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 high-LET radiation-induced gastrointestinal (GI) tumorigenesis inApc1638N/+mice. Using the same model system, i.e.,Apc1638N/+mice, here, we report qualitative differences in the cellular phenotype of low- and high-LET radiation-induced GI tumors. Stem cell (SC) phenotypes were identified using BMI1, ALDH1, CD133, DCLK1, MSI1, and LGR5 markers in low (γ-rays)- and high (56Fe)-LET radiation-induced 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 inApc1638N/+mice was observed, where the ALDH1, BMI1, CD133, MSI1, and DCLK1 expressing cells were increased, while LGR5 expressing cells were decreased in56Fe-induced tumors compared to γ-ray-induced and spontaneous tumors. Furthermore, higher β-catenin activation (marked by nuclear localization) was observed in56Fe-induced tumors compared to γ and spontaneous tumors. Since differential tumor cell phenotype along with activated β-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.
评估计划执行未来深空任务的宇航员患癌风险，需要理解低线性能量转移（LET）与高LET辐射暴露后辐射诱发癌症在定量和定性上的差异。先前，我们报道了高LET辐射在Apc1638N/+小鼠中诱发胃肠道（GI）肿瘤发生的相对生物效能（RBE）高出数倍。使用相同的模型系统（即Apc1638N/+小鼠），本文报告了低LET与高LET辐射诱发GI肿瘤在细胞表型上的定性差异。我们利用BMI1、ALDH1、CD133、DCLK1、MSI1和LGR5标记物，在低LET（γ射线）和高LET（56Fe）辐射诱发以及自发性肿瘤中鉴定了干细胞（SC）表型。同时评估了这些标记物在邻近正常黏膜中的表达。结果显示，与邻近正常肠道组织相比，所有六种假定的SC标记物在肿瘤中均呈过表达。在Apc1638N/+小鼠的自发性和辐射性肠道肿瘤中观察到差异性的SC表型：与γ射线诱发及自发性肿瘤相比，56Fe诱发肿瘤中表达ALDH1、BMI1、CD133、MSI1和DCLK1的细胞增多，而表达LGR5的细胞减少。此外，与γ射线诱发及自发性肿瘤相比，56Fe诱发肿瘤中观察到更高的β-连环蛋白激活（以核定位为标志）。由于差异性的肿瘤细胞表型连同激活的β-连环蛋白很可能影响恶性进展，我们的发现对于理解高LET辐射更高的致癌风险具有重要意义。考虑到我们的结果表明辐射后干细胞特性增强，本研究对于评估宇航员的GI癌症风险以及估算接受强子治疗患者的继发性癌症风险具有参考价值。
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