Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Department of Biochemistry and Molecular & Cellular Biology and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
Curr Oncol. 2023 Jun 7;30(6):5497-5514. doi: 10.3390/curroncol30060416.
Ionizing radiation (IR) dose, dose rate, and linear energy transfer (LET) determine cellular DNA damage quality and quantity. High-LET heavy ions are prevalent in the deep space environment and can deposit a much greater fraction of total energy in a shorter distance within a cell, causing extensive DNA damage relative to the same dose of low-LET photon radiation. Based on the DNA damage tolerance of a cell, cellular responses are initiated for recovery, cell death, senescence, or proliferation, which are determined through a concerted action of signaling networks classified as DNA damage response (DDR) signaling. The IR-induced DDR initiates cell cycle arrest to repair damaged DNA. When DNA damage is beyond the cellular repair capacity, the DDR for cell death is initiated. An alternative DDR-associated anti-proliferative pathway is the onset of cellular senescence with persistent cell cycle arrest, which is primarily a defense mechanism against oncogenesis. Ongoing DNA damage accumulation below the cell death threshold but above the senescence threshold, along with persistent SASP signaling after chronic exposure to space radiation, pose an increased risk of tumorigenesis in the proliferative gastrointestinal (GI) epithelium, where a subset of IR-induced senescent cells can acquire a senescence-associated secretory phenotype (SASP) and potentially drive oncogenic signaling in nearby bystander cells. Moreover, DDR alterations could result in both somatic gene mutations as well as activation of the pro-inflammatory, pro-oncogenic SASP signaling known to accelerate adenoma-to-carcinoma progression during radiation-induced GI cancer development. In this review, we describe the complex interplay between persistent DNA damage, DDR, cellular senescence, and SASP-associated pro-inflammatory oncogenic signaling in the context of GI carcinogenesis.
电离辐射（IR）剂量、剂量率和线性能量传递（LET）决定了细胞 DNA 损伤的质量和数量。高 LET 重离子在深空中环境中很常见，它们可以在细胞内更短的距离内沉积更多的总能量，与相同剂量的低 LET 光子辐射相比，造成广泛的 DNA 损伤。基于细胞对 DNA 损伤的耐受性，细胞会启动恢复、细胞死亡、衰老或增殖的反应，这些反应是通过信号网络的协同作用来确定的，这些信号网络被归类为 DNA 损伤反应（DDR）信号。IR 诱导的 DDR 会启动细胞周期停滞以修复受损的 DNA。当 DNA 损伤超出细胞修复能力时，就会启动 DDR 以促进细胞死亡。另一种与 DDR 相关的抗增殖途径是细胞衰老的发生，伴有持续的细胞周期停滞，这主要是一种针对致癌作用的防御机制。在低于细胞死亡阈值但高于衰老阈值的持续 DNA 损伤积累，以及在慢性暴露于空间辐射后持续的 SASP 信号，增加了增殖性胃肠道（GI）上皮中肿瘤发生的风险，其中一部分 IR 诱导的衰老细胞可以获得衰老相关的分泌表型（SASP），并可能在附近的旁观者细胞中驱动致癌信号。此外，DDR 的改变可能导致体细胞基因突变，以及促炎、致癌的 SASP 信号的激活，已知这种信号会加速辐射诱导的 GI 癌症发展过程中腺瘤向癌的进展。在这篇综述中，我们描述了持续的 DNA 损伤、DDR、细胞衰老和与 SASP 相关的促炎致癌信号之间在 GI 癌变中的复杂相互作用。
