Insights into radiation carcinogenesis based on dose-rate effects in tissue stem cells.

IF 2.1 4区 医学 Q2 BIOLOGY International Journal of Radiation Biology Pub Date : 2023-01-01 Epub Date: 2023-03-31 DOI:10.1080/09553002.2023.2194398
Kensuke Otsuka, Toshiyasu Iwasaki
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Abstract

Purpose: Increasing epidemiological and biological evidence suggests that radiation exposure enhances cancer risk in a dose-dependent manner. This can be attributed to the 'dose-rate effect,' where the biological effect of low dose-rate radiation is lower than that of the same dose at a high dose-rate. This effect has been reported in epidemiological studies and experimental biology, although the underlying biological mechanisms are not completely understood. In this review, we aim to propose a suitable model for radiation carcinogenesis based on the dose-rate effect in tissue stem cells.

Methods: We surveyed and summarized the latest studies on the mechanisms of carcinogenesis. Next, we summarized the radiosensitivity of intestinal stem cells and the role of dose-rate in the modulation of stem-cell dynamics after irradiation.

Results: Consistently, driver mutations can be detected in most cancers from past to present, supporting the hypothesis that cancer progression is initiated by the accumulation of driver mutations. Recent reports demonstrated that driver mutations can be observed even in normal tissues, which suggests that the accumulation of mutations is a necessary condition for cancer progression. In addition, driver mutations in tissue stem cells can cause tumors, whereas they are not sufficient when they occur in non-stem cells. For non-stem cells, tissue remodeling induced by marked inflammation after the loss of tissue cells is important in addition to the accumulation of mutations. Therefore, the mechanism of carcinogenesis differs according to the cell type and magnitude of stress. In addition, our results indicated that non-irradiated stem cells tend to be eliminated from three-dimensional cultures of intestinal stem cells (organoids) composed of irradiated and non-irradiated stem cells, supporting the stem-cell competition.

Conclusions: We propose a unique scheme in which the dose-rate dependent response of intestinal stem cells incorporates the concept of the threshold of stem-cell competition and context-dependent target shift from stem cells to whole tissue. The concept highlights four key issues that should be considered in radiation carcinogenesis: i.e. accumulation of mutations; tissue reconstitution; stem-cell competition; and environmental factors like epigenetic modifications.

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基于组织干细胞剂量率效应的辐射致癌研究。
目的:越来越多的流行病学和生物学证据表明,辐射暴露以剂量依赖的方式增加癌症风险。这可归因于“剂量率效应”,即低剂量率辐射的生物学效应低于高剂量率下相同剂量的生物学效应。流行病学研究和实验生物学中已经报道了这种影响,尽管其潜在的生物学机制尚不完全清楚。在这篇综述中,我们的目的是基于组织干细胞的剂量率效应,提出一个合适的辐射致癌模型。方法:对肿瘤发生机制的最新研究进行综述。接下来,我们总结了肠道干细胞的放射敏感性以及剂量率在辐射后干细胞动力学调节中的作用。结果:从过去到现在,在大多数癌症中都可以检测到驱动突变,这支持了癌症进展是由驱动突变积累引发的假设。最近的报告表明,即使在正常组织中也可以观察到驱动突变,这表明突变的积累是癌症进展的必要条件。此外,组织干细胞中的驱动突变会导致肿瘤,而当它们发生在非干细胞中时还不够。对于非干细胞来说,除了突变的积累外,组织细胞损失后由显著炎症诱导的组织重塑也很重要。因此,致癌机制因细胞类型和应激程度而异。此外,我们的研究结果表明,未经辐照的干细胞往往会从由经辐照和未经辐照干细胞组成的肠道干细胞(类器官)的三维培养物中被消除,从而支持干细胞的竞争。结论:我们提出了一种独特的方案,其中肠道干细胞的剂量率依赖性反应结合了干细胞竞争阈值和从干细胞到整个组织的上下文依赖性靶点转移的概念。该概念强调了辐射致癌过程中应考虑的四个关键问题:即突变的积累;组织重建;干细胞竞争;以及环境因素,如表观遗传修饰。
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来源期刊
CiteScore
5.00
自引率
11.50%
发文量
142
审稿时长
3 months
期刊介绍: The International Journal of Radiation Biology publishes original papers, reviews, current topic articles, technical notes/reports, and meeting reports on the effects of ionizing, UV and visible radiation, accelerated particles, electromagnetic fields, ultrasound, heat and related modalities. The focus is on the biological effects of such radiations: from radiation chemistry to the spectrum of responses of living organisms and underlying mechanisms, including genetic abnormalities, repair phenomena, cell death, dose modifying agents and tissue responses. Application of basic studies to medical uses of radiation extends the coverage to practical problems such as physical and chemical adjuvants which improve the effectiveness of radiation in cancer therapy. Assessment of the hazards of low doses of radiation is also considered.
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