Fractionated and acute proton radiation show differential intestinal tumorigenesis and DNA damage and repair pathway response in ApcMin/+ mice.

Abstract

PURPOSE\nProton radiation is a major component of the radiation field in outer space and is also used clinically in radiotherapy of resistant cancers. Although epidemiological studies in atom bomb survivors and radiological workers have established radiation as a risk factor for colorectal cancer (CRC), we have yet to determine the risk of CRC posed by proton radiation due to lack of sufficient human or animal data. The purpose of the current study was to quantitatively and qualitatively characterize differential effects of acute and fractionated high energy protons on colorectal carcinogenesis.\n\n\nMETHODS AND MATERIALS\nWe used ApcMin/+ mice, a well-studied CRC model, to examine acute vs. fractionated proton radiation-induced differences in intestinal tumorigenesis and associated signaling pathways. 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). Intestinal tumor number and grade were scored 100 to 110 days after irradiation and tumor and tumor-adjacent normal tissues were harvested to assess proliferative β-catenin/Akt pathways and DNA damage response and repair pathways relevant to colorectal carcinogenesis.\n\n\nRESULTS\nSignificantly higher intestinal tumor number and grade along with decreased differentiation, were observed after acute relative to fractionated radiation. Acute protons induced upregulation of β-catenin and Akt pathways with increased proliferative marker phospho-histone H3. Increased DNA damage along with decreased DNA repair factors involved in mismatch repair and non-homologous end joining were also observed after acute protons.\n\n\nCONCLUSIONS\nWe show that increased γH2AX, 53BP1, and 8-oxo-dG, suggesting increased ongoing DNA damage with decreased DNA repair factors along with an increased proliferative response could be triggering higher intestinal tumors relative to fractionated exposures in ApcMin/+ mice. Taken together, our data are suggestive of higher carcinogenic potential of acute relative to fractionated proton radiation.