicular stomatitis virus (VSV) is a prototypic non-segmented, negative-strand RNA virus with inherent OV qualities. Antiviral responses induced by type I interferon pathways are believed to be impaired in most cancer cells, making them more susceptible to VSV than normal cells. Several other factors make VSV a promising OV candidate for clinical use, including its well-studied biology, a small, easily manipulated genome, relative independence of a receptor or cell cycle, cytoplasmic replication without risk of host-cell transformation, and lack of pre-existing immunity in humans. Moreover, various VSV-based recombinant viruses have been engineered via reverse genetics to improve oncoselectivity, safety, oncotoxicity and stimulation of tumour-specific immunity. Alternative delivery methods are also being studied to minimize premature immune clearance of VSV. OV treatment as a monotherapy is being explored, although many studies have employed VSV in combination with radiotherapy, chemotherapy or other OVs. Preclinical studies with various cancers have demonstrated that VSV is a promising OV; as a result, a human clinical trial using VSV is currently in progress.
    Journal of General Virology 10/2012; 93(Pt_12). DOI:10.1099/vir.0.046672-0 · 3.18 Impact Factor
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