title: Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts.
abstract: Mesenchymal stem cells (MSCs) have been recognized as promising delivery vehicles for gene therapy of tumors. Gastric cancer is the third leading cause of worldwide cancer mortality, and novel treatment modalities are urgently needed. NK4 is an antagonist of hepatocyte growth factor receptors (Met) which are often aberrantly activated in gastric cancer and thus represent a useful candidate for targeted therapies. This study investigated MSC-delivered NK4 gene therapy in nude mice bearing gastric cancer xenografts. MSCs were transduced with lentiviral vectors carrying NK4 complementary DNA or enhanced green fluorescent protein (GFP). Such transduction did not change the phenotype of MSCs. Gastric cancer xenografts were established in BALB/C nude mice, and the mice were treated with phosphate-buffered saline (PBS), MSCs-GFP, Lenti-NK4, or MSCs-NK4. The tropism of MSCs toward gastric cancer cells was determined by an in vitro migration assay using MKN45 cells, GES-1 cells and human fibroblasts and their presence in tumor xenografts. Tumor growth, tumor cell apoptosis and intratumoral microvessel density of tumor tissue were measured in nude mice bearing gastric cancer xenografts treated with PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4 via tail vein injection. The results showed that MSCs migrated preferably to gastric cancer cells in vitro. Systemic MSCs-NK4 injection significantly suppressed the growth of gastric cancer xenografts. MSCs-NK4 migrated and accumulated in tumor tissues after systemic injection. The microvessel density of tumor xenografts was decreased, and tumor cellular apoptosis was significantly induced in the mice treated with MSCs-NK4 compared to control mice. These findings demonstrate that MSC-based NK4 gene therapy can obviously inhibit the growth of gastric cancer xenografts, and MSCs are a better vehicle for NK4 gene therapy than lentiviral vectors. Further studies are warranted to explore the efficacy and safety of the MSC-based NK4 gene therapy in animals and cancer patients.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi, People's Republic of China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Jiangxi, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People's Republic of China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Zeng
authors.affiliation: Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People's Republic of China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People's Republic of China.
authors.forename: Shi-Wen
authors.initials: SW
authors.lastname: Luo
authors.affiliation: Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People's Republic of China.
authors.forename: Kun-He
authors.initials: KH
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi, People's Republic of China ; Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People's Republic of China.
authors.forename: Nong-Hua
authors.initials: NH
authors.lastname: Lu
mesh_terms: D000818:Animals; D002460:Cell Line; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013274:Stomach Neoplasms / Q000235:genetics* / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017228:Hepatocyte Growth Factor
keywords: angiogenesis; apoptosis; gastric cancer; gene therapy; hepatocyte growth factor; lentivirus; tumor xenograft