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


METHODS
K-ras(LA1) 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-ras(LA1) 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.
Authors' Affiliations: Departments of Cell Biology; Pathology; Molecular Biology; Plastic Surgery; and Clinical Sciences; Simmons Comprehensive Cancer Center; Hamon Center for Therapeutic Oncology; Departments of Internal Medicine; Pharmacology; and Radiation Oncology, UT Southwestern Medical Center, Dallas; Departments of Thoracic/Head and Neck Medical Oncology; and Translational Molecular Pathology; The University of Texas MD Anderson Cancer Center, Houston, Texas; and Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
Oliver
O
Delgado
Kimberly G
KG
Batten
James A
JA
Richardson
Xian-Jin
XJ
Xie
Adi F
AF
Gazdar
Aadil A
AA
Kaisani
Luc
L
Girard
Carmen
C
Behrens
Milind
M
Suraokar
Gail
G
Fasciani
Woodring E
WE
Wright
Michael D
MD
Story
Ignacio I
II
Wistuba
John D
JD
Minna
Jerry W
JW
Shay
D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology / Q000532:radiotherapy; D002277:Carcinoma / Q000473:pathology* / Q000532:radiotherapy; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000473:pathology* / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009381:Neoplasms, Radiation-Induced / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D011833:Radiation Injuries, Experimental / Q000473:pathology*