Researchers in the US found of two groups of mice given the same cancer-inducing treatment, the group whose sleep was disrupted developed larger, more aggressive tumors than the well-rested mice.
In the journal Cancer Research, the team also reports how they found the immune system of the sleep-disrupted mice was less effective at fighting the early stages of cancer than the immune system of the well-rested mice.
Study director Prof. David Gozal says:
“It’s not the tumor, it’s the immune system. Fragmented sleep changes how the immune system deals with cancer in ways that make the disease more aggressive.”
“Fortunately, our study also points to a potential drug target,” he adds, describing how they found a biological messenger – the protein TLR4 – helps to activate the innate immune system.
He says TLR4 seems to act as a “lynchpin” between sleep loss and cancer promotion – the effects of fragmented sleep they focused on “were not seen in mice that lacked this protein.”
The researchers believe their study, which was funded by the National Institutes of Health, is the first to show, in an animal model, how fragmented sleep directly impacts tumor growth and aggressiveness.
The study came about because research linking sleep apnea and death from cancer caught the attention of Prof. Gozal, an authority on the consequences of sleep apnea, and its hallmark, disrupted sleep.
For example, in 2012, researchers reported two studies that found a strong link between sleep apnea and cancer mortality.
So he and his colleagues, from the Universities of Chicago and Louisville, carried out a series of experiments using lab mice to look at this more closely.
During the day, when the small groups of mice were normally asleep in their cages, a silent, motorized brush passed through half the cages, forcing the mice to wake up and then go back to sleep. The rest of the mice were left in peace.
After a week, the mice received injections of tumor cells that caused all of them to develop tumors. Four weeks later, the researchers examined the mice.
The researchers found that the mice whose sleep was disrupted had tumors twice the size of those in the mice that slept normally.
And then in a further experiment, where they implanted tumor cells in the mice’s thigh muscles – which usually restricts cancer growth – in the mice with disrupted sleep, the tumors were more aggressive and invaded surrounding tissue.
Prof. Gozal explains that, usually in muscle, tumors become encased in a tissue capsule rather like a scar: they become “little spheres,” with a clear separation between cancerous and normal tissue.
However, in the mice that had disrupted sleep, the tumors had pushed through the capsule and gone into the muscle and bone.
When they looked at the underlying molecular mechanisms, the team found the difference in the two groups of mice appears driven by immune cells called tumor-associated macrophages or TAMs.
TAMs work in one of two ways, depending on what signals they receive. One way causes them to eliminate cancer cells, while the other way causes them to help the growth of new blood vessels for the tumor.
The team found the well-rested mice had mostly TAMs working in the core of the tumors, eliminating cancer cells. But in the sleep-disrupted mice, the TAMs, which were all around the outside edges of the tumors, were busy promoting blood vessel growth to bring a blood supply to help the tumors grow.
The sleep-disrupted mice also had high levels of TLR4. This signalling protein seems to team up with two others, MYD88 and TRIF, to cause the TAMs in the sleep-disrupted mice to be more of the type that favor tumor growth.
So in a final set of experiments, the researchers injected cells into mice bred to lack one of these three signalling proteins.
They found the tumors grew a little less rapidly in sleep-disrupted mice lacking MYD88 or TRIF. But in sleep-disrupted mice lacking TLR4, the tumors grew no faster than in well-rested mice.
It appears that TLR4 is a major culprit of tumor growth, as Prof. Gozal explains:
“When we injected tumor cells into mice that lacked TLR4, the differences between undisturbed and sleep-fragmented mice disappeared.”
He believes the findings offer a biological explanation for observed links between disrupted sleep and cancer, noting that “the take home message is to take care of your sleep quality and quantity like you take care of your bank account.”
The US Centers for Disease Control and Prevention (CDC) says around 70 million Americans have chronic sleep problems. Considering how this sleep disruption, like cancer, strikes more in middle-aged and older people, the authors say their findings have “far-reaching implications.” The team now plans to look at whether sleep disruption affects how readily cancer spreads (metastasis), and response to chemotherapy.
Previously, Medical News Today reported on a study connecting sleep disruption to an increased risk of prostate cancer in men.