VEGI-armed oncolytic adenovirus inhibits tumor neovascularization and directly induces mitochondria-mediated cancer cell apoptosis  

作　　者：Tian Xiao Jun Kai Fan Hong Ling Huang Jin Fa Gu Lu-Yuan Li Xin Yuan Liu 

机构地区：[1]Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China [2]Department of Pathology, University of Pittsburgh Medical Center, Pittsurgh, PA 15213, USA [3]Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou 310018, China

出　　处：《Cell Research》2010年第3期367-378,共12页细胞研究（英文版）

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）; 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.

摘　　要：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.

关 键 词：VEGI-251 oncolytic adenovirus ANTIANGIOGENESIS APOPTOSIS tumor therapy 

分 类 号：Q463[生物学—生理学] Q78