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2007年，世界卫生组织国际癌症研究机构将昼夜节律紊乱列为可能致癌因素，此前长期研究也得出结论，空乘人员和倒班护士等长期夜间工作者发生乳腺癌的风险较高。 2022年6月22日，全球自然科学三大旗舰期刊之首、英国《自然》正刊发表瑞士苏黎世联邦理工学院、巴塞尔大学、巴塞尔大学医院、巴塞尔州立医院的研究报告，发现睡眠期间乳腺癌转移扩散反而加速。 乳腺癌的转移扩散，主要通过血液循环肿瘤细胞血行传播实现。不过，一般而言，决定血液循环肿瘤细胞转移能力产生的时间动力学特征尚不明确，并且通常认为血液循环肿瘤细胞是全天不断从生长的肿瘤中脱落或由于机械损伤而脱落。 该研究对21例早期乳腺癌和9例晚期乳腺癌住院患者、激素受体阳性乳腺癌（BR16）和三阴性乳腺癌（MDA-MB-231、4T1）小鼠模型进行观察，发现其血液循环肿瘤细胞生成动力学模式独特，出乎意料的是，大多数自发血液循环肿瘤细胞内渗事件发生于睡眠期间（人类为夜间，小鼠为白天）。 
此外，该研究证实，睡眠期血液循环肿瘤细胞非常容易转移，而活动期产生的血液循环肿瘤细胞缺乏转移能力。 
对血液循环肿瘤细胞进行单细胞RNA测序分析表明，乳腺癌患者和乳腺癌小鼠模型的有丝分裂基因仅高表达于睡眠期，从而提高转移能力。 
全身的褪黑激素、睾酮、糖皮质激素等昼夜节律关键激素可决定血液循环肿瘤细胞生成动力学，而体内胰岛素随着昼夜节律可直接促进肿瘤细胞增殖。 
因此，该研究结果表明，具有高转移倾向的血液循环肿瘤细胞自发生成并非全天连续发生，而是集中于受影响个体的睡眠期，这提示我们开展乳腺癌研究和临床治疗时，有必要记录时间并且考虑昼夜节律的影响因素。 对此，密歇根大学发表同期述评：睡眠期间癌细胞扩散加速。《自然》也配发同期报道：这些癌细胞在人们睡觉时醒来。 
相关链接 Nature. 2022 Jun 22. Online ahead of print.The metastatic spread of breast cancer accelerates during sleep.Zoi Diamantopoulou, Francesc Castro-Giner, Fabienne Dominique Schwab, Christiane Foerster, Massimo Saini, Selina Budinjas, Karin Strittmatter, Ilona Krol, Bettina Seifert, Viola Heinzelmann-Schwarz, Christian Kurzeder, Christoph Rochlitz, Marcus Vetter, Walter Paul Weber, Nicola Aceto.Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland; University of Basel, Basel, Switzerland; University Hospital Basel, Basel, Switzerland; University Hospital Basel and University of Basel, Basel, Switzerland; Cantonal Hospital Basel-Land, Liestal, Switzerland.A study of patients with breast cancer and mouse models demonstrates that most circulating tumour cells are generated during the rest phase of the circadian rhythm, and that these cells are highly prone to metastasize.The metastatic spread of cancer is achieved by the haematogenous dissemination of circulating tumour cells (CTCs). Generally, however, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized, and it is often assumed that CTCs are constantly shed from growing tumours or are shed as a consequence of mechanical insults1. Here we observe a striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and mouse models, highlighting that most spontaneous CTC intravasation events occur during sleep. Further, we demonstrate that rest-phase CTCs are highly prone to metastasize, whereas CTCs generated during the active phase are devoid of metastatic ability. Mechanistically, single-cell RNA sequencing analysis of CTCs reveals a marked upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models, enabling metastasis proficiency. Systemically, we find that key circadian rhythm hormones such as melatonin, testosterone and glucocorticoids dictate CTC generation dynamics, and as a consequence, that insulin directly promotes tumour cell proliferation in vivo, yet in a time-dependent manner. Thus, the spontaneous generation of CTCs with a high proclivity to metastasize does not occur continuously, but it is concentrated within the rest phase of the affected individual, providing a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers.DOI: 10.1038/s41586-022-04875-yNature. 2022 Jun 22. Online ahead of print.Cancer cells spread aggressively during sleep.Harrison Ball, Sunitha Nagrath.
Rogel Cancer Center, Bio-interfaces Institute, University of Michigan, Ann Arbor, Michigan, USA.The deadly spread of cancer occurs predominantly during sleep, as revealed by an analysis of migrating human tumour cells in the bloodstream. What are the implications of this finding for the treatment of cancer?DOI: 10.1038/d41586-022-01639-6Nature. 2022 Jun 22. Online ahead of print.These cancer cells wake up when people sleep.Researchers make 'striking' discovery that breast cancer cells are more likely to jump into the blood when people are resting.DOI: 10.1038/d41586-022-01724-w
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