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Cancer Lett. 2016 Oct 10;381(1):85-95. doi: 10.1016/j.canlet.2016.07.019. Epub 2016 Jul 20.

Mesenchymal stem cells deliver and release conditionally replicative adenovirus depending on hepatic differentiation to eliminate hepatocellular carcinoma cells specifically.

Author information

1
State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Nankai Hospital, Tianjin Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin 300100, China.
2
State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
3
National-Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China.
4
Central Hospital of Karamay, Karamay, Xinjiang 834000, China.
5
State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China. Electronic address: junjunfriend@126.com.
6
Central Hospital of Karamay, Karamay, Xinjiang 834000, China. Electronic address: yezhou126@126.com.
7
State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China. Electronic address: dsxiong@ihcams.ac.cn.

Abstract

Currently, it is a key challenge to remove the postsurgical residuals and metastasis of hepatocellular carcinoma (HCC). Oncolytic adenoviral virotherapy is an attractive treatment modality for cancer; however, the difficulty remains regarding its intravenous administration. The aim of this study was to develop a targeted therapeutic system which has great potential to overcome the postsurgical residuals and metastasis of HCC. In this system, we developed a conditionally replicative adenovirus (CRAd) loaded on human umbilical cord-derived mesenchymal stem cells (HUMSCs), in which the CRAd contained an adenovirus E1A gene dual regulated by α-fetoprotein promoter and microRNA-122 target sequence. When HUMSCs homed to the tumor sites and differentiated into hepatocyte-like cells within tumor microenvironment, the CRAds were packaged and released strictly to the local tumor. Subsequently, the CRAd lysed tumor cells selectively with the post-infection regulation. The study showed the specific oncolytic effect of the CRAd to HCC cells and the production of the CRAd by differentiated HUMSCs in vitro. Furthermore, we proved the hepatocyte-like transformation of HUMSC in the microenvironment of orthotopic or heterotopic hepatoma. Finally, this therapeutic system exhibited dramatic tumor inhibition on both orthotopic and subcutaneous hepatic xenograft tumor model mice with less toxicity on normal organs. The study results have demonstrated that this targeted therapeutic strategy is a promising method to resolve the problem of postsurgical residuals and metastasis of HCC.

KEYWORDS:

AFP promoter; CRAd; HUMSC; Hepatic differentiation; Hepatocellular carcinoma; microRNA-122

PMID:
27450327
DOI:
10.1016/j.canlet.2016.07.019
[Indexed for MEDLINE]

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