Expression of Stem Cell Markers in High-LET Space Radiation-Induced Intestinal Tumors in Apc^1638N/+ Mouse Intestine

Exposure to ionizing radiation (IR) poses risks to the expanding interest in human space exploration; in atomic bomb survivors and radiological professionals, IR exposure has been linked to GI diseases, including colon cancer. Here, we assessed the expression of multiple stem cell markers in premalignant tumors and adjacent normal mucosa after low- and high-linear energy transfer (LET) irradiation. Our results revealed a noticeable correlation between increased levels of stemness markers and fi-catenin activation in premalignant tumors, which was more prominent in tumors induced after exposure to high-LET radiation compared to low-LET induced tumors. Our findings also highlight the complex relationship between radiation types and stem cell phenotypes and their potential influence on carcinogenesis processes, which has significant implications for cancer risk assessments. Estimation of cancer risk among astronauts planning to undertake future deep-space missions requires understanding the quantitative and qualitative differences in radiogenic cancers after low- and high-LET radiation exposures. Previously, we reported a multifold higher RBE for highLET radiation-induced gastrointestinal (GI) tumorigenesis in Apc(1638N/+) mice. Using the same model system, i.e., Apc(1638N/+) mice, here, we report qualitative differences in the cellular phenotype of lowand high-LET radiation-induced GI tumors. Stem cell (SC) phenotypes were identified using BMI1, ALDH1, CD133, DCLK1, MSI1, and LGR5 markers in low (gamma-rays)- and high (Fe-56)-LET radiationinduced and spontaneous tumors. We also assessed the expression of these markers in the adjacent normal mucosa. All six of these putative SC markers were shown to be overexpressed in tumors compared to the adjacent normal intestinal tissue. A differential SC phenotype for spontaneous and radiogenic intestinal tumors in Apc(1638N/+) mice was observed, where the ALDH1, BMI1, CD133, MSI1, and DCLK1 expressing cells were increased, while LGR5 expressing cells were decreased in 56Fe-induced tumors compared to gamma-ray-induced and spontaneous tumors. Furthermore, higher fi-catenin activation (marked by nuclear localization) was observed in 56Fe-induced tumors compared to gamma and spontaneous tumors. Since differential tumor cell phenotype along with activated beta-catenin may very well affect malignant progression, our findings are relevant to understanding the higher carcinogenic risk of high-LET radiation. This study has implications for the assessment of GI-cancer risk among astronauts, as well as for the estimation of secondary cancer risk among patients receiving hadron therapy, considering that our results indicate increased stemness properties after radiation.