GP73-regulated oncolytic adenoviruses possess potent killing effect on human liver cancer stem-like cells
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Xinmin Zhang1,*, Shulin Meng1,*, Rong Zhang1, Buyun Ma1,6, Tao Liu2, Yu Yang3, Wenjie Xie1, Xianglei Liu1, Fang Huang4, Tao Liu5, Xiumei Zhou1, Xinyuan Liu1,2, Yigang Wang1
1Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, PR China
2Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China
3Central China Normal University, Wuhan 430079, China
4School of Public Health, Zhejiang University, Hangzhou 310058, China
5Department of Otolaryngology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
6Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam 3015, Netherlands
*These authors contributed equally to this work
Yigang Wang, e-mail: [email protected]
Keywords: GP73, oncolytic adenovirus, liver cancer stem-like cells
Received: December 03, 2015 Accepted: March 28, 2016 Published: April 18, 2016
Cancer stem cells (CSCs), also known as tumor-initiating cells, are highly metastatic, chemo-resistant and tumorigenic, and are critical for cancer development, maintenance and recurrence. Oncolytic adenovirus could targetedly kill CSCs and has been acted as a promising anticancer agent. Currently, a novel GP73-regulated oncolytic adenovirus GD55 was constructed to specifically treat liver cancer and exhibited obvious cytotoxicity effect. However, there remains to be confirmed that whether GD55 could effectively eliminate liver CSCs. We first utilized the suspension culture to enrich the liver CSCs-like cells, which acquires the properties of liver CSCs in self-renewal, differentiation, quiescence, chemo-resistance and tumorigenicity. The results indicated that GD55 elicited more significant cytotoxicity and stronger oncolytic effect in liver CSC-like cells compared to common oncolytic virus ZD55. Additionally, GD55 possessed the greater efficacy in suppressing the growth of implanted tumors derived from liver CSC-like cells than ZD55. Furthermore, GD55 induced remarkable apoptosis of liver CSC-like cells in vitro and in vivo, and inhibited the propogation of cells and angiogenesis in xenograft tumor tissues. Thus, GD55 may virtually represent an attractive therapeutic agent for targeting liver CSCs to achieve better clinical outcomes for HCC patients.
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