These cancer cells wake up when people sleep

These cancer cells wake up when people sleep

Metastatic cancer cells travel from one place in the body to another to become a new tumor.Credit: Science Photo Library

Cancer is most deadly when cells from a tumor find their way into the bloodstream and travel to a new location in the body to establish themselves, 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 of the basic human physiology that has so far gone unnoticed and could lead to better ways of tracking cancer 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 the steps forward are good for patients in the long run.” The research was published June 22 in Nature1.

cancer on the clock

In 2007, the International Agency for Research on Cancer listed disturbed circadian rhythm as a “probable” carcinogen after long-term studies concluded that people who work infrequent hours, such as flight attendants and night nurses, had an increased risk of developing breast cancer.two. Why this happens is still an open question.

A person’s circadian clock, controlled by several genes that express specific molecules on a 24-hour schedule, influences many processes in the body, including metabolism and sleep. However, most researchers had initially thought that cancer cells were “so screwed up, so highly mutated” that they wouldn’t fit that program, Aceto says.

For metastasis, the first hint that this might not be strictly true came when Aceto and colleagues noted that CTC levels in tumor-bearing mice varied depending on the time of day their blood was drawn. That observation led Aceto to collect blood from 30 hospitalized women with breast cancer, once at 4 a.m. and again at 10 a.m.

The researchers found that most 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,” says Aceto. “But the data was very clear. So shortly after the surprise, 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 cancer tumors onto mice and analyzed the animals’ CTC levels throughout the day. Compared to humans, mice have an inverted circadian rhythm, meaning 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 a concentration that was up to 88 times higher than baseline, when the animals were in a resting state.

Additionally, the researchers collected CTCs from the mice, both while the animals were resting and while they were active. They added different fluorescent labels to the two sets of cells and then injected them back into the mice. Most of the cells that developed into new tumors were those collected 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 you take a sample of blood can give misleading information,” he said. he says. This means doctors may want to rethink when following cancer, she adds.

sleep is not the enemy

Why human breast cancer cells are more active at night probably depends on a multitude of factors that still need to be investigated, says Aceto. Hormones, which are a tool the body uses to signal when it’s time to wake up or go to bed, could play a role. 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, says Dang, but that reality is probably still a long way off. More studies are needed first to unravel the complicated web connecting circadian rhythms and cancers, she adds.

Meanwhile, Meng cautions against thinking of sleep as the enemy of people with breast cancer. Some studies have shown that people with cancer who typically sleep less than seven hours a night have a higher risk of death.3and messing with circadian rhythms in mice can make cancer move faster4. The findings are not an indication that “you don’t need sleep or that you need less sleep,” she says. “It just means that these cells prefer a specific phase of the 24-hour cycle to enter the bloodstream.”

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