A new study shows that breast cancer spreads more efficiently while patients are sleeping. The finding could significantly change the way cancer is diagnosed and treated in future.
A study in Nature Medicine shows that cancer cells migrate from a tumour through the bloodstream mainly during sleep. Researchers from the Swiss Federal Institute of Technology studied patients with breast cancer and mouse models.
Cancer metastasises when cells break free from a primary tumour and travel to other body sites through the bloodstream. These cells, known as circulating tumour cells (CTCs) retain their ability to proliferate. Until now, it was often assumed that CTCs were shed constantly from tumours or were shed due to mechanical insults.
The research community has been discussing for decades how the body’s circadian rhythm influences cancer. These findings indicate that circadian rhythms have a much bigger role in cancer metastases than previously realised. With this study, it has become clear that “tumours wake up when patients are sleeping”, says co-author Nicola Aceto in a Nature Comment.
When studying patients with breast cancer, the authors took blood samples at 4 am (the body’s resting phase) and 10 am (the body’s active phase). Remarkably, almost 80% of all the CTCs obtained were from the resting-phase samples.
To test the generality of these findings and characterise the timing of the events, the authors then used four mouse models of breast cancer. The level of CTCs in the models fluctuated, peaking when the mice were resting. The authors next monitored CTC levels when the circadian rhythms of the mice were disrupted, either through hormone treatment, alterations in light cycles or genetic manipulation. Again, in each model, CTC levels were highest when the mice were resting.
The researchers then analysed the ability of rest- and active-phase CTCs to metastasise and form tumours in mouse models during different phases of the animals’ circadian cycle. Rest-phase CTCs not only formed tumours more aggressively than active-phase CTCs, but were also more likely to form tumours when injected into resting mice than into active mice. In other words, rest-phase CTCs were highly metastatic but active-phase CTCs lacked metastatic ability.
To understand the molecular mechanisms driving the aggressive properties of rest-phase CTCs, the authors conducted single-cell RNA sequencing of CTCs. This showed that mitotic genes were exclusively upregulated during the rest phase in patients and mouse models, which enabled metastatic proficiency.
Further experiments showed that key circadian rhythm hormones such as melatonin, testosterone and glucocorticoids dictated the dynamics of CTC generation. As a consequence, insulin directly promoted the proliferation of tumour cells in a time-dependent manner.
The findings need to be replicated in large-scale clinical trials before circadian rhythms can be incorporated into cancer care.
According to the authors, the results provide “a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers.”
However, the researchers note in a Nature Comment that the findings aren’t an indication that you don’t need sleep, or that you need less sleep. It simply means these cells prefer a specific phase of the 24-hour cycle to go into the bloodstream.
Written by Charlotte Harrison, Science Writer
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