title: VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection.
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.
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Rozanne
authors.initials: R
authors.lastname: Arulanandam
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Cory
authors.initials: C
authors.lastname: Batenchuk
authors.affiliation: Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Angarita
authors.affiliation: Toronto General Research Institute (TGRI), University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Ottolino-Perry
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Cousineau
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Amelia
authors.initials: A
authors.lastname: Mottashed
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Emma
authors.initials: E
authors.lastname: Burgess
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Falls
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Naomi
authors.initials: N
authors.lastname: De Silva
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Jovian
authors.initials: J
authors.lastname: Tsang
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Howe
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Bourgeois-Daigneault
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: David P
authors.initials: DP
authors.lastname: Conrad
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Manijeh
authors.initials: M
authors.lastname: Daneshmand
authors.affiliation: SillaJen Biotherapeutics, San Francisco, CA 94111-3380, USA.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Breitbach
authors.affiliation: SillaJen Biotherapeutics, San Francisco, CA 94111-3380, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Kirn
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
authors.forename: Leda
authors.initials: L
authors.lastname: Raptis
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Subash
authors.initials: S
authors.lastname: Sad
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Harold
authors.initials: H
authors.lastname: Atkins
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Huh
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Jean-Simon
authors.initials: JS
authors.lastname: Diallo
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lichty
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Carolina S
authors.initials: CS
authors.lastname: Ilkow
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Le Boeuf
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Addison
authors.affiliation: 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.
authors.forename: J Andrea
authors.initials: JA
authors.lastname: McCart
authors.affiliation: Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Electronic address: jbell@ohri.ca.
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D006801:Humans; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000098:blood supply / Q000628:therapy / Q000821:virology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000821:virology; D050504:Oncolytic Viruses / Q000502:physiology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D034622:RNA Interference; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014616:Vaccinia virus / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: C513258:Prdm1 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; D040262:Receptors, Vascular Endothelial Growth Factor