For years, the dream of curing cancer has been to understand and eliminate metastases. This ability allows a tumor to send cells to the blood vessels so that they can implant in other organs and give rise to new tumors. Nine out of ten cancer deaths are due to this process. Today, a study shows that this spread throughout the body is more aggressive at night, a surprising fact that may have important implications for the diagnosis and treatment of the disease.
Until now, it was assumed that tumors constantly release cancer cells into the blood, regardless of the time of day. The team led by Swiss oncologist Nicola Aceto took two blood samples from 30 women with and without metastatic breast cancer; one at 10 a.m. and one at four in the morning. The results show that the concentration of tumor cells in the blood is much higher at night and that these nocturnal cells are also much more aggressive.
Faced with the impossibility of tagging each of the malignant cells discovered in the patients and tracing their fate, the researchers resorted to a series of experiments on mice. These animals are nocturnal, but even in these rodents, the tumor cells were much more active during the day; during rest periods.
Tumor cells harvested during sleep can cause metastases when injected into healthy mice, which is not the case with those harvested during the day. In both humans and mice, nocturnal malignant cells have activated genes that promote cell proliferation, a mechanism that drives tumor growth. The work appears today in Nature, Speaker of the best world science.
This study provides new clues about the relationship between cancer and the circadian rhythm, the body clock that dictates periods of physical and mental activity and rest throughout the 24-hour day. This cycle is closely linked to the times of day and night on Earth, and its alteration through work or artificial light is linked to many diseases, including the risk of breast, prostate, colon, liver, pancreas or lung cancer. Night shift jobs that disrupt circadian rhythms are “probably carcinogenic,” the second most dangerous category out of four, according to the US. International Agency for Research on Cancerdependent on the UN.
Daily routine is determined by hormones such as melatonin, which promotes sleep, and cortisol, which wakes us up. In 2014, a team from the Weizmann Institute in Israel showed a link between nocturnal hormones and the spread of cancer. In mice, they showed that administration of the same oncology drug reduced tumors more or less depending on whether it was administered during the day or at night. The new work also sees a clear link between hormones and metastasis, so molecules of this type that start the daily activity phase appear to decrease the cancer’s ability to travel through the circulatory system.
Harrison Ball and Sunitha Nagrath of the Rogel Cancer Center at the University of Michigan (USA) point out that these results have “surprising implications” for cancer treatment. Both researchers call for large-scale clinical trials involving patients to confirm these findings. “Oncologists may need to be more careful about what time of day they perform some treatments,” they add.
Roger Gomis heads the Metastases Research Group at the Barcelona Biomedical Research Institute. “This work is important from a conceptual point of view,” he emphasizes. “It is consistent with other work uncovering a systemic component in cancer and its spread. An example would be the effects of diet on the success of some cancer treatments,” he says. “The difficult thing,” he warns, “will be applying this basic knowledge to treatment and diagnosis, because it’s impossible to keep patients from sleeping, and early-morning biopsies present great challenges,” he argues.
María Casanova, a researcher at the National Cancer Research Center, believes the work has “tremendous” value. “It is necessary to take a lot of blood to measure the circulating tumor cells and at very advanced stages it is something very delicate. It is only done on a few patients to see how well the chemotherapy is working for them. Having this data from 30 patients is really a lot,” he emphasizes.
The fact that metastatic cells are more active at night is no coincidence. Humans are a diurnal species and we are more exposed to harmful viruses and bacteria during the day than at night. That’s why the part of the immune system that controls circulation is less active at night when we’re resting. This partly explains why the fever or asthma is stronger at night. During the hours of rest, other immune cells called neutrophils, which are fixed in the various organs and help to repair them, are activated. Cancer has its own circadian clock, and at this point, the tumor’s cancer cells would leave the tissue and burst into the bloodstream, where little monitoring takes place, Casanova explains.
There are cancer treatments that are less effective when given in the afternoon. There are also components of the circadian clock that could explain other ailments, such as the fact that most strokes happen in the morning, says Casanova. The specific mechanisms that explain these observations are still unknown, but there is already an emerging discipline called chronotherapy, which studies the coincidence of the disease, the therapies used, and the time of day and night. “We may find a way to synchronize the immune system so that it can fight cancer better when it is more active,” summarizes Casanova.
Andrés Hidalgo, researcher at the National Center for Cardiovascular Research, points out that this study is “shocking”. “It presents us with a less predictable cancer biology than we thought and obviously confirms that the disease doesn’t follow the same schedules as our medical staff. This can be very important, as radiation has been shown to be much more effective when applied when the tumor is in the active phase and growing, rather than when it is dormant. It is possible that sometimes we bomb when the enemy is protected in his bunker,” he points out.