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Published in: Journal of Gastroenterology 7/2013

01-07-2013 | Original Article—Alimentary Tract

Chimeric 5/35 adenovirus-mediated Dickkopf-1 overexpression suppressed tumorigenicity of CD44+ gastric cancer cells via attenuating Wnt signaling

Authors: Bin Wang, Jia Liu, Lei Na Ma, Hua Liang Xiao, Ya Zhou Wang, Yan Li, Zhe Wang, Linli Fan, Chunhui Lan, Min Yang, Lu Hu, Yanlin Wei, Xiu Wu Bian, Dongfeng Chen, Jun Wang

Published in: Journal of Gastroenterology | Issue 7/2013

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Abstract

Background

Gastric cancer stem cells (CSCs), which require activation of Wnt signaling to maintain their self-renewal and tumorigenicity, are proposed to be critical targets for effective therapy of gastric carcinomas. Gene therapies that are delivered by adenovirus of serotype 5 (Ad5) or chimeric 5/35(Ad5/35) adenovirus have shown promise for treating various cancers. Here we aimed to develop a gene therapy strategy that targeted gastric CSCs (CD44+ cells).

Methods

CD44+ cells were isolated by fluorescence activated cell sorting from both primary gastric cancer cells and cell lines. Expression of adenovirus receptors was examined in CD44+ and CD44 cells. A potent Wnt antagonist Dickkopf-1 (DKK1) was delivered into CD44+ cells using Ad5/35 (Ad5/35-DKK1). The therapeutic outcomes were evaluated.

Results

Expression of Coxsakievirus adenovirus receptor for Ad5 was significantly reduced, while abundance of CD46, the receptor for Ad5/35, was slightly higher in CD44+ cells. Accordingly, CD44+ cells were sensitive to Ad5/35 infection, but not to Ad5. Ad5/35-DKK1 introduced DKK1 into CD44+ cells and deactivated endogenous Wnt/β-catenin signaling efficiently. Overexpression of DKK1 inhibited survival, anchorage-independent colony formation, and invasion of CD44+ cells, which were restored by a GSK-3 specific inhibitor BIO-acetoxime. More importantly, introduction of DKK1 abrogated the tumorigenicity of CD44+ cells in vivo. However, Ad5/35-DKK1 only showed minimal cytotoxicity to normal tissue-derived cells, L-02 and GES-1.

Conclusions

We developed, for the first time, a novel Ad5/35-DKK1-based approach to abrogate Wnt signaling in CSCs and demonstrated that gastric CSC-targeting gene therapy was effective in preclinical experiments.
Appendix
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Metadata
Title
Chimeric 5/35 adenovirus-mediated Dickkopf-1 overexpression suppressed tumorigenicity of CD44+ gastric cancer cells via attenuating Wnt signaling
Authors
Bin Wang
Jia Liu
Lei Na Ma
Hua Liang Xiao
Ya Zhou Wang
Yan Li
Zhe Wang
Linli Fan
Chunhui Lan
Min Yang
Lu Hu
Yanlin Wei
Xiu Wu Bian
Dongfeng Chen
Jun Wang
Publication date
01-07-2013
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 7/2013
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-012-0711-z

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