Radiation-enhanced lung cancer progression in a transgenic mouse model of lung cancer is predictive of outcomes in human lung and breast cancer

Oliver Delgado, Kimberly G. Batten, James A. Richardson, Xian Jin Xie, Adi F. Gazdar, Aadil A. Kaisani, Luc Girard, Carmen Behrens, Milind Suraokar, Gail Fasciani, Woodring E. Wright, Michael D. Story, Ignacio I. Wistuba, John D. Minna, Jerry W. Shay

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Purpose: Carcinogenesis is an adaptive process between nascent tumor cells and their microenvironment, including the modification of inflammatory responses from antitumorigenic to protumorigenic. Radiation exposure can stimulate inflammatory responses that inhibit or promote carcinogenesis. The purpose of this study is to determine the impact of radiation exposure on lung cancer progression in vivo and assess the relevance of this knowledge to human carcinogenesis. Experimental Design: K-rasLA1 mice were irradiated with various doses and dose regimens and then monitored until death. Microarray analyses were performed using Illumina BeadChips on whole lung tissue 70 days after irradiation with a fractionated or acute dose of radiation and compared with age-matched unirradiated controls. Unique group classifiers were derived by comparative genomic analysis of three experimental cohorts. Survival analyses were performed using principal component analysis and k-means clustering on three lung adenocarcinoma, three breast adenocarcinoma, and two lung squamous carcinoma annotated microarray datasets. Results: Radiation exposure accelerates lung cancer progression in the K-rasLA1 lung cancer mouse model with dose fractionation being more permissive for cancer progression. A nonrandom inflammatory signature associated with this progression was elicited from whole lung tissue containing only benign lesions and predicts human lung and breast cancer patient survival across multiple datasets. Immunohistochemical analyses suggest that tumor cells drive predictive signature. Conclusions: These results demonstrate that radiation exposure can cooperate with benign lesions in a transgenic model of cancer by affecting inflammatory pathways, and that clinically relevant similarities exist between human lung and breast carcinogenesis.

Original languageEnglish (US)
Pages (from-to)1610-1622
Number of pages13
JournalClinical Cancer Research
Volume20
Issue number6
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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