Abstract 5057: Exposure to highly energetic charged (hze) particle radiation is associated with higher colitis and colorectal cancer incidence in IL10-/- mice

Abstract

Abstract Epidemiological data from atom-bomb survivors and from radiotherapy patients have highlight an underlying risk of colitis and colorectal cancer (CRC) after ionizing radiation-exposure. In contrast, astronauts planning to undertake deep space exploration such as mission to Mars have risk of radiation exposure from highly energetic charged (HZE) particles present in galactic cosmic radiation (GCR) and risk of colitis and CRC after HZE-exposure is yet to be determined. Therefore, animal studies are warranted to address existing uncertainties in colitis and CRC risk prediction after exposure to HZE radiation. Here we report IL10-/- mice as a suitable mouse model for assessment of colitis and CRC risk after exposure to space radiation. Male mice (n=12 mice/group) were whole-body exposed to sham-radiation, γ-rays and 28Si-ion (300 MeV/n; 70 keV/μm; 1.4 Gy). Mice were sacrificed three months after irradiation, and colon swiss-rolls sections were analyzed for colitis and CRC grade was noted in hematoxylin and eosin stained sections. Immunohistochemistry (β-catenin, Cyclin-D1, phospho-H3, iNOS, phoshoNfKβ-p65, and Cox2) was also performed to assess HZE-induced proliferative and inflammatory signaling. Further, inflammation-associated gene-expression analysis was also conducted in both radiation-induced tumor and adjoining normal tissue area. Here we report that relative to controls and γ-ray, colitis score, colon tumor incidence, size and grade was significantly higher after space (28Si-ion) radiation exposure. Higher number of phospho-H3 positive cells in 28Si-ion exposed mouse colon demonstrated increased proliferative index and in increased colon tumors of higher grade, could be due to greater activation of β-catenin and its downstream effector cyclin D1. In addition, higher accumulation of iNOS, phoshoNfKβ-p65, and Cox2 in stromal and epithelial cells after space radiation exposure clearly indicates upregulation of both immune and epithelial inflammation as drivers of colitis and CRC development. Inflammation associated protein markers and gene expression signatures were more pronounced after 28Si-ion exposure. Significant up-regulation of GATA4, ICAM1, ITGA2 and EGFR were exclusive to 28Si-ion exposed mouse colon, however PTGES and TGFβ1 were upregulated in both γ and 28Si-ion exposed mice. Overall, this study suggests that IL10-/- mouse are a suitable model to assess IR-induced colitis and CRC risk, and that space radiation carries higher risk of colitis and CRC incidence, relative to γ-rays at comparable doses. This study has implications for risk prediction in astronauts planning for deep space mission and also for cancer patients planning to undergo particle radiotherapy. Citation Format: Shubhankar Suman, Bo-Hyun Moon, Albert J. Fornace, Kamal Datta. Exposure to highly energetic charged (hze) particle radiation is associated with higher colitis and colorectal cancer incidence in IL10-/- mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5057.