Fractionated and Acute Proton Radiation Show Differential Intestinal Tumorigenesis and DNA Damage and Repair Pathway Response in ApcMin/+ Mice
Proton radiation is a major component of the radiation field in outer space and is used clinically in radiation therapy of resistant cancers. Although epidemiologic studies in atom bomb survivors and radiologic workers have established radiation as a risk factor for colorectal cancer (CRC), we have...
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Published in | International journal of radiation oncology, biology, physics Vol. 105; no. 3; pp. 525 - 536 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Inc
01.11.2019
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Online Access | Get full text |
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Summary: | Proton radiation is a major component of the radiation field in outer space and is used clinically in radiation therapy of resistant cancers. Although epidemiologic studies in atom bomb survivors and radiologic 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 owing to a 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.
We used ApcMin/+ mice, a well-studied CRC model, to examine acute versus 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 × 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.
Significantly higher intestinal tumor number and grade, along with decreased differentiation, were observed after acute radiation 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 nonhomologous end joining were also observed after exposure to acute protons.
We show increased γH2AX, 53BP1, and 8-oxo-dG, suggesting that increased ongoing DNA damage along with decreased DNA repair factors and increased proliferative responses could be triggering a higher number of intestinal tumors after acute relative to fractionated proton exposures in ApcMin/+ mice. Taken together, our data suggest greater carcinogenic potential of acute relative to fractionated proton radiation. |
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ISSN: | 0360-3016 1879-355X |
DOI: | 10.1016/j.ijrobp.2019.06.2532 |