E1A-engineered human umbilical cord mesenchymal stem cells as carriers and amplifiers for adenovirus suppress hepatocarcinoma in mice

// Zhenzhen Li 1, 2 , Zhou Ye 3 , Xiaolong Zhang 1 , Qing Zhang 1 , Dongmei Fan 1 , Yanjun Zhang 1 , Hongbo R. Luo 4 , Xiangfei Yuan 1, 5 , Zongfang Li 2 , Dongsheng Xiong 1 1 State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China 2 National-Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, China 3 Central Hospital of Karamay, Karamay, Xinjiang 834000, China 4 Department of Pathology, Joint Program in Transfusion Medicine, Harvard Medical School, and Department of Laboratory Medicine, Children’s Hospital Boston, Boston, MA 02115, USA 5 Tianjin Institute of Integrative Medicine for Acute Abdominal Diseases, Nankai Hospital, Tianjin 300100, China Correspondence to: Dongsheng Xiong, email: dsxiong@ihcams.ac.cn Zongfang Li, email: lzf2568@mail.xjtu.edu.cn Xiangfei Yuan, email: yuanxiangfei100@163.com Keywords: HUMSC, adenovirus delivery, gene therapy, hepatocellular carcinoma Received: September 28, 2015     Accepted: May 17, 2016     Published: June 17, 2016 ABSTRACT 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.