How important is sleep?
For the "migrant workers" who are tired of dealing with heavy work, pushing bosses and complex interpersonal relationships every day, sleeping is simply the existence of "returning to the city to return blood". As the saying goes, "if you don't sleep at noon, you will collapse in the afternoon; if you don't sleep at night, you will collapse in the day". Adequate sleep makes you flexible and energetic; On the other hand, modern science also shows that good sleep also has the advantages of promoting metabolism, increasing memory and improving body immunity. It has to be said that sleeping is the most important activity besides eating.
However, it seems that this kind of sleep, which is "Baili but harmless", has recently "overturned". A research paper published in the international top academic journal Nature entitled: the metallic spread of breast cancer accelerates during sleep lists an unexpected "side effect of sleep" -- when you lie in bed and fall asleep, the tumor cells in your body may "sneak to the ground" while you are asleep and complete the diffusion with the blood circulation!
Circulating tumor cells (CTC) play an important role in this process. Malignant tumors often spread to other organs of the body through the blood, and tumor metastasis is the main cause of death of tumor patients. Tumor cells invade the surrounding tissues of the primary tumor, enter the blood and lymphatic system, form CTC, transport to the distal tissue, then exude again, adapt to the new microenvironment, and finally "sow", "proliferate", "colonize", and form metastatic foci. Therefore, the level of CTC in blood is also regarded as an important basis for evaluating the degree of tumor metastasis.
In this study, in order to investigate the metastasis characteristics of circulating tumor cells, the researchers recruited 30 female breast cancer patients, of which 21 were early breast cancer (no metastasis) and 9 were stage IV metastatic diseases. The same is that they are in the state of not receiving treatment or temporarily stopping treatment. Subsequently, the researchers collected their blood samples during the daytime activity period (10 a.m.) and the night sleep period (4 a.m.). Unexpectedly, the analysis results showed that the circulating tumor cells in the blood samples collected during sleep were as high as 78.3%!
Left, human circadian rhythm; The right figure shows the percentage of single CTC, CTC clusters, and ctc-wbc clusters separated during rest and activity in patients with early or advanced breast cancer
"Sunset and rest" actually contributed to the spread of cancer cells! In order to find out whether this fantastic result is "accidental deviation" or "scientific truth", researchers designed a batch of breast cancer mouse models for deeper analysis. Interestingly, consistent with the data of patients with breast cancer, more than 90% of circulating tumor cells appeared in the sleep phase of mice; Moreover, due to the living habits of mice in the daytime and out at night, their breast cancer tumors are more active in the daytime.
Analysis of circadian rhythm and time dynamics in mice
So, is the tumor spread in mice due to circadian rhythm? Based on this doubt, scientists artificially damaged the biological clock of mice, making their work and rest disordered, and re analyzed the blood samples after a period of time. The results showed that compared with normal mice, the number of single CTC and CTC clusters in dysrhythmic mice decreased by 38~282 times and 63~484 times, and the size of primary tumor did not change. It is obvious that even if the circadian rhythm of mice is disturbed, the tumor metastasis in their bodies still rises at rest (sleep) and decreases when they are active (awake).
CTC content in mice with impaired circadian rhythm
At this time, a question popped up in the minds of researchers: apart from the increase in the sleep phase, does CTC also have different metastatic potential at different stages of the circadian rhythm?
With this conjecture, they built a xenogeneic mouse transplantation model. At different time points of the circadian rhythm, zt0, ZT4 (corresponding to the rest time of the mice), zt12, zt16 (corresponding to the activity time of the mice) collected the spontaneously exfoliated CTCs, and injected them into the mice through the caudal vein to determine the direct transfer ability of CTC. Surprisingly, most of the tumor metastases occurred in ZT4 (mouse sleep time), indicating that the CTC that fell off during the rest period also had a stronger ability to metastasize.
The CTC spontaneously shed from mice was injected into tumor free mice through tail vein, and its direct metastasis ability was measured at different time points of circadian rhythm (zt0, ZT4, zt12, zt16)
Single cell RNA sequencing analysis of these circulating tumor cells showed that mitosis related genes were significantly up-regulated during the rest period. Compared with the circulating tumor cells shed in the active phase, the circulating tumor cells shed in the sleep phase will divide faster, so they have a higher tendency of tumor metastasis.
Single cell RNA sequencing of CTC from patients with breast cancer
So, the question arises: since the proliferation of circulating tumor cells in the body is affected by circadian rhythms, can rhythm related hormones regulate the metastasis of CTC? This inspiration inspired researchers to find that this enhanced tumor metastasis ability is indeed affected by the effects of circadian rhythm regulating hormones (such as testosterone and glucocorticoids), and they determine the formation kinetics of circulating tumor cells.
Circadian hormone regulates intravascular infiltration of CTC
At this point, most readers must be shaking with their pillows and afraid to go to sleep. In fact, the significance of this study is more to inspire oncologists or doctors to test and treat cancer patients at a specific time.
As the corresponding author Aceto said, "some of my colleagues work in the early morning or late afternoon. Sometimes, they also analyze blood samples at irregular times. This study tells us that medical staff may need to systematically record the time when they perform tissue biopsy, which will help to obtain more comparable data."
Reference:
Diamantopoulou Z, Castro-Giner F, Schwab FD, Foerster C, Saini M, Budinjas S, Strittmatter K, Krol I, Seifert B, Heinzelmann-Schwarz V, Kurzeder C, Rochlitz C, Vetter M, Weber WP, Aceto N. The metastatic spread of breast cancer accelerates during sleep. Nature. 2022 Jun 22. doi: 10.1038/s41586-022-04875-y.
Article link:
https://www.medsci.cn/article/show_article.do;jsessionid=D6E4AA68370D0F526E51D688B26709A4?id=1b97e30610a2
