title: Suppression of orthotopically implanted hepatocarcinoma in mice by umbilical cord-derived mesenchymal stem cells with sTRAIL gene expression driven by AFP promoter.
abstract: Mesenchymal stem cells (MSCs) are promising vehicles for delivering therapeutic agents in tumor therapy. Human umbilical cord-derived mesenchymal stem cells (HUMSCs) resemble bone marrow-derived MSCs with respect to hepatic differentiation potential in injured livers in animals, while their hepatic differentiation under the hepatocarcinoma microenvironment is unclear. In this study, HUMSCs were isolated and transduced by lentiviral vectors coding the soluble human tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) gene driven by alpha-fetoprotein (AFP) promoter to investigate the therapeutic effects of these HUMSC against orthotopically implanted hepatocarcinoma in mice. We showed that HUMSCs can be transduced by lentivirus efficiently. HUMSCs developed cuboidal morphology, and expressed AFP and albumin in a two-step protocol. HUMSCs were capable of migrating to hepatocarcinoma in vitro as well as in vivo. In the orthotopical hepatocarcinoma microenvironment, the AFP promoter was activated during the early hepatic differentiation of HUMSCs. After intravenous injected, MSC.AFPILZ-sTRAIL expressed sTRAIL exclusively at the tumor site, and exhibited significant antitumor activity. This effect was stronger when in combination with 5-FU. The treatment was tolerated well in mice. Collectively, our results provide a potential strategy for targeted tumor therapy relying on the use of the tumor tropism and specific differentiation of HUMSCs as vehicles.
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, Number 188, Nanjing Road, Heping District, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, China; National Clinical Research Center of Cancer, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
authors.forename: Cihui
authors.initials: C
authors.lastname: Yan
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, Number 188, Nanjing Road, Heping District, Tianjin, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
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, Number 188, Nanjing Road, Heping District, Tianjin, 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, Number 188, Nanjing Road, Heping District, Tianjin, China.
authors.forename: Shuangjing
authors.initials: S
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, Number 188, Nanjing Road, Heping District, Tianjin, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
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, Number 188, Nanjing Road, Heping District, Tianjin, 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, Number 188, Nanjing Road, Heping District, Tianjin, China.
authors.forename: Yanjun
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, Number 188, Nanjing Road, Heping District, Tianjin, China.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
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, Number 188, Nanjing Road, Heping District, Tianjin, China. Electronic address: dsxiong@hotmail.com.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xiong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000628:therapy*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D016086:Lentivirus / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012995:Solubility; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D014470:Umbilical Cord / Q000166:cytology*; D000509:alpha-Fetoproteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D053221:TNF-Related Apoptosis-Inducing Ligand; D000509:alpha-Fetoproteins; D005472:Fluorouracil
keywords: Alpha-fetoprotein; Hepatocarcinoma; Mesenchymal stem cell; TRAIL; Targeted therapy