Shi Zheng, Hu Cuilan, Zheng Xiaogang, Sun Chao, Li Qiang
Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.
Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China.
Exp Hematol Oncol. 2024 May 22;13(1):55. doi: 10.1186/s40164-024-00519-1.
Radiotherapy is one of the mainstream approaches for cancer treatment, although the clinical outcomes are limited due to the radioresistance of tumor cells. Hypoxia and metabolic reprogramming are the hallmarks of tumor initiation and progression and are closely linked to radioresistance. Inside a tumor, the rate of angiogenesis lags behind cell proliferation, and the underdevelopment and abnormal functions of blood vessels in some loci result in oxygen deficiency in cancer cells, i.e., hypoxia. This prevents radiation from effectively eliminating the hypoxic cancer cells. Cancer cells switch to glycolysis as the main source of energy, a phenomenon known as the Warburg effect, to sustain their rapid proliferation rates. Therefore, pathways involved in metabolic reprogramming and hypoxia-induced radioresistance are promising intervention targets for cancer treatment. In this review, we discussed the mechanisms and pathways underlying radioresistance due to hypoxia and metabolic reprogramming in detail, including DNA repair, role of cancer stem cells, oxidative stress relief, autophagy regulation, angiogenesis and immune escape. In addition, we proposed the existence of a feedback loop between energy metabolic reprogramming and hypoxia, which is associated with the development and exacerbation of radioresistance in tumors. Simultaneous blockade of this feedback loop and other tumor-specific targets can be an effective approach to overcome radioresistance of cancer cells. This comprehensive overview provides new insights into the mechanisms underlying tumor radiosensitivity and progression.
放射治疗是癌症治疗的主流方法之一，尽管由于肿瘤细胞的放射抗性，临床疗效有限。缺氧和代谢重编程是肿瘤发生和进展的标志，并且与放射抗性密切相关。在肿瘤内部，血管生成的速度落后于细胞增殖，一些部位血管发育不全和功能异常导致癌细胞缺氧，即低氧状态。这使得辐射无法有效地清除低氧癌细胞。癌细胞转向糖酵解作为主要能量来源，这种现象称为瓦伯格效应，以维持其快速增殖率。因此，参与代谢重编程和缺氧诱导的放射抗性的途径是癌症治疗有前景的干预靶点。在本综述中，我们详细讨论了缺氧和代谢重编程导致放射抗性的机制和途径，包括DNA修复、癌症干细胞的作用、氧化应激缓解、自噬调节、血管生成和免疫逃逸。此外，我们提出能量代谢重编程和缺氧之间存在反馈回路，这与肿瘤放射抗性的发展和加剧有关。同时阻断该反馈回路和其他肿瘤特异性靶点可能是克服癌细胞放射抗性的有效方法。这一全面概述为肿瘤放射敏感性和进展的潜在机制提供了新的见解。
