Cancer is more lethal when cells from a tumor enter the bloodstream and travel to a new location in the body to open a store, a process called metastasis. Now, a study finds that for people with breast cancer, these rogue cells – called circulating cancer cells or CTCs – are more likely to jump into the bloodstream at night than during the day.
The discovery reveals some basic human physiologies that have so far escaped the radar and could lead to better ways to monitor cancer progression, says Qing-Jun Meng, a chronobiologist at the University of Manchester, UK.
The research community has been debating how the body’s circadian rhythm affects cancer for decades. With this study, it became clear that “tumors wake up when patients are asleep,” says co-author Nicola Aceto, a cancer biologist at the ETH Zurich, Switzerland. It’s a “breakthrough” in understanding metastases, he says. “And progress is good for long-term patients.” The research was published on June 22 in Nature1.
Cancer on the way
In 2007, the International Agency for Research on Cancer listed disruption of the circadian rhythm as “probable” carcinogenic after long-term studies concluded that people who work odd hours, such as flight attendants and night nurses, they were at greater 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 over a 24-hour schedule, affects many processes in the body, including metabolism and sleep. Most researchers, however, initially thought the cancer cells were “so messed up, so highly mutated” that they didn’t fit into that schedule, Aceto says.
For metastases, the first clue that this may not be entirely true came when Aceto and his colleagues noted that CTC levels in mice with tumors varied depending on the time of day the blood was drawn. This observation led Aceto to collect the blood of 30 women hospitalized for breast cancer, once at 4 and again at 10.
The researchers found that most of the CTCs they found in the blood samples – nearly 80 percent – appeared in the portion collected at 4am, when patients were still resting. At first, “I was surprised because the dogma is that tumors continually emit circulating cells,” Aceto says. “But the data was very clear. So, right after we were surprised, we started to get 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 tumors into mice and tested the animals’ CTC levels throughout the day. Compared to humans, mice have an inverted circadian rhythm, which means they are more active at night and tend to rest during the day. The team found that the animals’ CTC levels peaked during the day, sometimes at concentrations up to 88 times above baseline, when the animals were in their resting state.
Additionally, the researchers collected CTCs from the mice, both while the animals were resting and while they were active. They added several fluorescent tags to the two groups of cells and then injected them back into the mice. Most of the cells that grew into new tumors were those harvested when the mice were resting, suggesting that these CTCs are somehow better at metastasizing.
This revelation is “surprising,” says Chi Van Dang, a cancer biologist at the Ludwig Institute for Cancer Research in New York City. Doctors measure CTC levels in the blood – a type of liquid biopsy – to help see how cancer patients are progressing, so “the first lesson for me is that the time of day a blood sample is taken. it can give you misleading information, “he says. This means doctors may want to rethink when tracking cancer, she adds.
Sleep is not the enemy
Why breast cancer cells in humans are more active at night likely depends on a multitude of factors that have yet to be studied, Aceto says. Hormones, which are a tool the body uses to signal it’s time to wake up or go to bed, may play a role. The team found that treating the mice with hormones such as testosterone or insulin impacted CTC levels, either 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 network that connects circadian rhythms and tumors, she adds.
Meanwhile, Meng cautions against thinking of sleep as the enemy for people with breast cancer. Studies have shown that people who have cancer and who commonly sleep less than seven hours a night are at increased risk of dying3and messing with circadian rhythms in mice can make the cancer move faster4. The results don’t indicate that “you don’t need to sleep or that you need less sleep,” she says. “It simply means that these cells prefer a specific phase of the 24-hour cycle to enter the bloodstream.”