Cancer is at its deadliest when a tumour’s cells worm their way into the bloodstream and travel to a new location in the body to set up shop — a process called metastasis. Now, a study finds that for people with breast cancer, these rogue cells — called circulating tumor cells, or CTCs — are more likely to jump into the blood at night than during the day.
The discovery reveals some basic human physiology that has so far flown under the radar and could lead to better ways of tracking cancer’s progression, says Qing-Jun Meng, a chronobiologist at the University of Manchester, UK.
The research community has been discussing for decades how the body’s circadian rhythm influences cancer. With this study, it has become clear that “tumors wake up when patients are sleeping”, says co-author Nicola Aceto, a cancer biologist at the Swiss Federal Institute of Technology in Zurich, Switzerland. It’s a “step forward” in understanding metastasis, he says. “And steps forward are a good thing for patients in the long-term”. The research was published on 22 June in Nature1.
cancer on the clock
In 2007, the International Agency for Research on Cancer listed disrupted circadian rhythm as a “probable” carcinogen after long-term studies concluded that people who work odd hours — such as flight attendants and night nurses — were at a higher risk of developing breast cancer2. Why this happens remains an open question.
A person’s circadian clock, controlled by various genes that express specific molecules on a 24-hour timetable, influences many processes in the body, including metabolism and sleep. Most researchers, however, had initially thought that cancer cells were “so screwed up, so highly mutated” that they wouldn’t conform to such a schedule, Aceto says.
For metastasis, the first hint that this might not be strictly true came when Aceto and his colleagues noticed that levels of CTCs in mice with tumors varied depending on the time of day that their blood was drawn. That observation led Aceto to collect blood from 30 women hospitalized with breast cancer, once at 4 am and again at 10 am
The researchers found that the bulk of the CTCs they found in the blood samples — almost 80% — appeared in the portion collected at 4 am, when the patients were still resting. At first, “I was surprised because the dogma is that tumors send out circulating cells all the time”, Aceto says. “But the data were very clear. So, soon after being surprised, we started being very excited.”
The next step for the researchers was to confirm whether this was true beyond these few patients. To do this, the team grafted breast cancer tumors into mice and tested the animals’ CTC levels throughout the day. Compared with humans, mice have an inverted circadian rhythm, meaning that they are most active at night and tend to rest during the day. The team found that the animals’ CTC levels peaked during the day — sometimes at a concentration that was up to 88 times higher than baseline — when the animals were in their resting state.
Furthermore, the researchers collected CTCs from the mice, both while the animals were resting and while they were active. They added different fluorescent tags to the two sets of cells, and then injected them back into the mice. Most of the cells that grew into new tumors were those collected when the mice were resting, suggesting that these CTCs are somehow better at metastasizing.
This revelation is “striking”, says Chi Van Dang, a cancer biologist at the Ludwig Institute for Cancer Research in New York City. Physicians measure CTC levels in the blood — a type of liquid biopsy — to help see how patients with cancer are progressing, so “the first lesson for me is that the time of day you take a blood sample can give you misleading information”, he says. This means that physicians might want to rethink when they track cancer, he adds.
Sleep is not the enemy
Why breast cancer cells in humans are more active at night probably depends on a multitude of factors that still need to be investigated, Aceto says. Hormones, which are one tool the body uses to signal that it’s time to wake up or go to bed, might play apart. The team found that treating mice with hormones such as testosterone or insulin had an impact on CTC levels — lowering or raising them, depending on when the hormones were administered.
Understanding how this process works could one day lead to better cancer treatments, Dang says, but that reality is probably still a long way off. More studies are needed first, to untangle the complicated web connecting circadian rhythms and cancers, he adds.
In the meantime, Meng cautions against thinking of sleep as the enemy for people with breast cancer. Some studies have shown that people who have cancer and who commonly get less than seven hours of sleep per night are at higher risk of death3and messing with circadian rhythms in mice can make cancer move faster4. The findings aren’t an indication that “you don’t need sleep, or that you need less sleep”, he says. “It simply means these cells prefer a specific phase of the 24-hour cycle to go into the bloodstream.”