ABSTRACT

We recently made an important discovery that radiation induces myofibroblasts, which play a role in radiation-related carcinogenesis via tumor microenvironment formation. Here, we investigated the threshold dose and the mechanisms of myofibroblast induction to assess adverse radiation effects on normal cells. Single-dose of healthy human fibroblasts in vitro promotes myofibroblast induction at high doses (≥ 5 Gy). In contrast, repeated low dose of fractionated radiation is at least equivalent to high-dose single radiation regarding myofibroblast induction. ROS play a pivotal role in the process of myofibroblast induction in normal tissue injury. Antioxidants, such as epicatechin and ascorbic acid can prevent myofibroblast induction by scavenging ROS. We further investigated the role of DNA damage responses (DDR) on myofibroblast induction. Blocking the DDR using DNA-PK or AKT inhibitors enhanced cellular sensitivity to radiation and facilitated myofibroblast induction, whereas an ATM inhibitor also enhanced radiation sensitivity but abrogated ROS accumulation and myofibroblast induction. In contrast to standard culture conditions, myofibroblasts remained after low or moderate doses of radiation (below 2.5 Gy) under growth-restricted conditions. In conclusion, the recovery of damaged cells from radiation is essential for myofibroblast clearance, which restores stromal cell dormancy and prevents tumor microenvironment formation. However, residual ROS, by way of sustaining myofibroblast presence, can facilitate tumor microenvironment formation. Targeting ROS using antioxidants is effective in the mitigation of radiation-related adverse effects, such as growth retardation and myofibroblast induction, and helps protect normal tissues.

摘要

我们最近取得了一个重要发现，即辐射会诱导肌成纤维细胞，肌成纤维细胞通过肿瘤微环境的形成在辐射相关的致癌作用中发挥作用。在这里，我们研究了肌成纤维细胞诱导的阈值剂量和机制，以评估辐射对正常细胞的不利影响。体外单剂量健康人成纤维细胞在高剂量（≥ 5 Gy）下促进肌成纤维细胞的诱导。相比之下，在肌成纤维细胞诱导方面，重复低剂量的分次放疗至少相当于高剂量的单次放疗。ROS在正常组织损伤的肌成纤维细胞诱导过程中起关键作用。抗氧化剂，如表儿茶素和抗坏血酸，可以通过清除 ROS 来阻止肌成纤维细胞的诱导。我们进一步研究了 DNA 损伤反应 (DDR) 对肌成纤维细胞诱导的作用。使用 DNA-PK 或 AKT 抑制剂阻断 DDR 增强了细胞对辐射的敏感性并促进了肌成纤维细胞的诱导，而 ATM 抑制剂也增强了辐射敏感性但消除了 ROS 积累和肌成纤维细胞诱导。与标准培养条件相比，在生长受限的条件下，低或中等剂量的辐射（低于 2.5 Gy）后，肌成纤维细胞仍然存在。总之，从辐射中恢复受损细胞对于肌成纤维细胞清除至关重要，这可以恢复基质细胞休眠并防止肿瘤微环境的形成。然而，残留的 ROS 通过维持肌成纤维细胞的存在，可以促进肿瘤微环境的形成。使用抗氧化剂靶向 ROS 可有效减轻与辐射相关的不良反应，例如生长迟缓和肌成纤维细胞诱导，并有助于保护正常组织。残留的 ROS 通过维持肌成纤维细胞的存在，可以促进肿瘤微环境的形成。使用抗氧化剂靶向 ROS 可有效减轻与辐射相关的不良反应，例如生长迟缓和肌成纤维细胞诱导，并有助于保护正常组织。残留的 ROS 通过维持肌成纤维细胞的存在，可以促进肿瘤微环境的形成。使用抗氧化剂靶向 ROS 可有效减轻与辐射相关的不良反应，例如生长迟缓和肌成纤维细胞诱导，并有助于保护正常组织。