Kabakov Alexander E, Yakimova Anna O
Department of Radiation Biochemistry, A. Tsyb Medical Radiological Research Center-Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Koroleva 4, 249036 Obninsk, Russia.
Cancers (Basel). 2021 Mar 4;13(5):1102. doi: 10.3390/cancers13051102.
Within aggressive malignancies, there usually are the "hypoxic zones"-poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial-mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.
在侵袭性恶性肿瘤中，通常存在“缺氧区域”，即血管化不良的区域，肿瘤细胞因血液供应不足而缺氧。此外，抗血管生成治疗或经动脉栓塞可能导致肿瘤出现缺氧。为适应缺氧，肿瘤细胞获得一种抗缺氧表型，在信号传导、基因表达和代谢方面发生特征性改变。缺氧本身以及缺氧反应性表型调节都使肿瘤细胞对放疗更具抗性，因此缺氧肿瘤对放射治疗构成严峻挑战。了解缺氧肿瘤放射抗性的原因有助于开发克服这一挑战的新方法。本综述探讨了缺氧肿瘤放射增敏的分子靶点和各种方法。本文分析了缺氧诱导的细胞反应，包括缺氧诱导因子-1、热休克转录因子1、热休克蛋白、葡萄糖调节蛋白、表观遗传调节因子、自噬、能量代谢重编程、上皮-间质转化和外泌体生成，如何导致缺氧肿瘤的放射抗性，或可如何被抑制以减弱这种放射抗性。对癌细胞适应缺氧进行多靶点抑制的预处理似乎是使缺氧性癌、胶质瘤、淋巴瘤、肉瘤对放疗敏感，以及使肝肿瘤对放射性栓塞敏感的一种有前景的方法。
