期刊
CURRENT GENE THERAPY
卷 14, 期 2, 页码 75-85出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1566523214666140305223912
关键词
VNP20009; histidine-proline-rich glycoprotein; anti-angiogenesis; vessel normalization; tumor growth; tumor metastasis
资金
- Ministry of Science and Technology [2012CB967004, 2014CB744501, 2012AA020809, 2012ZX09401012]
- Doctoral Station Science Foundation from the Chinese Ministry of Education [20130091130003]
- Chinese National Natural Sciences Foundation [81121062, 31200572]
- Jiangsu Provincial Nature Science Foundation [BZ2012050, BE2013630]
- Bureau of Science and Technology of Changzhou [CZ20130011, CE20135013, CZ20120004, CM20122003, WF201207]
Histidine-proline-rich glycoprotein (HPRG) is a plasma protein of vertebrates, which has potent anti-angiogenic and tumor vessel normalization properties. Attenuated Salmonella Typhimurium strain VNP20009 preferentially accumulates and replicates in hypoxic tumor regions. In this study, we engineered VNP20009 to express HPRG under the control of a hypoxia-induced NirB promoter and evaluated the efficacy of the VNP20009-mediated targeted expression of HPRG (VNP-pNHPRG) on tumor growth in primary and metastatic tumor models. When VNP-pNHPRG was administered to melanoma tumor mice by intraperitoneal injection, the NirB promoter controlled HPRG expression in tumor, which inhibited tumor vessel density and areas as well as regulated vascular normalization. VNP-pNHPRG significantly delayed tumor growth and enhanced survival time in primary B16F10 mice model and markedly suppressed lung metastatic tumor growth and prolonged survival time in B16F10 metastatic tumor models. Furthermore, VNP-pNHPRG down-regulated the HIF-1 alpha-VEGF/Ang-2 signal pathway by altering the hypoxic tumor microenvironment. These results showed that VNP20009-mediated targeted expression of HPRG provides a novel cancer gene therapeutic approach for the treatment of primary and metastatic cancer.
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