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Cancer Cell. 2015 Aug 10;28(2):210-24. doi: 10.1016/j.ccell.2015.06.009. Epub 2015 Jul 23.

VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection.

Author information

1
Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
2
Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 2M9, Canada.
3
SillaJen Biotherapeutics, San Francisco, CA 94111-3380, USA.
4
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
5
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
6
McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada.
7
Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 2M9, Canada; Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada.
8
Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Electronic address: jbell@ohri.ca.

Abstract

Oncolytic viruses designed to attack malignant cells can in addition infect and destroy tumor vascular endothelial cells. We show here that this expanded tropism of oncolytic vaccinia virus to the endothelial compartment is a consequence of VEGF-mediated suppression of the intrinsic antiviral response. VEGF/VEGFR2 signaling through Erk1/2 and Stat3 leads to upregulation, nuclear localization, and activation of the transcription repressor PRD1-BF1/Blimp1. PRD1-BF1 does not contribute to the mitogenic effects of VEGF, but directly represses genes involved in type I interferon (IFN)-mediated antiviral signaling. In vivo suppression of VEGF signaling diminishes PRD1-BF1/Blimp1 expression in tumor vasculature and inhibits intravenously administered oncolytic vaccinia delivery to and consequent spread within the tumor.

PMID:
26212250
DOI:
10.1016/j.ccell.2015.06.009
[Indexed for MEDLINE]
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