Tumor-Specific Delivery of Histidine-Rich Glycoprotein Suppresses Tumor Growth and Metastasis by Anti-angiogenesis and Vessel Normalization

ISSN: 1566-5232 (Print)
ISSN: 1875-5631 (Online)


Volume 14, 6 Issues, 2014


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Editor-in-Chief:
Ignacio Anegon
Director INSERM UMR 1064-Center for Research in Transplantation and Immunology
CHU de Nantes. 30, boulevard
Nantes
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Tumor-Specific Delivery of Histidine-Rich Glycoprotein Suppresses Tumor Growth and Metastasis by Anti-angiogenesis and Vessel Normalization

Author(s): 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.

Abstract

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.

Keywords: VNP20009, histidine-proline-rich glycoprotein, anti-angiogenesis, vessel normalization, tumor growth, tumor metastasis.

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Article Details

Volume: 14
Issue Number: 2
First Page: 75
Last Page: 85
Page Count: 11
DOI: 10.2174/1566523214666140305223912
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