title: Vascular endothelial growth factor A promotes vaccinia virus entry into host cells via activation of the Akt pathway.
abstract: Vaccinia virus (VV) is an enveloped DNA virus from the poxvirus family and has played a crucial role in the eradication of smallpox. It continues to be used in immunotherapy for the prevention of infectious diseases and treatment of cancer. However, the mechanisms of poxvirus entry, the host factors that affect viral virulence, and the reasons for its natural tropism for tumor cells are incompletely understood. By studying the effect of hypoxia on VV infection, we found that vascular endothelial growth factor A (VEGF-A) augments oncolytic VV cytotoxicity. VEGF derived from tumor cells acts to increase VV internalization, resulting in increased replication and cytotoxicity in an AKT-dependent manner in both tumor cells and normal respiratory epithelial cells. Overexpression of VEGF also enhances VV infection within tumor tissue in vivo after systemic delivery. These results highlight the importance of VEGF expression in VV infection and have potential implications for the design of new strategies to prevent poxvirus infection and the development of future generations of oncolytic VV in combination with conventional or biological therapies.
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Crispin T
authors.initials: CT
authors.lastname: Hiley
authors.forename: Louisa S
authors.initials: LS
authors.lastname: Chard
authors.forename: Rathi
authors.initials: R
authors.lastname: Gangeswaran
authors.forename: James R
authors.initials: JR
authors.lastname: Tysome
authors.forename: Arnaud
authors.initials: A
authors.lastname: Briat
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Lemoine
authors.forename: Yaohe
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000821:virology; D017930:Genes, Reporter; D006801:Humans; D000860:Hypoxia; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D020545:Respiratory Mucosa / Q000821:virology; D014615:Vaccinia / Q000378:metabolism / Q000821:virology; D014616:Vaccinia virus / Q000235:genetics / Q000472:pathogenicity*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D056189:Viral Tropism; D053586:Virus Internalization; D014779:Virus Replication / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt