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Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model
The A/J mouse is highly susceptible to lung tumor induction and has been widely used as a screening model in carcinogenicity testing and chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops lung tumors spontaneously. Moreover, there is a consider...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Slovak Toxicology Society SETOX
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427718/ https://www.ncbi.nlm.nih.gov/pubmed/26109882 http://dx.doi.org/10.2478/intox-2014-0010 |
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author | Luettich, Karsta Xiang, Yang Iskandar, Anita Sewer, Alain Martin, Florian Talikka, Marja Vanscheeuwijck, Patrick Berges, An Veljkovic, Emilija Gonzalez-Suarez, Ignacio Schlage, Walter Hoeng, Julia Peitsch, Manuel |
author_facet | Luettich, Karsta Xiang, Yang Iskandar, Anita Sewer, Alain Martin, Florian Talikka, Marja Vanscheeuwijck, Patrick Berges, An Veljkovic, Emilija Gonzalez-Suarez, Ignacio Schlage, Walter Hoeng, Julia Peitsch, Manuel |
author_sort | Luettich, Karsta |
collection | PubMed |
description | The A/J mouse is highly susceptible to lung tumor induction and has been widely used as a screening model in carcinogenicity testing and chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops lung tumors spontaneously. Moreover, there is a considerable gap in our understanding of the underlying mechanisms of pulmonary chemical carcinogenesis in the A/J mouse. Therefore, we examined the differences between spontaneous and cigarette smoke-related lung tumors in the A/J mouse model using mRNA and microRNA (miRNA) profiling. Male A/J mice were exposed whole-body to mainstream cigarette smoke (MS) for 18 months. Gene expression interaction term analysis of lung tumors and surrounding non-tumorous parenchyma samples from animals that were exposed to either 300 mg/m(3) MS or sham-exposed to fresh air indicated significant differential expression of 296 genes. Ingenuity Pathway Analysis(®) (IPA(®)) indicated an overall suppression of the humoral immune response, which was accompanied by a disruption of sphingolipid and glycosaminoglycan metabolism and a deregulation of potentially oncogenic miRNA in tumors of MS-exposed A/J mice. Thus, we propose that MS exposure leads to severe perturbations in pathways essential for tumor recognition by the immune system, thereby potentiating the ability of tumor cells to escape from immune surveillance. Further, exposure to MS appeared to affect expression of miRNA, which have previously been implicated in carcinogenesis and are thought to contribute to tumor progression. Finally, we identified a 50-gene expression signature and show its utility in distinguishing between cigarette smoke-related and spontaneous lung tumors. |
format | Online Article Text |
id | pubmed-4427718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Slovak Toxicology Society SETOX |
record_format | MEDLINE/PubMed |
spelling | pubmed-44277182015-06-24 Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model Luettich, Karsta Xiang, Yang Iskandar, Anita Sewer, Alain Martin, Florian Talikka, Marja Vanscheeuwijck, Patrick Berges, An Veljkovic, Emilija Gonzalez-Suarez, Ignacio Schlage, Walter Hoeng, Julia Peitsch, Manuel Interdiscip Toxicol Original Article The A/J mouse is highly susceptible to lung tumor induction and has been widely used as a screening model in carcinogenicity testing and chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops lung tumors spontaneously. Moreover, there is a considerable gap in our understanding of the underlying mechanisms of pulmonary chemical carcinogenesis in the A/J mouse. Therefore, we examined the differences between spontaneous and cigarette smoke-related lung tumors in the A/J mouse model using mRNA and microRNA (miRNA) profiling. Male A/J mice were exposed whole-body to mainstream cigarette smoke (MS) for 18 months. Gene expression interaction term analysis of lung tumors and surrounding non-tumorous parenchyma samples from animals that were exposed to either 300 mg/m(3) MS or sham-exposed to fresh air indicated significant differential expression of 296 genes. Ingenuity Pathway Analysis(®) (IPA(®)) indicated an overall suppression of the humoral immune response, which was accompanied by a disruption of sphingolipid and glycosaminoglycan metabolism and a deregulation of potentially oncogenic miRNA in tumors of MS-exposed A/J mice. Thus, we propose that MS exposure leads to severe perturbations in pathways essential for tumor recognition by the immune system, thereby potentiating the ability of tumor cells to escape from immune surveillance. Further, exposure to MS appeared to affect expression of miRNA, which have previously been implicated in carcinogenesis and are thought to contribute to tumor progression. Finally, we identified a 50-gene expression signature and show its utility in distinguishing between cigarette smoke-related and spontaneous lung tumors. Slovak Toxicology Society SETOX 2014-06 2014-11-15 /pmc/articles/PMC4427718/ /pubmed/26109882 http://dx.doi.org/10.2478/intox-2014-0010 Text en Copyright © 2014 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. http://creativecommons.org/licenses/by/2.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Luettich, Karsta Xiang, Yang Iskandar, Anita Sewer, Alain Martin, Florian Talikka, Marja Vanscheeuwijck, Patrick Berges, An Veljkovic, Emilija Gonzalez-Suarez, Ignacio Schlage, Walter Hoeng, Julia Peitsch, Manuel Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model |
title | Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model |
title_full | Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model |
title_fullStr | Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model |
title_full_unstemmed | Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model |
title_short | Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model |
title_sort | systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the a/j mouse model |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427718/ https://www.ncbi.nlm.nih.gov/pubmed/26109882 http://dx.doi.org/10.2478/intox-2014-0010 |
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