title: Mesenchymal stem cells deliver and release conditionally replicative adenovirus depending on hepatic differentiation to eliminate hepatocellular carcinoma cells specifically.
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.
authors.affiliation: 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.
authors.forename: Xiangfei
authors.initials: X
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: National-Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Shiqi
authors.initials: S
authors.lastname: Bao
authors.affiliation: 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.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Fan
authors.affiliation: 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.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Ru
authors.affiliation: 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.
authors.forename: Shuxu
authors.initials: S
authors.lastname: Dong
authors.affiliation: Central Hospital of Karamay, Karamay, Xinjiang 834000, China.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Central Hospital of Karamay, Karamay, Xinjiang 834000, China. Electronic address: yezhou126@126.com.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Ye
authors.affiliation: 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.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xiong
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D002454:Cell Differentiation; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism / Q000637:transplantation* / Q000821:virology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000821:virology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D050130:Oncolytic Virotherapy / Q000379:methods*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D059016:Tumor Microenvironment; D014779:Virus Replication; D059631:Wharton Jelly / Q000166:cytology*; D023041:Xenograft Model Antitumor Assays; D000509:alpha-Fetoproteins / Q000235:genetics
chemical_list: C097353:AFP protein, human; D017500:Adenovirus E1A Proteins; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D000509:alpha-Fetoproteins
keywords: AFP promoter; CRAd; HUMSC; Hepatic differentiation; Hepatocellular carcinoma; microRNA-122