Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts
Yin Zhu,1,* Ming Cheng,2,* Zhen Yang,3 Chun-Yan Zeng,3 Jiang Chen,3 Yong Xie,3 Shi-Wen Luo,3 Kun-He Zhang,3 Shu-Feng Zhou,4 Nong-Hua Lu1,31Department of Gastroenterology, 2Department of Orthopedics, 3Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, Peopl...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2014-12-01
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| Series: | Drug Design, Development and Therapy |
| Online Access: | http://www.dovepress.com/mesenchymal-stem-cell-based-nk4-gene-therapy-in-nude-mice-bearing-gast-peer-reviewed-article-DDDT |
| _version_ | 1819202309368840192 |
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| author | Zhu Y Cheng M Yang Z Zeng CY Chen J Xie Y Luo SW Zhang KH Zhou SF Lu NH |
| author_facet | Zhu Y Cheng M Yang Z Zeng CY Chen J Xie Y Luo SW Zhang KH Zhou SF Lu NH |
| author_sort | Zhu Y |
| collection | DOAJ |
| description | Yin Zhu,1,* Ming Cheng,2,* Zhen Yang,3 Chun-Yan Zeng,3 Jiang Chen,3 Yong Xie,3 Shi-Wen Luo,3 Kun-He Zhang,3 Shu-Feng Zhou,4 Nong-Hua Lu1,31Department of Gastroenterology, 2Department of Orthopedics, 3Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China; 4Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA*These authors contributed equally to this workAbstract: 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.Keywords: gastric cancer, gene therapy, tumor xenograft, hepatocyte growth factor, lentivirus, angiogenesis, apoptosis |
| first_indexed | 2024-12-23T04:01:58Z |
| format | Article |
| id | doaj.art-3e6b50726aa44ef69bd2ae93168c460c |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-12-23T04:01:58Z |
| publishDate | 2014-12-01 |
| publisher | Dove Medical Press |
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| series | Drug Design, Development and Therapy |
| spelling | doaj.art-3e6b50726aa44ef69bd2ae93168c460c2022-12-21T18:00:43ZengDove Medical PressDrug Design, Development and Therapy1177-88812014-12-012014default2449246219488Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenograftsZhu YCheng MYang ZZeng CYChen JXie YLuo SWZhang KHZhou SFLu NHYin Zhu,1,* Ming Cheng,2,* Zhen Yang,3 Chun-Yan Zeng,3 Jiang Chen,3 Yong Xie,3 Shi-Wen Luo,3 Kun-He Zhang,3 Shu-Feng Zhou,4 Nong-Hua Lu1,31Department of Gastroenterology, 2Department of Orthopedics, 3Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China; 4Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA*These authors contributed equally to this workAbstract: 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.Keywords: gastric cancer, gene therapy, tumor xenograft, hepatocyte growth factor, lentivirus, angiogenesis, apoptosishttp://www.dovepress.com/mesenchymal-stem-cell-based-nk4-gene-therapy-in-nude-mice-bearing-gast-peer-reviewed-article-DDDT |
| spellingShingle | Zhu Y Cheng M Yang Z Zeng CY Chen J Xie Y Luo SW Zhang KH Zhou SF Lu NH Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts Drug Design, Development and Therapy |
| title | Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts |
| title_full | Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts |
| title_fullStr | Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts |
| title_full_unstemmed | Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts |
| title_short | Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts |
| title_sort | mesenchymal stem cell based nk4 gene therapy in nude mice bearing gastric cancer xenografts |
| url | http://www.dovepress.com/mesenchymal-stem-cell-based-nk4-gene-therapy-in-nude-mice-bearing-gast-peer-reviewed-article-DDDT |
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