Abstract 4158: Differential intestinal tumorigenesis and DNA repair response in APCMin/+ mice after acute and fractionated proton radiation

Abstract

Abstract Ionizing radiation (IR) exposure is a risk factor for colorectal cancer (CRC) development. With increasing interest in exploring outer space, astronauts on prolonged space missions such as a mission to Mars are expected to receive IR doses that could heighten the risk of CRC. It is estimated that about 90% of the IR in outer space is energetic protons, and the radiation dose during solar particle events (SPEs) could reach up to 2 Gy behind shielding. However, the risk of CRC after energetic proton radiation is not yet fully defined due to lack of human or animal model data. The purpose of the current study was to quantitatively and qualitatively compare and characterize differences in intestinal tumorigenesis between acute and fractionated proton irradiation in APCMin/+ mice, a well-established mouse model for human CRC. Mice were exposed to 1.88 Gy of proton radiation delivered in a single fraction or in 4 equal daily fractions (0.47 Gy x 4). Since proton dose to astronauts are variable based on space environment, in this initial study we chose a high single dose and a lower daily dose pattern to assess intestinal tumorigenesis. Intestinal tumor frequency and grade were noted, and tumor samples were collected from irradiated and control mice euthanized 100 to 110 days after radiation exposure. Molecular analysis was focused on DNA damage and repair, and cellular proliferative signaling pathways relevant to CRC using immunoblots, immunohistochemistry, and qPCR. Relative to control and fractionated-protons, there was significantly higher intestinal tumor frequency and grade after acute (single dose) proton irradiation. Decreased cellular differentiation and increased oxidative damage to DNA was observed after acute proton radiation. At the molecular level, our data showed increased DNA double strand breaks associated with decreased levels of DNA repair proteins, and upregulation of proliferative β-catenin and Akt signaling after acute proton exposure. Since increased DNA damage was not associated with concomitant increased apoptosis, our data suggest continued proliferation of cells bearing sub-lethal damage to promote tumorigenesis. In the fractionated proton group, tumor frequency and grade as well as molecular changes were comparable to sham-irradiated control group. When considered along with decreased tumor frequency and upregulation of DNA repair pathways after fractionation, our data are suggestive of marked differences in carcinogenic effects of acute vs. fractionated proton radiation. In summary, our data suggest that acute exposure to proton radiation is associated with higher risk of intestinal tumorigenesis in APCMin/+ mice with implications for gastrointestinal cancer risk in astronauts undertaking long duration space missions and in patients undergoing proton radiotherapy. Citation Format: Kamal Datta, Shubhankar Suman, Santosh Kumar, Albert J. Fornace. Differential intestinal tumorigenesis and DNA repair response in APCMin/+ mice after acute and fractionated proton radiation [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 4158.