Surprising finding: Breast cancer tumors are most active when we sleep. They produce the most metastases and spread cancer cells at night, a study with humans and mice reveals.

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The cancer cells that settle at night are also more active and form metastases more quickly. This reversed daily rhythm of the cancer cells is controlled by the hormones of our internal clock, as the researchers report in “Nature”. They now want to find out whether this also applies to other types of cancer.

The most feared consequence of cancer is metastases, as they are often difficult to remove or treat. These metastases form when cancer cells or clumps of cells break away from the primary tumor and travel to other tissues and organs with the blood.

Whether and how strongly a cancer spreads depends on its genetic signature, but also on environmental factors. Suspicions include stress hormones, metabolic products and tumor disorders caused by mechanical injury or chemotherapy.

But one question has so far largely gone unnoticed: When does a tumor spread? “Until now, it was mostly assumed that growing tumors constantly released cancer cells that were spreading,” explain Zoi Diamantopoulou from ETH Zurich and her colleagues. On the other hand, the team observed that cancer cell cultures can contain very different amounts of free cells depending on the time of day and night.

In order to follow this lead, the researchers examined blood samples from 30 breast cancer patients, which were taken at 10 a.m. in the morning and then again at 4 a.m. at night.

And indeed: “We found most of the circulating cancer cells – 78.3 percent – in the blood samples taken during the nocturnal rest period,” reports the team. This suggested that breast cancer tumors spread more at night than during the day.

To check whether this is a general phenomenon and what mechanisms might be behind it, Diamantopoulou and her team performed additional tests with four different groups of mice that either suffered from a murine form of breast cancer or had been implanted with human breast cancer cells and tumors.

They also monitored the amount of circulating cancer cells in the animals at different times of the day. Because mice are nocturnal, their rest period is during the day.

The result: The mice also showed a clear connection between the time of day and the number of cancer cells that had spread. While the animals were resting, their tumors shed up to 88 times more individual cancer cells and up to 278 times more cancer cell clumps, the researchers found.

Also interesting: If they artificially put the mice into jetlag, the times of the greatest metastasis in breast cancer tumors also shifted.

According to the researchers, this demonstrates that metastasis is closely linked to the internal clock and the daily rhythm: “The tumor wakes up when the affected patient is asleep,” says senior author Nicola Aceto from ETH Zurich. Contrary to what was previously assumed, the tumor does not spread all the time, but primarily during the nocturnal sleep period. This was also reflected in the gene activity of the primary tumor and the disseminated cancer cells.

In addition, the experiments showed that the cancer cells circulating at night divided faster than the few released during the day. “The cancer cells circulating during the resting phase have a strong tendency to form metastases, while the cancer cells generated during the day show no metastatic effect,” Diamantopoulou and her colleagues report. According to this, the tumor not only spreads more at night, the spread cells are also more active and therefore more prone to metastases.

But how does the tumor know when it is night? To find out, the researchers administered various messenger substances to the mice that are known for their effect on the internal clock and daily rhythm, including the sleep hormone melatonin, the steroid hormone dexamethasone and testosterone. The team administered the first two hormones to the mice in the opposite direction to the normal rhythm, and the testosterone was released slowly but steadily via an implanted pellet.

It turned out that both melatonin and dexamethasone changed the release of cancer cells that had spread from the primary tumor. For example, if the mice received a dose of cortisone at the beginning of their resting phase, their tumors produced significantly fewer cancer cells than normal. Testosterone also significantly and persistently reduced the number of circulating cancer cells, Diamantopoulou and her team report.

“Taken together, these results indicate that the proliferation and spread of breast cancer cells depend on fluctuations in important hormones of the circadian rhythm,” the researchers state.

The new findings could now help to find new approaches to metastasis prevention and cancer treatment. For example, chemotherapy could be more or less effective against the tumor and metastasis depending on the time of day.

The daily rhythm of the cancer cells could also be important for the diagnosis and monitoring of cancer. Because a biopsy or blood sample can possibly produce different results depending on the time of day.

So far, the researchers have only detected nocturnal activity in breast cancer tumors and cells. Next, they now want to check whether such a daily rhythm also exists in other types of cancer.

Source: ETH Zurich

This article was written by Nadja Podbregar

The original to this post “Breast cancer: Increased formation of metastases at night could change treatment” comes from scinexx.