Journal article
Changes in Susceptibility to Oncolytic Vesicular Stomatitis Virus during Progression of Prostate Cancer
Journal of virology, Vol.89(10), pp.5250-5263
05/01/2015
DOI: 10.1128/JVI.00257-15
PMCID: PMC4442527
PMID: 25741004
Abstract
A major challenge to oncolytic virus therapy is that individual cancers vary in their sensitivity to oncolytic viruses, even when these cancers arise from the same tissue type. Variability in response may arise due to differences in the initial genetic lesions leading to cancer development. Alternatively, susceptibility to viral oncolysis may change during cancer progression. These hypotheses were tested using cells from a transgenic mouse model of prostate cancer infected with vesicular stomatitis virus (VSV). Primary cultures from murine cancers derived from prostate-specific Pten deletion contained a mixture of cells that were susceptible and resistant to VSV. Castration-resistant cancers contained a higher percentage of susceptible cells than cancers from non-castrated mice. These results indicate both susceptible and resistant cells can evolve within the same tumor. The role of Pten deletion was further investigated using clonal populations of murine prostate epithelial (MPE) progenitor cells and tumor-derived Pten(-/-) cells. Deletion of Pten in MPE progenitor cells using a lentivirus vector resulted in cells that responded poorly to interferon and were susceptible to VSV infection. In contrast, tumor-derived Pten(-/-) cells expressed higher levels of the antiviral transcription factor STAT1, activated STAT1 in response to VSV, and were resistant to VSV infection. These results suggest that early in tumor development following Pten deletion, cells are primarily sensitive to VSV, but subsequent evolution in tumors leads to development of cells that are resistant to VSV infection. Further evolution in castration-resistant tumors leads to tumors in which cells are primarily sensitive to VSV.
IMPORTANCE
There has been a great deal of progress in the development of replication-competent viruses that kill cancer cells (oncolytic viruses). However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses, even when these cancers arise from the same tissue type. The experiments presented here were to determine whether both sensitive and resistant cells are present in prostate cancers originating from a single genetic lesion in transgenic mice, prostate-specific deletion of the gene for the tumor suppressor Pten. The results indicate that murine prostate cancers are composed of both cells that are sensitive and cells that are resistant to oncolytic vesicular stomatitis virus (VSV). Furthermore, androgen deprivation led to castration-resistant prostate cancers that were composed primarily of cells that were sensitive to VSV. These results are encouraging for the use of VSV for the treatment of prostate cancers that are resistant to androgen deprivation therapy.
Details
- Title: Subtitle
- Changes in Susceptibility to Oncolytic Vesicular Stomatitis Virus during Progression of Prostate Cancer
- Creators
- Nanmeng Yu - Wake Forest UniversityShelby Puckett - Wake Forest UniversityPeter A. Antinozzi - Wake Forest UniversityScott D. Cramer - University of Colorado Anschutz Medical CampusDouglas S. Lyles - Wake Forest University
- Resource Type
- Journal article
- Publication Details
- Journal of virology, Vol.89(10), pp.5250-5263
- Publisher
- Amer Soc Microbiology
- DOI
- 10.1128/JVI.00257-15
- PMID
- 25741004
- PMCID
- PMC4442527
- ISSN
- 0022-538X
- eISSN
- 1098-5514
- Number of pages
- 14
- Grant note
- R01 AI032983; R01 AI105012 / National Institutes of Health (NIH) grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30 CA012197 / NIH grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30CA012197 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01AI105012 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 05/01/2015
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984694748002771
Metrics
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