Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1782264777188311040 |
---|---|
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. |
format | Online Article Text |
id | pubmed-3613757 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT perezbradforda assessingtheradiationresponseoflungcancerwithdifferentgenemutationsusinggeneticallyengineeredmice AT ghafooriapaiman assessingtheradiationresponseoflungcancerwithdifferentgenemutationsusinggeneticallyengineeredmice AT leechanglung assessingtheradiationresponseoflungcancerwithdifferentgenemutationsusinggeneticallyengineeredmice AT johnstonsamuelm assessingtheradiationresponseoflungcancerwithdifferentgenemutationsusinggeneticallyengineeredmice AT liyifan assessingtheradiationresponseoflungcancerwithdifferentgenemutationsusinggeneticallyengineeredmice AT moroshekjacobg assessingtheradiationresponseoflungcancerwithdifferentgenemutationsusinggeneticallyengineeredmice AT mayan assessingtheradiationresponseoflungcancerwithdifferentgenemutationsusinggeneticallyengineeredmice AT mukherjeesayan assessingtheradiationresponseoflungcancerwithdifferentgenemutationsusinggeneticallyengineeredmice AT kimyongbaek assessingtheradiationresponseoflungcancerwithdifferentgenemutationsusinggeneticallyengineeredmice AT badeacristiant assessingtheradiationresponseoflungcancerwithdifferentgenemutationsusinggeneticallyengineeredmice AT kirschdavidg assessingtheradiationresponseoflungcancerwithdifferentgenemutationsusinggeneticallyengineeredmice |