Doubts in cancer-rhythms connections Circadian clocks help to coordinate physiological processes with the daily cycles of light and dark and periods of feeding, activity, and rest. Being out of sync with such 24-hour cycles can have unhealthy effects. Sancar and Van Gelder review the available evidence regarding circadian disruption and predisposition to cancer and circadian variations in response to cancer chemotherapy. The literature can be difficult to interpret. For example, complete knockouts of clock genes are not the same as shift work. Overall, they find that the jury is still out on whether circadian disruption can promote cancer in general and if the timing of cancer treatment can be optimized. However, enough indications are present that further research is recommended. Science, this issue p. 42 BACKGROUND The core of the mammalian circadian clock mechanism is a time-delayed transcription-translation feedback loop (TTFL), which influences the transcription and expression of a large fraction of the transcriptome. Through this mechanism, the mammalian circadian clock modulates many physiological functions, including the timing of cell division and rates of metabolism in specific tissues. Circadian clock dysfunction is associated with several human disease states, including jet lag and sleep phase disorders, and it likely contributes significantly to the development of metabolic syndrome. With respect to cancer, animal studies have suggested that specific carcinogenic mechanisms, such as ultraviolet radiation for skin cancer, have a strong circadian rhythm. Epidemiologic studies have yielded conflicting results as to whether circadian clock disruption by night or shift work is carcinogenic. In animal studies, tumors grafted into animals with disrupted rhythms grow more rapidly than those grafted into control animals. Studies of mice genetically lacking specific components of the circadian clock show increased rates of tumorigenesis for certain clock genes and certain tumors but show reduced rates for other clock genes. Similarly, the response to chemotherapy may also vary with time of day, which has led to enthusiasm for chronochemotherapy as a means to improve the therapeutic efficacy of cancer treatment while limiting toxicity. However, clinical trials of chronochemotherapy have generally not shown improved efficacy and have even shown worse outcomes in subsets of patients compared with conventionally timed therapies. ADVANCES Polymorphisms in circadian clock genes including Npas2 and Clock have been identified in genome-wide association studies as relatively weak but significant modifiers of breast cancer incidence, and core circadian clock gene expression is frequently dysregulated in human tumors. However, it is not possible to generalize that loss of the clock leads to increased cancer incidence, as some clockless animals actually show resistance to specific cancer pathways (e.g., Cryptochrome-less mice are resistant to p53 mutation–induced tumors). In other cases, different clock gene mutations result in opposite phenotypes with respect to carcinogenesis for the same tumor type. Perhaps the best-studied mechanistic interaction between circadian clock and carcinogenesis involves studies of the circadian rhythms of nucleotide excision DNA repair. Although basal excision repair has a circadian rhythm with a specific maximal phase, the rhythm of an individual gene’s repair is dependent on the phase of that gene’s transcriptional rhythm; there is no single phase at which DNA is generally more or less easily repaired. Other notable advances in the field include the demonstration of direct mechanistic linkage of c-MYC expression to circadian clock control and the demonstration that oncogenes c-Myc, p53, and Ras all affect the circadian core TTFL, consistent with the finding that the circadian clock of tumors is frequently dysregulated. OUTLOOK Tumorigenesis is clearly affected by circadian mechanisms, but the hypothesis that circadian clock genes are general tumor suppressors is not supported. Rather, specific tumors and their underlying mechanisms are differentially affected by the function of specific clock genes. Conversely, specific oncogenes may cause dysregulation of the circadian clock in tumors; the pathogenic significance of the dysregulated clock in tumors is not fully understood. The example of circadian control of DNA nucleotide excision repair illuminates the challenges in exploiting the interaction between clocks and cancer clinically, as the phase of circadian susceptibility to DNA damage varies for each gene on the basis of its underlying transcriptional rhythm. Although the concept of chronochemotherapy is attractive, the complexities of clock-cancer interactions make prediction of the effects of timed drug administration challenging. Mistiming of chemotherapeutic agents has the potential to be harmful. As chemotherapeutic agents increase in specificity, the circadian effects of administration may be better understood and optimized by understanding the specific interactions between the circadian clock mechanism and therapeutic targets. Mammalian circadian clock controls transcription and DNA repair. (Left) The mammalian circadian clock mechanism is a time-delayed TTFL. BMAL1-CLOCK constitute the positive arm and cryptochrome (CRY1 and CRY2)–period (PER1 and PER2) constitute the repressive arm; the primary feedback loop is consolidated by a secondary loop made up of REV-ERBα inhibitor and RORα activator. In a given tissue, ~10% of the genes are expressed with significant circadian (near–24 hour) periodicity. (Right) Effect of the clock on transcription and nucleotide excision repair in mice is shown in two heatmaps, where the green (transcription) and yellow (repair) represent the intensity of the signal. The left-side expression heatmap shows 854 clock-controlled transcripts in the livers of mice kept in the dark for 44 hours [adapted from B. H. Miller et al., Proc. Natl. Acad. Sci. U.S.A. 104, 3342 (2007), Copyright (2007) National Academy of Sciences]. Each of these genes is expressed maximally at a specific time of day. The right-side repair heatmap shows 1661 genes from the kidneys of mice kept under a 12-hour light–12-hour dark condition treated with the chemotherapeutic cisplatin [adapted from Y. Yang et al., Proc. Natl. Acad Sci. U.S.A. 115, E4777 (2018), Copyright (2018) National Academy of Sciences]. Damage is quantified for both transcribed strands (TS) and nontranscribed strands (NTS). The NTS shows a monophasic rhythm for all genes with a peak in early evening. For the TS, each gene shows a specific maximum for repair during the cycle corresponding to its peak phase of transcription. The complexity of individual gene repair timing creates substantial challenges for optimizing circadian timing of chemotherapy administration. The circadian clock coordinates daily rhythmicity of biochemical, physiologic, and behavioral functions in humans. Gene expression, cell division, and DNA repair are modulated by the clock, which gives rise to the hypothesis that clock dysfunction may predispose individuals to cancer. Although the results of many epidemiologic and animal studies are consistent with there being a role for the clock in the genesis and progression of tumors, available data are insufficient to conclude that clock disruption is generally carcinogenic. Similarly, studies have suggested a circadian time-dependent efficacy of chemotherapy, but clinical trials of chronochemotherapy have not demonstrated improved outcomes compared with conventional regimens. Future hypothesis-driven and discovery-oriented research should focus on specific interactions between clock components and carcinogenic mechanisms to realize the full clinical potential of the relationship between clocks and cancer.

中文翻译：

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时钟、癌症和时间化学疗法

对癌症与节律联系的怀疑 生物钟有助于协调生理过程与每日的明暗周期以及进食、活动和休息时间。与这种 24 小时周期不同步可能会产生不健康的影响。Sancar 和 Van Gelder 回顾了有关昼夜节律紊乱和癌症易感性以及对癌症化疗反应的昼夜节律变化的现有证据。文献可能难以解释。例如，时钟基因的完全敲除与轮班工作不同。总体而言，他们发现，昼夜节律紊乱是否会促进癌症的发生，以及癌症治疗的时机是否可以优化，尚无定论。但是，有足够的迹象表明建议进一步研究。科学，这个问题 p。42 背景 哺乳动物生物钟机制的核心是延时转录-翻译反馈环 (TTFL)，它影响大部分转录组的转录和表达。通过这种机制，哺乳动物的生物钟调节许多生理功能，包括细胞分裂的时间和特定组织的新陈代谢率。生物钟功能障碍与多种人类疾病状态有关，包括时差和睡眠时相障碍，并且它可能对代谢综合征的发展有重大影响。关于癌症，动物研究表明，特定的致癌机制，例如皮肤癌的紫外线辐射，具有强烈的昼夜节律。关于夜间或轮班工作造成的生物钟紊乱是否致癌，流行病学研究得出了相互矛盾的结果。在动物研究中，移植到节律紊乱的动物体内的肿瘤比移植到对照动物体内的肿瘤生长得更快。对遗传上缺乏生物钟特定成分的小鼠的研究表明，某些生物钟基因和某些肿瘤的肿瘤发生率增加，但其他生物钟基因的发生率降低。同样，对化疗的反应也可能随着一天中的时间而变化，这导致人们对计时化疗作为一种提高癌症治疗疗效同时限制毒性的手段的热情。然而，与常规定时疗法相比，计时化学疗法的临床试验通常没有显示出更好的疗效，甚至在部分患者中显示出更差的结果。进展 在全基因组关联研究中，包括 Npas2 和 Clock 在内的生物钟基因的多态性已被确定为相对较弱但显着的乳腺癌发病率调节剂，并且核心生物钟基因表达在人类肿瘤中经常失调。然而，不可能一概而论，时钟的丧失会导致癌症发病率的增加，因为一些无时钟的动物实际上表现出对特定癌症途径的抵抗力（例如，无隐花色素的小鼠对 p53 突变诱导的肿瘤具有抵抗力）。在其他情况下，对于相同的肿瘤类型，不同的时钟基因突变导致不同的致癌表型。也许对生物钟和致癌作用之间研究最多的机械相互作用涉及核苷酸切除 DNA 修复的昼夜节律的研究。尽管基底切除修复具有特定最大时相的昼夜节律，但单个基因修复的节律取决于该基因转录节律的时相；不存在 DNA 通常或多或少容易修复的单一阶段。该领域的其他显着进展包括证明 c-MYC 表达与生物钟控制的直接机械联系，以及证明致癌基因 c-Myc、p53 和 Ras 都影响昼夜节律核心 TTFL，与肿瘤生物钟经常失调的发现一致。展望 肿瘤发生显然受到昼夜节律机制的影响，但不支持昼夜节律基因是一般肿瘤抑制因子的假设。相反，特定的肿瘤及其潜在机制受到特定时钟基因功能的不同影响。相反，特定的癌基因可能会导致肿瘤生物钟失调；肿瘤中时钟失调的致病意义尚不完全清楚。DNA 核苷酸切除修复的昼夜节律控制的例子说明了在临床上利用时钟与癌症之间的相互作用的挑战，因为每个基因对 DNA 损伤的昼夜节律易感性的阶段根据其潜在的转录节律而异。尽管时间化学疗法的概念很有吸引力，但时钟与癌症相互作用的复杂性使得预测定时给药的效果具有挑战性。化疗药物的误用有可能是有害的。随着化疗药物特异性的增加，通过了解生物钟机制和治疗靶点之间的特定相互作用，可以更好地理解和优化给药的昼夜节律效应。哺乳动物生物钟控制转录和 DNA 修复。（左）哺乳动物的生物钟机制是延时 TTFL。BMAL1-CLOCK 构成阳性臂，隐花色素（CRY1 和 CRY2）-周期（PER1 和 PER2）构成抑制臂；初级反馈回路由由 REV-ERBα 抑制剂和 RORα 激活剂组成的二级回路巩固。在给定的组织中，约 10% 的基因以显着的昼夜节律（近 24 小时）周期性表达。（右）时钟对小鼠转录和核苷酸切除修复的影响显示在两个热图中，其中绿色（转录）和黄色（修复）代表信号强度。左侧表达热图显示在黑暗中保持 44 小时的小鼠肝脏中有 854 个时钟控制的转录本 [改编自 BH Miller 等人，Proc. 纳特尔。阿卡德。科学。美国 104, 3342 (2007)，版权所有 (2007) 美国国家科学院]。这些基因中的每一个都在一天中的特定时间最大程度地表达。右侧修复热图显示了小鼠肾脏的 1661 个基因，这些基因保持在 12 小时光照 - 12 小时黑暗条件下，用顺铂化疗 [改编自 Y. Yang 等人，Proc. 纳特尔。Acad 科学。美国 115, E4777 (2018), 版权所有 (2018) 美国国家科学院]。对转录链 (TS) 和非转录链 (NTS) 的损伤进行量化。NTS 显示所有基因的单相节律，峰值出现在傍晚。对于 TS，每个基因在与其转录高峰期相对应的循环期间显示出特定的最大修复量。个体基因修复时间的复杂性为优化化疗给药的昼夜节律时间带来了巨大挑战。生物钟协调人类生化、生理和行为功能的日常节律。基因表达、细胞分裂和 DNA 修复受时钟调节，这就产生了时钟功能障碍可能使个体易患癌症的假设。尽管许多流行病学和动物研究的结果与生物钟在肿瘤发生和进展中的作用一致，但现有数据不足以得出生物钟紊乱通常具有致癌性的结论。同样，研究表明化疗具有昼夜节律时间依赖性疗效，但与常规方案相比，计时化疗的临床试验并未显示出改善的结果。未来的假设驱动和以发现为导向的研究应侧重于时钟组件和致癌机制之间的特定相互作用，以实现时钟与癌症之间关系的全部临床潜力。现有数据不足以得出时钟中断通常具有致癌性的结论。同样，研究表明化疗具有昼夜节律时间依赖性疗效，但与常规方案相比，计时化疗的临床试验并未显示出改善的结果。未来的假设驱动和以发现为导向的研究应侧重于时钟组件和致癌机制之间的特定相互作用，以实现时钟与癌症之间关系的全部临床潜力。现有数据不足以得出时钟中断通常具有致癌性的结论。同样，研究表明化疗具有昼夜节律时间依赖性疗效，但与常规方案相比，计时化疗的临床试验并未显示出改善的结果。未来的假设驱动和以发现为导向的研究应侧重于时钟组件和致癌机制之间的特定相互作用，以实现时钟与癌症之间关系的全部临床潜力。