Tumor-Specific Delivery of Histidine-Rich Glycoprotein Suppresses Tumor Growth and Metastasis by Anti-angiogenesis and Vessel Normalization
Xiawei Cheng, Xiaoxin Zhang, Wei Cheng, Jianxiang Chen, Cailie Ma, Bingya Yang and Zi-Chun Hua
Affiliation: Department of Biochemistry, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu Province, P.R. China.
Keywords: VNP20009, histidine-proline-rich glycoprotein, anti-angiogenesis, vessel normalization, tumor growth, tumor metastasis.
Histidine-proline-rich glycoprotein (HPRG) is a plasma protein of vertebrates, which has potent antiangiogenic
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 expressionof
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-1α-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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