E1A-engineered human umbilical cord mesenchymal stem cells as carriers and amplifiers for adenovirus suppress hepatocarcinoma in mice
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Zhenzhen Li1,2, Zhou Ye3, Xiaolong Zhang1, Qing Zhang1, Dongmei Fan1, Yanjun Zhang1, Hongbo R. Luo4, Xiangfei Yuan1,5, Zongfang Li2, Dongsheng Xiong1
1State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
2National-Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, China
3Central Hospital of Karamay, Karamay, Xinjiang 834000, China
4Department of Pathology, Joint Program in Transfusion Medicine, Harvard Medical School, and Department of Laboratory Medicine, Children’s Hospital Boston, Boston, MA 02115, USA
5Tianjin Institute of Integrative Medicine for Acute Abdominal Diseases, Nankai Hospital, Tianjin 300100, China
Dongsheng Xiong, email: [email protected]
Zongfang Li, email: [email protected]
Xiangfei Yuan, email: [email protected]
Keywords: HUMSC, adenovirus delivery, gene therapy, hepatocellular carcinoma
Received: September 28, 2015 Accepted: May 17, 2016 Published: June 17, 2016
Gene therapy is an attractive approach for hepatocellular carcinoma (HCC) patients. Nevertheless, efficient transgene delivery remains a challenge. In this study, we explored a new targeted system based on human umbilical cord-derived mesenchymal stem cells (HUMSCs), which were engineered to deliver adenovirus to tumor sites, and to replicate and assemble into new adenovirus against HCC. Our results showed that HUMSCs infected by Ad-hTERTp-IL24 followed by LentiR.E1A infection could specifically migrate to HepG2 tumor cells and support adenoviral replication in vitro and in vivo 36 h after LentiR.E1A infection. Ad-hTERTp-IL24 specifically inhibited HepG2 cells growth, and this inhibitory effect was enhanced by low doses of 5-fluorouracil (5-Fu), because the expression levels of coxsackie adenovirus receptor (CAR) and integrin ανβ3 on tumor cells were significantly increased, causing higher viral uptake. Compared with the no treatment groups, Ad-hTERTp-IL24 and LentiR.E1A co-loaded HUMSCs exhibited significant anti-tumor activity in vivo, particularly in combination with low doses of 5-Fu. In summary, this study provides a promising targeted gene therapeutic strategy dependent on the tumor tropism of HUMSCs, to improve the outcome of virotherapy for tumor patients especially those with metastatic diseases.
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