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 po...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 angiogen- esis 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.展开更多
基金We thank Lanying Sun, Yang Xiao, Yuelei Chen, Hua Zhou and Cell Analysis Center （Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences） for professional technical assistance. This work was supported in part by grants from Hi-Tech Research Development Program of China （863 Program, No. 2007AA021006） the Key Project of the Chinese Academy of Sciences （No. KSCX2-YW- R-09）+1 种基金 the 973 Project （No. 2004CB518804） Grant 30623003 from National Nature Science Foundation of China and Grant 06DZ22032 from Science and Technology Commission of Shang- hai Municipality.
文摘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 angiogen- esis 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.
