Radiation-Enhanced Lung Cancer Progression in a Transgenic Mouse Model of Lung Cancer Is Predictive of Outcomes in Human Lung and Breast Cancer

Abstract

Purpose Carcinogenesis is an adaptive process between nascent tumor cells and their microenvironment including the modification of inflammatory responses from anti-tumorigenic to pro-tumorigenic. 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 till death. Microarray analyses were performed using Illumina® BeadChips on whole lung tissue 70 days post-irradiation with a fractionated or acute dose of radiation and compared to 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 non-random 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 impacting inflammatory pathways, and that clinically relevant similarities exist between human lung and breast carcinogenesis.

An extra copy of p53 suppresses development of spontaneous Kras-driven but not radiation-induced cancer

“…We chose 5 daily fractions of 0.2 Gy iron ions because this dose and fractionation has been shown to increase the incidence of invasive lung adenocarcinoma in LA-1 mice (29). An X-ray dose of 1.2 Gy was chosen because this was the maximum dose that could be delivered for 5 consecutive days without causing bone-marrow failure and the hematopoietic acute radiation syndrome.…”

“…At 6 months after radiation exposure, most of the lung tumors were well-differentiated adenomas, and we observed no poorly differentiated, invasive lung tumors. It is possible that changes in tumor grade would be greater at later time points following radiation exposure (29). …”

“…LA-1 mice develop low-grade lung adenomas with 100% penetrance and lymphomas at a lower rate. Exposure to fractionated low-LET and high-LET radiation has recently been shown to accelerate lung cancer progression in LA-1 mice (29). Deletion of p53 in LA-1 mice increases lung tumor grade (25), but the effect of p53 levels on tumor initiation has not been described.…”

TRPA1 deficiency is protective in cuprizone-induced demyelination-A new target against oligodendrocyte apoptosis

“…The following antibodies were used at a dilution of 1:1000 unless otherwise stated: anti-myelin-associated glycoprotein (MAG) (Santa Cruz Biotechnology, Santa Cruz, CA), antiphospho-p38 (pThr 180 /pTyr 182 ) (Sigma-Aldrich, Steinheim, Germany), anti-p44/42 MAPK (ERK1/2), anti-phospho-p44/42 MAPK (p-ERK1/2) (Thr 202 /Tyr 204 ), anti-phospho-SAPK/JNK (Thr 183 /Tyr 185 ), anti-phospho-c-Jun (Ser 73 ), anti-b actin (all from Cell Signalling Technology, Beverly, MA), and anti-Hsp90 (1:2,000, Santa Cruz Biotechnology, Santa Cruz, CA) (Delgado et al, 2014;Gomez et al, 2011;Hao and ElShamy, 2007;Kim et al, 2015;Liu et al, 2014;Petrov et al, 2015;Watanabe et al, 2015). The CC of each animal was homogenized in ice-cold 0.5 M Tris buffer, pH 7.4 (containing 5 M sodium chloride, 50% glycerol, 100 mM ethylene glycol tetraacetic acid, 10 mM sodium orthovanadate, 1 mM zinc chloride, 0.5 mM sodium fluoride, aprotinin, 200 mM phenylmethylsulfonyl fluoride, 10% Triton X-100, and distilled water; (all purchased from Sigma-Aldrich, Steinheim, Germany).…”

Galactic cosmic ray simulation at the NASA Space Radiation Laboratory

“…These limitations are not isolated to cancer research; the bones, eyes, CNS, cardiovascular, and other systems may incur substantial and short timeframe damage and functional degradation in the compressed timeframe of current lab experiments which may or may not be accurate for space. Data from human exposures for cardiovascular effects note varying results with fractionated exposures in humans (low-LET) and the inverse dose rate effect seen with high LET 252 Cf neutron exposures for lung and mammary carcinogenesis (Ullrich et al, 1977) suggest that effects of dose-rate for high-LET radiation must be considered (Delgado et al, 2014). …”