Breast cancer can apparently develop malignant wanderlust, especially at night: the spread of the disease through the formation of metastases mainly takes place during sleep, researchers report. This emerges from an analysis of tumor cells in the blood of patients and from studies in the mouse model. Apparently, the hormone concentrations in the body that change during sleep play a role in this effect. The findings could be of importance for the diagnosis of cancer diseases and their treatment, say the scientists.
“The cancer has metastasized…” This finding is one of the worst things doctors have to tell their patients. Because the chances of survival for those affected are drastically reduced when a primary tumor has formed daughter colonies in the body. This also applies to one of the most common types of cancer: around 2.3 million people worldwide are diagnosed with breast cancer every year. In the early stages, patients usually respond well to treatment. However, there is a great danger if so-called circulating cancer cells detach from the original tumor, migrate through the body via blood vessels and form new tumors in other organs. Due to its great importance for the course of the disease, the process of metastasis has long been the focus of cancer research.
Target evil pioneers
However, one aspect has apparently received little attention up to now: the extent to which the time of day has an influence on how strongly tumors secrete metastatic cells. It was simply assumed that this would take place continuously. The research team led by Nicola Aceto from the Swiss Federal Institute of Technology in Zurich (ETH) only came across the research topic by accident: “Some of my colleagues work early in the morning or late in the evening and sometimes they also analyze blood samples at very unusual times,” says the cancer researcher. The findings showed that the samples taken at different times of the day showed very different amounts of circulating cancer cells. The scientists specifically followed this lead.
They took blood samples from 30 people with breast cancer at 4 a.m. and 10 a.m. – when the body is at rest as opposed to when it is active. These samples were then assayed for levels of circulating cancer cells (CTCs) by laboratory methods. It was found that in the phase associated with sleep, significantly more of the potentially dangerous cells are on the move in the body than in the morning. Subsequent studies on mice, which serve as a model for breast cancer, then confirmed this finding: the CTC concentration in the animals fluctuated and peaked when the mice were at rest.
Particularly keen on wandering and aggressive
The researchers also recorded CTC levels when the mice’s circadian rhythms were disrupted in a variety of ways, including treatment with the “sleep hormone” melatonin and changes in light cycles. The results showed more and more clearly: “The tumor wakes up during sleep,” says Aceto. The first author of the study, Zoi Diamantopoulou from ETH Zurich, continues: “Our results also suggest that the escape of circulating cancer cells from the original tumor is controlled by hormones such as melatonin, which determine our circadian rhythm”. Studies of gene activity in the CTCs also showed that cells that leave the tumor at night are comparatively aggressive: they divide faster and therefore have a higher potential to form metastases than circulating cells that a tumor releases during the day, the scientists report .
According to them, the results could now have significant implications for monitoring the development of breast cancer and for treatments. Because the study shows that the time at which tumor or blood samples are taken can have a significant impact on the findings. “We believe our results make it clear that healthcare professionals should systematically record the time they perform biopsies. That could help make the data really comparable,” says Aceto.
It is also becoming apparent that the time of day that cancer therapies are administered could be important for the success of the treatment. With further investigations, the researchers now want to find out more precisely how the new findings can be integrated into existing cancer treatments in order to optimize therapies. In addition, she will focus on a question that is now almost irresistible: To what extent does the tendency to metastasize in other types of cancer depend on the circadian rhythm of the patient?
Source: Swiss Federal Institute of Technology in Zurich, specialist article: Nature, doi: 10.1038/s41586-022-04875-y