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Oncolysis of prostate cancers induced by vesicular stomatitis virus in PTEN knockout mice
Maryam Moussavi1, Ladan Fazli, Howard Tearle
1Vancouver Prostate Centre, Department of Medicine, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
Abstract:
Vesicular stomatitis virus (VSV) is an oncolytic virus which selectively infects and kills cancer cells. The goal of the present study was to determine the safety and efficacy of VSV treatment of prostate tumors that arise in situ in immunocompetent, transgenic prostate-specific PTEN-null (PTEN(-/-)) mice. Interferon-sensitive VSV(AV3 strain), which expresses luciferase, was injected intraprostatically into tumor-bearing PTEN(-/-) and control mice and then monitored for tissue bioluminescence over 96 hours. Virus readily dispersed throughout the bodies of mice after only 3 hours; however, it persisted at high levels for >72 hours in PTEN(-/-) mice, but at relatively low levels and for only approximately 48 hours in controls. Plaque assays provided a similar pattern, with much higher concentrations of replicating virus in prostates of PTEN(-/-) mice than in controls. Transient, low levels of virus were detected in the spleens of both groups. Apoptotic analyses by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining revealed that VSV(AV3) is able to selectively infect and kill prostate cells in PTEN(-/-) mice, while sparing normal cells in control mice. The primary mechanism for cell kill is apparently apoptotic oncolysis as opposed to neutrophil invasion as has been reported using xenograft models. These results suggest that control of locally advanced human prostate cancer may be achievable through intraprostatic injection and amplification of a safe oncolytic virus, such as VSV(AV3).
Insights
Vesicular stomatitis virus (VSV) selectively targets and eliminates prostate cancer cells in mice. This oncolytic virus therapy shows promise for treating prostate cancer by inducing apoptosis, sparing healthy cells.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Prostate cancer remains a significant health concern, necessitating novel therapeutic strategies.
- Oncolytic viruses offer a targeted approach to cancer treatment by selectively infecting and destroying tumor cells.
- Vesicular stomatitis virus (VSV) has demonstrated oncolytic potential, but its efficacy in prostate cancer models requires further investigation.
Purpose of the Study:
- To evaluate the safety and efficacy of intraprostatic VSV treatment in a transgenic mouse model of prostate cancer.
- To assess the viral distribution, persistence, and tumor cell killing mechanisms of VSV in PTEN-null mice.
Main Methods:
- Intraprostatic injection of interferon-sensitive VSV(AV3) expressing luciferase into PTEN(-/-) mice and control mice.
- Monitoring of viral tissue bioluminescence over 96 hours.
- Quantification of viral replication using plaque assays and assessment of cell death via TUNEL staining.
Main Results:
- VSV(AV3) demonstrated significantly higher and prolonged viral levels in the prostates of PTEN(-/-) mice compared to controls.
- Apoptotic oncolysis was identified as the primary mechanism of cancer cell death, with minimal impact on normal cells.
- Transient, low-level viral presence was detected in the spleens of both groups, indicating limited systemic spread.
Conclusions:
- Intraprostatic injection of VSV(AV3) is a safe and effective strategy for targeting and eliminating prostate cancer in situ.
- VSV(AV3) selectively induces apoptotic oncolysis in prostate cancer cells, offering a promising therapeutic avenue.
- These findings support the potential of VSV(AV3) as an oncolytic virotherapy for locally advanced prostate cancer.
