title: VEGI-armed oncolytic adenovirus inhibits tumor neovascularization and directly induces mitochondria-mediated cancer cell apoptosis.
abstract: Vascular endothelial cell growth inhibitor (VEGI) is a member of the tumor necrosis factor superfamily and plays an important role in vascular homeostasis. In this study, to investigate the anticancer therapeutic potential of this gene, a secreted isoform of VEGI (VEGI-251) was inserted into a selectively replicating adenovirus with E1B 55 kDa gene deletion (ZD55) to construct ZD55-VEGI-251. We report here that secreted VEGI-251 produced from ZD55-VEGI-251-infected cancer cells potently inhibits endothelial cell proliferation, tube formation in vitro and angiogenesis of chick chorioallantoic membrane in vivo. Additionally, ZD55-VEGI-251 infection leads to a much more severe cytopathic effect than control viruses on several human cancer cell lines, including cervical cancer cell line HeLa, hepatoma cell line SMMC-7721 and colorectal cancer cell line SW620. Further study reveals that the increased cytotoxicity is a result of VEGI-251 autocrine-dependent, mitochondria-mediated apoptosis accompanied by caspase-9 activation, enhanced caspase-3 activation and PARP cleavage. Moreover, ZD55-VEGI-251-treatment of athymic nude mice bearing human cervical and colorectal tumor xenografts markedly suppressed tumor growth. Our findings indicate that the combined effect of antiangiogenesis and apoptosis-induction activity makes the VEGI-251-armed oncolytic adenovirus a promising therapeutic agent for cancer.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Xiao
authors.forename: Jun Kai
authors.initials: JK
authors.lastname: Fan
authors.forename: Hong Ling
authors.initials: HL
authors.lastname: Huang
authors.forename: Jin Fa
authors.initials: JF
authors.lastname: Gu
authors.forename: Lu-Yuan
authors.initials: LY
authors.lastname: Li
authors.forename: Xin Yuan
authors.initials: XY
authors.lastname: Liu
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics* / Q000378:metabolism
chemical_list: D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D053148:Caspase 3; D053453:Caspase 9