Abstract：
Radiation therapy (RT) is a common treatment for lung cancer. Still, it can lead to irreversible loss of pulmonary function and a significant reduction in quality of life for one-third of patients. Preexisting comorbidities, such as chronic obstructive pulmonary disease (COPD), are frequent in patients with lung cancer and further increase the risk of complications. Because lung stem cells are crucial for the regeneration of lung tissue following injury, we hypothesized that airway stem cells from patients with COPD with lung cancer might contribute to increased radiation sensitivity. We used the air-liquid interface model, a three-dimensional (3D) culture system, to compare the radiation response of primary human airway stem cells from healthy and patients with COPD. We found that COPD-derived airway stem cells, compared to healthy airway stem cell cultures, exhibited disproportionate pathological mucociliary differentiation, aberrant cell cycle checkpoints, residual DNA damage, reduced survival of stem cells and self-renewal, and terminally differentiated cells post-irradiation, which could be reversed by blocking the Notch pathway using small-molecule γ-secretase inhibitors. Our findings shed light on the mechanisms underlying the increased radiation sensitivity of COPD and suggest that airway stem cells reflect part of the pathological remodeling seen in lung tissue from patients with lung cancer receiving thoracic RT.
摘要：
放射治疗（RT）是肺癌的常用治疗方法。尽管如此，可导致1/3患者肺功能不可逆丧失,生活质量显著下降.先前存在的合并症，如慢性阻塞性肺疾病（COPD），肺癌患者经常发生，并进一步增加并发症的风险。因为肺干细胞对于损伤后肺组织的再生至关重要，我们假设COPD合并肺癌患者的气道干细胞可能有助于提高放射敏感性.我们使用了气液界面模型,三维（3D）文化系统，比较健康和COPD患者的原发性气道干细胞的辐射反应。我们发现COPD来源的气道干细胞，与健康的气道干细胞培养相比，表现出不成比例的病理性粘液纤毛分化，异常细胞周期检查点，残余DNA损伤，减少干细胞的存活和自我更新，和辐射后的终末分化细胞，可以通过使用小分子γ-分泌酶抑制剂阻断Notch途径来逆转。我们的发现揭示了COPD辐射敏感性增加的潜在机制，并表明气道干细胞反映了接受胸部RT的肺癌患者肺组织中可见的部分病理重塑。
