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Published on: November 24, 2014
Molecular determinants of susceptibility to oncolytic vesicular stomatitis virus in pancreatic adenocarcinoma
Aaron U Blackham1, Scott A Northrup1, Mark Willingham2
1Division of Surgical Sciences, Department of General Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Background:
M protein mutant vesicular stomatitis virus (M51R-VSV) has oncolytic properties against many cancers. However, some cancer cells are resistant to M51R-VSV. Herein, we evaluate the molecular determinants of vesicular stomatitis virus (VSV) resistance in pancreatic adenocarcinoma cells.
Methods:
Cell viability and the effect of β-interferon (IFN) were analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Gene expression was evaluated via microarray analysis. Cell infectability was measured by flow cytometry. Xenografts were established in athymic nude mice and treated with intratumoral M51R-VSV.
Results:
Four of five pancreatic cancer cell lines were sensitive to M51R-VSV, whereas Panc 03.27 cells remained resistant (81 ± 3% viability 72 h after single-cycle infection). Comparing sensitive MiaPaCa2 cells with resistant Panc 03.27 cells, significant differences in gene expression were found relating to IFN signaling (P = 2 × 10(-5)), viral entry (P = 3 × 10(-4)), and endocytosis (P = 7 × 10(-4)). MiaPaCa2 cells permitted high levels of VSV infection, whereas Panc 03.27 cells were capable of resisting VSV cell entry even at high multiplicities of infection. Extrinsic β-IFN overcame apparent defects in IFN-mediated pathways in MiaPaCa2 cells conferring VSV resistance. In contrast, β-IFN decreased cell viability in Panc 3.27 cells, suggesting intact antiviral mechanisms. VSV-treated xenografts exhibited reduced tumor growth relative to controls in both MiaPaCa2 (1423 ± 345% versus 164 ± 136%; P < 0.001) and Panc 3.27 (979 ± 153% versus 50 ± 56%; P = 0.002) tumors. Significant lymphocytic infiltration was seen in M51R-VSV-treated Panc 03.27 xenografts.
Conclusions:
Inhibition of VSV endocytosis and intact IFN-mediated defenses are responsible for M51R-VSV resistance in pancreatic adenocarcinoma cells. M51R-VSV treatment appears to induce antitumor cellular immunity in vivo, which may expand its clinical efficacy.
Insights
M protein mutant vesicular stomatitis virus (M51R-VSV) shows oncolytic potential, but resistance occurs in some pancreatic cancer cells due to inhibited viral entry and intact interferon defenses. M51R-VSV also stimulates antitumor immunity in vivo.
Area of Science:
- Oncolytic virology
- Cancer biology
- Immunology
Background:
- M protein mutant vesicular stomatitis virus (M51R-VSV) exhibits oncolytic properties against various cancers.
- Pancreatic adenocarcinoma cells can display resistance to M51R-VSV, necessitating an understanding of the underlying molecular mechanisms.
Purpose of the Study:
- To investigate the molecular determinants responsible for resistance to M protein mutant vesicular stomatitis virus (M51R-VSV) in pancreatic adenocarcinoma cells.
- To compare gene expression profiles and cellular responses between M51R-VSV-sensitive and resistant pancreatic cancer cell lines.
Main Methods:
- Cell viability assays (MTT) were performed to assess the effects of M51R-VSV and beta-interferon (IFN).
- Gene expression analysis using microarrays identified differences between sensitive and resistant cell lines.
- Cell infectability was quantified by flow cytometry, and in vivo efficacy was evaluated in M51R-VSV-treated xenografts in mice.
Main Results:
- Panc 03.27 cells demonstrated resistance to M51R-VSV, unlike four other sensitive pancreatic cancer cell lines.
- Gene expression analysis revealed significant differences in pathways related to interferon signaling, viral entry, and endocytosis between sensitive (MiaPaCa2) and resistant (Panc 03.27) cells.
- M51R-VSV treatment reduced tumor growth in both sensitive and resistant xenografts, with notable lymphocytic infiltration observed in resistant tumor xenografts.
Conclusions:
- Resistance to M51R-VSV in pancreatic adenocarcinoma is linked to inhibited viral endocytosis and robust interferon-mediated antiviral defenses.
- M51R-VSV treatment can elicit an antitumor cellular immune response in vivo, suggesting potential for enhanced clinical applications.
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