These cancer cells wake up when people sleep

Cancer is at its deadliest when tumours spread throughout the body, often to distant sites such as bone, lung or brain. However, researchers have found that the deadly journey begins much closer to home. In a study published Thursday in Nature Communications, researchers report that cancerous tumours release specialised cells into the bloodstream that can colonise new locations in the body, setting up shop and growing outwards.

The findings reveal some basic human physiology that had so far flown under the radarscope. Circulating tumour cells (CTCs), say the authors, are more likely to enter the bloodstream at night than during the daytime. This finding suggests that the body’s circadian clock plays a role in regulating the migration of cancer cells.

Researchers have known for several years that the circadian cycle affects many aspects of our biology, including hormone levels, metabolism and immune function. But this is the first time scientists have shown that the body’ s internal clock controls movement of cancer cells.

“This step forward in understanding metastasis represents a major advance in cancer research,” says Nicola Aceto, a researcher at the Swiss Federal Institute for Technology in Zurich who led the study. “It provides us with a new tool to understand what happens inside the patient’s body and potentially develop therapies based on this knowledge.”

Aceto and his colleagues used a technique called single cell RNA sequencing to analyse the expression patterns of thousands of genes in individual cells taken from blood samples from women with breast cancer. They found that the expression of hundreds of genes changed depending on whether the cells came from the bloodstream during the day or the night.

Circadian rhythms normally regulate daily cycles of activity and rest. These rhythms are driven by a master clock located in the suprachiasmatic nucleus of the hypothalamus, which sends signals to other parts of the body via hormones called melatonin and cortisol. Melatonin helps control sleepiness and cortisol regulates stress responses.

In the current study, the team discovered that nearly half of the genes whose expression varied between night and day encoded proteins involved in transcriptional regulation. Moreover, most of those genes were turned off during the day, suggesting that the body’ re circadian clock suppresses the production of proteins needed to promote cancer growth.

Cancer on the clock

In 2007, the International Agency of Research on Cancer listed disrupted diurnal rhythms as “a probable cause of cancer.” But why this occurs remains an open question.

A person’s circadian clock, governed by various genes that express certain molecules on a 24-h timetable, controls many processes in the body. Among others, it influences metabolism and sleep. Most research to date suggests that cancer cells are too messed up to follow such a schedule, though some researchers have suggested otherwise.

For metastasis, the first clue that this might not be true came when Aceto observed that levels of circulating tumor cells in mice with tumors varied depending on the time at which their blood was collected. This prompted him to study 30 patients with breast cancer. He found that levels of CTC rose during the night and fell during the daytime.

Sleep is not the enemy

For women with breast cancer, sleep isn’t necessarily something you want to avoid. But researchers say it does seem to have some negative effects on tumor growth.

The findings come from a study published Wednesday in Nature Communications. Researchers looked at data collected from nearly 3,600 patients diagnosed with early stage breast cancer over a period of three decades. They wanted to see whether there was any link between nighttime activity and survival rates.

They found that patients whose tumors grew fastest tended to experience worse outcomes. And those who slept less than six hours per night were twice as likely to die within 10 years compared with those who got seven or more hours of shut-eye each night.

Lead author Dr. Alessandro Acquisti, a researcher at the University of Chicago, says that while the connection is clear, many questions remain unanswered. For example, why do some patients survive longer than others even though they’re sleeping less?

Acquisti says we don’t know what causes the difference in survival times among patients. He suggests that it could be due to differences in hormone levels, genetics, lifestyle choices like exercise or diet, or even stress.

But he notes that the study doesn’t prove that lack of sleep caused poor outcomes. “We just showed that there’s a correlation,” he says. “There’s no cause and effect.”

Still, Acquisti says the findings add to the growing body of evidence suggesting that sleep is important for health. Previous research has linked insomnia to heart disease, diabetes, obesity, depression, anxiety disorders and stroke.

RISK FACTORS OF SLEEP DISTURBANCES

In a study published in Sleep Medicine Reviews, researchers examined the prevalence, clinical characteristics, risk factors, and consequences of insomnia among women with breast cancer. They enrolled 300 women with newly diagnosed primary breast cancer into the study.

The participants completed questionnaires about demographic information, medical history, physical activity level, medication use, and psychological distress. In addition, the participants underwent a structured interview regarding insomnia symptoms and related health outcomes.

Results showed that approximately one third of the women had insomnia symptoms during the previous month. Insomnia was most commonly reported during the night. Women with insomnia tended to report greater pain intensity and poorer quality of life compared to those without insomnia. Furthermore, insomnia was associated with depression and anxiety.

Biological Rhythms

Circadian rhythms and sleep have been well studied in healthy individuals and patients with other diseases, but little is known about the connections between these domains in cancer patients. Cancer itself may be a result or consequence of disrupted biological rhythms. Disruptions in biological rhythmicity are related to cancer, to the proliferation properties of cancerous cells, to the treatment of cancer, and possibly to the patient’s quality of life.

There is increasing interest in studying the biological rhythms of cancer survivors. Actigraphy is a cost-effective and convenient tool to assess circadian activity cycles.

Mormont et al used actigraphy to study the circadian rhythm of the resting/active cycle and of serum cortisol levels, white blood cell counts, and neutrophils in patients with metastatic colonic cancer for three consecutive days prior to initiating chronomodulated chemotherapy (a form of chemotherapy administered according to circadian timing). They found significant differences in the distribution of the 24-hour periodogram power spectra between the normal group and the cancer group. In addition, there were statistically significant correlations between the total daily energy expenditure and the number of hours spent sleeping during a given day. These findings support the hypothesis that cancer disrupts circadian rhythms.