Srinivasan Dhasarathdev, Subbarayan Rajasekaran, Krishnan Madhan, Balakrishna Ranjith, Adtani Pooja, Shrestha Rupendra, Chauhan Ankush, Babu Shyamaladevi, Radhakrishnan Arunkumar
Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India.
Centre for Herbal Pharmacology and Environmental Sustainability, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, 603103, Tamil Nadu, India.
Radiat Environ Biophys. 2025 Mar;64(1):1-16. doi: 10.1007/s00411-024-01102-2. Epub 2025 Jan 6.
Radiation therapy (RT) is fundamental to the fight against cancer because of its exceptional ability to target and destroy cancer cells. However, conventional radiation therapy can significantly affect the adjacent normal tissues, leading to fibrosis, inflammation, and decreased organ function. This tissue damage not only reduces the quality of life but also prevents the total elimination of cancer. The transformation of epithelial cells into mesenchymal-like cells, termed epithelial-mesenchymal transition (EMT), is essential for processes such as fibrosis, embryogenesis, and wound healing. Conventional radiation therapy increases the asymmetric activation of fibrotic and inflammatory pathways, and the resulting chronic fibrotic changes and organ dysfunction are linked to radiation-induced epithelial-mesenchymal transition. Recent advances in radiation therapy, namely flash radiation therapy (FLASH-RT), have the potential to widen the therapeutic index. Radiation delivered by FLASH-RT at very high dose rates (exceeding 40 Gy/s) can protect normal tissue from radiation-induced damage, a phenomenon referred to as the "FLASH effect". Preclinical studies have demonstrated that FLASH-RT successfully inhibits processes associated with fibrosis and epithelial-mesenchymal transition, mitigates damage to normal tissue, and enhances regeneration. Three distinct types of EMT have been identified: type-1, associated with embryogenesis; Type-2, associated with injury potential; and type-3, related with cancer spread. The regulation of EMT via pathways, including TGF-β/SMAD, WNT/β-catenin, and NF-κB, is essential for radiation-induced tissue remodelling. This study examined radiation-induced EMT, TGF-β activity, multiple signalling pathways in fibrosis, and the potential of FLASH-RT to reduce tissue damage. FLASH-RT is a novel approach to treat chronic tissue injury and fibrosis post-irradiation by maintaining epithelial properties and regulating mesenchymal markers including vimentin and N-cadherin. Understanding these pathways will facilitate the development of future therapies that can alleviate fibrosis, improve the efficacy of cancer therapy, and improve the quality of life of patients.
放射治疗（RT）是对抗癌症的基础，因为它具有靶向和摧毁癌细胞的卓越能力。然而，传统放射治疗会显著影响相邻的正常组织，导致纤维化、炎症和器官功能下降。这种组织损伤不仅降低了生活质量，还阻碍了癌症的彻底消除。上皮细胞向间充质样细胞的转变，即上皮-间充质转化（EMT），对于纤维化、胚胎发育和伤口愈合等过程至关重要。传统放射治疗会增加纤维化和炎症途径的不对称激活，而由此产生的慢性纤维化变化和器官功能障碍与辐射诱导的上皮-间充质转化有关。放射治疗的最新进展，即闪光放射治疗（FLASH-RT），有可能扩大治疗指数。以非常高的剂量率（超过40 Gy/s）进行的FLASH-RT照射可保护正常组织免受辐射诱导的损伤，这种现象被称为“闪光效应”。临床前研究表明，FLASH-RT成功抑制了与纤维化和上皮-间充质转化相关的过程，减轻了对正常组织的损伤，并促进了再生。已确定三种不同类型的EMT：1型与胚胎发育相关；2型与损伤潜能相关；3型与癌症扩散相关。通过包括TGF-β/SMAD、WNT/β-连环蛋白和NF-κB在内的途径对EMT进行调控，对于辐射诱导的组织重塑至关重要。本研究检测了辐射诱导的EMT、TGF-β活性、纤维化中的多种信号通路以及FLASH-RT减少组织损伤的潜力。FLASH-RT是一种通过维持上皮特性并调节包括波形蛋白和N-钙黏蛋白在内的间充质标志物来治疗辐射后慢性组织损伤和纤维化的新方法。了解这些途径将有助于未来开发能够减轻纤维化、提高癌症治疗效果并改善患者生活质量的疗法。
