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Assessing the Radiation Response of Lung Cancer with Different Gene Mutations Using Genetically Engineered Mice

Purpose: Non-small cell lung cancers (NSCLC) are a heterogeneous group of carcinomas harboring a variety of different gene mutations. We have utilized two distinct genetically engineered mouse models of human NSCLC (adenocarcinoma) to investigate how genetic factors within tumor parenchymal cells in...

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Autores principales: Perez, Bradford A., Ghafoori, A. Paiman, Lee, Chang-Lung, Johnston, Samuel M., Li, Yifan, Moroshek, Jacob G., Ma, Yan, Mukherjee, Sayan, Kim, Yongbaek, Badea, Cristian T., Kirsch, David G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613757/
https://www.ncbi.nlm.nih.gov/pubmed/23565506
http://dx.doi.org/10.3389/fonc.2013.00072
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author Perez, Bradford A.
Ghafoori, A. Paiman
Lee, Chang-Lung
Johnston, Samuel M.
Li, Yifan
Moroshek, Jacob G.
Ma, Yan
Mukherjee, Sayan
Kim, Yongbaek
Badea, Cristian T.
Kirsch, David G.
author_facet Perez, Bradford A.
Ghafoori, A. Paiman
Lee, Chang-Lung
Johnston, Samuel M.
Li, Yifan
Moroshek, Jacob G.
Ma, Yan
Mukherjee, Sayan
Kim, Yongbaek
Badea, Cristian T.
Kirsch, David G.
author_sort Perez, Bradford A.
collection PubMed
description Purpose: Non-small cell lung cancers (NSCLC) are a heterogeneous group of carcinomas harboring a variety of different gene mutations. We have utilized two distinct genetically engineered mouse models of human NSCLC (adenocarcinoma) to investigate how genetic factors within tumor parenchymal cells influence the in vivo tumor growth delay after one or two fractions of radiation therapy (RT). Materials and Methods: Primary lung adenocarcinomas were generated in vivo in mice by intranasal delivery of an adenovirus expressing Cre-recombinase. Lung cancers expressed oncogenic Kras(G12D) and were also deficient in one of two tumor suppressor genes: p53 or Ink4a/ARF. Mice received no radiation treatment or whole lung irradiation in a single fraction (11.6 Gy) or in two 7.3 Gy fractions (14.6 Gy total) separated by 24 h. In each case, the biologically effective dose (BED) equaled 25 Gy(10). Response to RT was assessed by micro-CT 2 weeks after treatment. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining were performed to assess the integrity of the p53 pathway, the G1 cell-cycle checkpoint, and apoptosis. Results: Tumor growth rates prior to RT were similar for the two genetic variants of lung adenocarcinoma. Lung cancers with wild-type (WT) p53 (LSL-Kras; Ink4a/ARF(FL/FL) mice) responded better to two daily fractions of 7.3 Gy compared to a single fraction of 11.6 Gy (P = 0.002). There was no statistically significant difference in the response of lung cancers deficient in p53 (LSL-Kras; p53(FL/FL) mice) to a single fraction (11.6 Gy) compared to 7.3 Gy × 2 (P = 0.23). Expression of the p53 target genes p21 and PUMA were higher and bromodeoxyuridine uptake was lower after RT in tumors with WT p53. Conclusion: Using an in vivo model of malignant lung cancer in mice, we demonstrate that the response of primary lung cancers to one or two fractions of RT can be influenced by specific gene mutations.
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spelling pubmed-36137572013-04-05 Assessing the Radiation Response of Lung Cancer with Different Gene Mutations Using Genetically Engineered Mice Perez, Bradford A. Ghafoori, A. Paiman Lee, Chang-Lung Johnston, Samuel M. Li, Yifan Moroshek, Jacob G. Ma, Yan Mukherjee, Sayan Kim, Yongbaek Badea, Cristian T. Kirsch, David G. Front Oncol Oncology Purpose: Non-small cell lung cancers (NSCLC) are a heterogeneous group of carcinomas harboring a variety of different gene mutations. We have utilized two distinct genetically engineered mouse models of human NSCLC (adenocarcinoma) to investigate how genetic factors within tumor parenchymal cells influence the in vivo tumor growth delay after one or two fractions of radiation therapy (RT). Materials and Methods: Primary lung adenocarcinomas were generated in vivo in mice by intranasal delivery of an adenovirus expressing Cre-recombinase. Lung cancers expressed oncogenic Kras(G12D) and were also deficient in one of two tumor suppressor genes: p53 or Ink4a/ARF. Mice received no radiation treatment or whole lung irradiation in a single fraction (11.6 Gy) or in two 7.3 Gy fractions (14.6 Gy total) separated by 24 h. In each case, the biologically effective dose (BED) equaled 25 Gy(10). Response to RT was assessed by micro-CT 2 weeks after treatment. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining were performed to assess the integrity of the p53 pathway, the G1 cell-cycle checkpoint, and apoptosis. Results: Tumor growth rates prior to RT were similar for the two genetic variants of lung adenocarcinoma. Lung cancers with wild-type (WT) p53 (LSL-Kras; Ink4a/ARF(FL/FL) mice) responded better to two daily fractions of 7.3 Gy compared to a single fraction of 11.6 Gy (P = 0.002). There was no statistically significant difference in the response of lung cancers deficient in p53 (LSL-Kras; p53(FL/FL) mice) to a single fraction (11.6 Gy) compared to 7.3 Gy × 2 (P = 0.23). Expression of the p53 target genes p21 and PUMA were higher and bromodeoxyuridine uptake was lower after RT in tumors with WT p53. Conclusion: Using an in vivo model of malignant lung cancer in mice, we demonstrate that the response of primary lung cancers to one or two fractions of RT can be influenced by specific gene mutations. Frontiers Media S.A. 2013-04-02 /pmc/articles/PMC3613757/ /pubmed/23565506 http://dx.doi.org/10.3389/fonc.2013.00072 Text en Copyright © 2013 Perez, Ghafoori, Lee, Johnston, Li, Moroshek, Ma, Mukherjee, Kim, Badea and Kirsch. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
spellingShingle Oncology
Perez, Bradford A.
Ghafoori, A. Paiman
Lee, Chang-Lung
Johnston, Samuel M.
Li, Yifan
Moroshek, Jacob G.
Ma, Yan
Mukherjee, Sayan
Kim, Yongbaek
Badea, Cristian T.
Kirsch, David G.
Assessing the Radiation Response of Lung Cancer with Different Gene Mutations Using Genetically Engineered Mice
title Assessing the Radiation Response of Lung Cancer with Different Gene Mutations Using Genetically Engineered Mice
title_full Assessing the Radiation Response of Lung Cancer with Different Gene Mutations Using Genetically Engineered Mice
title_fullStr Assessing the Radiation Response of Lung Cancer with Different Gene Mutations Using Genetically Engineered Mice
title_full_unstemmed Assessing the Radiation Response of Lung Cancer with Different Gene Mutations Using Genetically Engineered Mice
title_short Assessing the Radiation Response of Lung Cancer with Different Gene Mutations Using Genetically Engineered Mice
title_sort assessing the radiation response of lung cancer with different gene mutations using genetically engineered mice
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613757/
https://www.ncbi.nlm.nih.gov/pubmed/23565506
http://dx.doi.org/10.3389/fonc.2013.00072
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