Kwiatkowski Elaina, Suman Shubhankar, Kallakury Bhaskar V S, Datta Kamal, Fornace Albert J, Kumar Santosh
Department of Biology, Georgetown University, Washington, DC 20057, USA.
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Cancers (Basel). 2023 Aug 24;15(17):4240. doi: 10.3390/cancers15174240.
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 in mice. Using the same model system, i.e., 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 (Fe)-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 in mice was observed, where the ALDH1, BMI1, CD133, MSI1, and DCLK1 expressing cells were increased, while LGR5 expressing cells were decreased in Fe-induced tumors compared to γ-ray-induced and spontaneous tumors. Furthermore, higher β-catenin activation (marked by nuclear localization) was observed in Fe-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.
对于计划执行未来深空任务的宇航员，评估其患癌风险需要了解低线性能量传递（LET）和高线性能量传递辐射暴露后辐射诱发癌症在定量和定性方面的差异。此前，我们报道了高线性能量传递辐射诱发小鼠胃肠道（GI）肿瘤形成的相对生物效应（RBE）高出数倍。在此，我们使用相同的模型系统，即小鼠，报告低线性能量传递和高线性能量传递辐射诱发的胃肠道肿瘤细胞表型的定性差异。在低（γ射线）线性能量传递和高（铁离子）线性能量传递辐射诱发的肿瘤以及自发肿瘤中，使用BMI1、醛脱氢酶1（ALDH1）、CD133、双皮质素样激酶1（DCLK1）、微卫星不稳定蛋白1（MSI1）和富含亮氨酸重复序列的G蛋白偶联受体5（LGR5）标记物来鉴定干细胞（SC）表型。我们还评估了这些标记物在相邻正常黏膜中的表达。与相邻正常肠组织相比，所有这六种假定的干细胞标记物在肿瘤中均呈过表达。观察到小鼠自发和辐射诱发的肠道肿瘤存在不同的干细胞表型，与γ射线诱发的肿瘤和自发肿瘤相比，在铁离子诱发的肿瘤中，表达ALDH1、BMI1、CD133、MSI1和DCLK1的细胞增加，而表达LGR5的细胞减少。此外，与γ射线诱发的肿瘤和自发肿瘤相比，在铁离子诱发的肿瘤中观察到更高的β-连环蛋白激活（以核定位为标志）。由于不同的肿瘤细胞表型以及激活的β-连环蛋白很可能会影响恶性进展，我们的研究结果对于理解高线性能量传递辐射更高的致癌风险具有重要意义。鉴于我们的结果表明辐射后干性特征增加，本研究对于评估宇航员患胃肠道癌症的风险以及估计接受强子治疗的患者发生继发性癌症的风险具有重要意义。
