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Fiber-modified hexon-chimeric oncolytic adenovirus targeting cancer associated fibroblasts inhibits tumor growth in gastric carcinoma

OBJECTIVE: To evaluate the effects of fiber-modified hexon-chimeric recombinant oncolytic adenovirus targeting cancer associated fibroblasts (CAFs) on the gastric CAFs and the transplantation tumor mice model of gastric carcinoma (GC). RESULTS: Compared with BJ cells and GPFs, the reproduction and i...

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Autores principales: Pang, Tao, Wang, Xinghua, Gao, Jun, Chen, Wei, Shen, Xiao Jun, Nie, Ming Ming, Luo, Tianhang, Yin, Kai, Fang, Guoen, Wang, Kai Xuan, Xue, Xu Chao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652720/
https://www.ncbi.nlm.nih.gov/pubmed/29100326
http://dx.doi.org/10.18632/oncotarget.20273
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author Pang, Tao
Wang, Xinghua
Gao, Jun
Chen, Wei
Shen, Xiao Jun
Nie, Ming Ming
Luo, Tianhang
Yin, Kai
Fang, Guoen
Wang, Kai Xuan
Xue, Xu Chao
author_facet Pang, Tao
Wang, Xinghua
Gao, Jun
Chen, Wei
Shen, Xiao Jun
Nie, Ming Ming
Luo, Tianhang
Yin, Kai
Fang, Guoen
Wang, Kai Xuan
Xue, Xu Chao
author_sort Pang, Tao
collection PubMed
description OBJECTIVE: To evaluate the effects of fiber-modified hexon-chimeric recombinant oncolytic adenovirus targeting cancer associated fibroblasts (CAFs) on the gastric CAFs and the transplantation tumor mice model of gastric carcinoma (GC). RESULTS: Compared with BJ cells and GPFs, the reproduction and infectivity of P9, P9-4C or GP adenoviruses were markedly higher in gastric CAFs. In addition, P9, P9-4C or GP had a significantly relatively more killing effect on gastric CAFs compared with GPFs, and have less oncolytic effect in BJ cells. Furthermore, in transplantation tumor mice model of GC we found significantly higher hexon protein expression in tumor tissues, more decreasing tumor growth and increasing inhibitory rates after treatment of P9, P9-4C or GP adenoviruses compared with Ad adenovirus. MATERIALS AND METHODS: Based on the construction of the recombinant oncolytic adenoviruses pRCAdHVR48-SDF1p-Ad/EGFP (Ad, as control) with the E1A gene transcription regulated by stromal-derived factor 1 (SDF1) promoter and the hexon replaced by hexon-chimeric (H5HVR48) gene, three fiber-modified hexon-chimeric oncolytic adenovirus through the modification fiber protein by insertion of different short peptides specifically binding to fibroblast activation protein (FAP), including pRCAdHVR48-SDF1p-FAP-P9/EGFP (P9), pRCAdHVR48-SDF1p-FAP-P9-4C/EGFP (P9-4C), pRCAdHVR48-SDF1p-FAP-GP/EGFP (GP), and their corresponding replication-defective adenovirus in parallel were reconstructed. Then the reproduction, infectivity and killing ability of the four above recombinant adenoviruses were evaluated in gastric CAFs compared with gastric para-mucosa fibroblasts (GPFs) and neonatal human foreskin fibroblasts (BJ). Furthermore, transplantation tumor mice model of GC was established, and then treated by the four above recombinant adenoviruses. Tumor size and tumor growth inhibitory rates were calculated, and histomorphology by HE staining and hexon expressions by immunohistochemistry were evaluated in tumor tissues. CONCLUSIONS: The fiber-modified hexon-chimeric recombinant oncolytic adenovirus targeting CAFs can relatively specifically kill gastric CAFs and inhibit GC cells growth in vivo.
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spelling pubmed-56527202017-11-02 Fiber-modified hexon-chimeric oncolytic adenovirus targeting cancer associated fibroblasts inhibits tumor growth in gastric carcinoma Pang, Tao Wang, Xinghua Gao, Jun Chen, Wei Shen, Xiao Jun Nie, Ming Ming Luo, Tianhang Yin, Kai Fang, Guoen Wang, Kai Xuan Xue, Xu Chao Oncotarget Research Paper OBJECTIVE: To evaluate the effects of fiber-modified hexon-chimeric recombinant oncolytic adenovirus targeting cancer associated fibroblasts (CAFs) on the gastric CAFs and the transplantation tumor mice model of gastric carcinoma (GC). RESULTS: Compared with BJ cells and GPFs, the reproduction and infectivity of P9, P9-4C or GP adenoviruses were markedly higher in gastric CAFs. In addition, P9, P9-4C or GP had a significantly relatively more killing effect on gastric CAFs compared with GPFs, and have less oncolytic effect in BJ cells. Furthermore, in transplantation tumor mice model of GC we found significantly higher hexon protein expression in tumor tissues, more decreasing tumor growth and increasing inhibitory rates after treatment of P9, P9-4C or GP adenoviruses compared with Ad adenovirus. MATERIALS AND METHODS: Based on the construction of the recombinant oncolytic adenoviruses pRCAdHVR48-SDF1p-Ad/EGFP (Ad, as control) with the E1A gene transcription regulated by stromal-derived factor 1 (SDF1) promoter and the hexon replaced by hexon-chimeric (H5HVR48) gene, three fiber-modified hexon-chimeric oncolytic adenovirus through the modification fiber protein by insertion of different short peptides specifically binding to fibroblast activation protein (FAP), including pRCAdHVR48-SDF1p-FAP-P9/EGFP (P9), pRCAdHVR48-SDF1p-FAP-P9-4C/EGFP (P9-4C), pRCAdHVR48-SDF1p-FAP-GP/EGFP (GP), and their corresponding replication-defective adenovirus in parallel were reconstructed. Then the reproduction, infectivity and killing ability of the four above recombinant adenoviruses were evaluated in gastric CAFs compared with gastric para-mucosa fibroblasts (GPFs) and neonatal human foreskin fibroblasts (BJ). Furthermore, transplantation tumor mice model of GC was established, and then treated by the four above recombinant adenoviruses. Tumor size and tumor growth inhibitory rates were calculated, and histomorphology by HE staining and hexon expressions by immunohistochemistry were evaluated in tumor tissues. CONCLUSIONS: The fiber-modified hexon-chimeric recombinant oncolytic adenovirus targeting CAFs can relatively specifically kill gastric CAFs and inhibit GC cells growth in vivo. Impact Journals LLC 2017-08-16 /pmc/articles/PMC5652720/ /pubmed/29100326 http://dx.doi.org/10.18632/oncotarget.20273 Text en Copyright: © 2017 Pang et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Pang, Tao
Wang, Xinghua
Gao, Jun
Chen, Wei
Shen, Xiao Jun
Nie, Ming Ming
Luo, Tianhang
Yin, Kai
Fang, Guoen
Wang, Kai Xuan
Xue, Xu Chao
Fiber-modified hexon-chimeric oncolytic adenovirus targeting cancer associated fibroblasts inhibits tumor growth in gastric carcinoma
title Fiber-modified hexon-chimeric oncolytic adenovirus targeting cancer associated fibroblasts inhibits tumor growth in gastric carcinoma
title_full Fiber-modified hexon-chimeric oncolytic adenovirus targeting cancer associated fibroblasts inhibits tumor growth in gastric carcinoma
title_fullStr Fiber-modified hexon-chimeric oncolytic adenovirus targeting cancer associated fibroblasts inhibits tumor growth in gastric carcinoma
title_full_unstemmed Fiber-modified hexon-chimeric oncolytic adenovirus targeting cancer associated fibroblasts inhibits tumor growth in gastric carcinoma
title_short Fiber-modified hexon-chimeric oncolytic adenovirus targeting cancer associated fibroblasts inhibits tumor growth in gastric carcinoma
title_sort fiber-modified hexon-chimeric oncolytic adenovirus targeting cancer associated fibroblasts inhibits tumor growth in gastric carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652720/
https://www.ncbi.nlm.nih.gov/pubmed/29100326
http://dx.doi.org/10.18632/oncotarget.20273
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