Dr. David Gozal at the Knapp Center for Biomedical Discovery Labs of the Department of Pediatrics at The University of Chicago Medical Center on Thursday, Feb. 27, 2014. (Zbigniew Bzdak, Chicago Tribune)
Not getting a good night's sleep may be a lot more harmful to your health than you thought. Beyond making you tired and cranky, it has been linked to heart disease, diabetes, obesity, depression and — most recently — cancer.
Two 2012 studies found that people who suffer from sleep apnea are more likely to be diagnosed with any type of cancer and more likely to die of the disease, than people with undisturbed sleep. (Sleep apnea, estimated to affect 28 million Americans, causes snoring and dangerous interruptions in breathing that deprive the body of oxygen and of restorative sleep.)
More recent studies have found that men who sleep too little or too much are more likely to develop prostate cancer, and breast cancer patients who don't get enough sleep have a higher risk of relapse. But all of those studies were observational: The correlations don't prove that lack of sleep causes cancer or makes it more aggressive.
Now, researchers think they understand better how poor-quality sleep directly affects cancer. Their findings, if corroborated, could lead to the development of new cancer-fighting drugs.
A team from the University of Chicago and the University of Louisville reported in January in the journal Cancer Research that interrupted sleep can speed cancer growth, increase tumor aggressiveness and dampen the immune system's ability to control early cancers. And they believe the culprit is a signaling molecule called TLR4 (for toll-like receptor 4), which helps control activation of the immune system.
"We have for the first time established biological plausibility that sleep can affect cancer biology," said Dr. David Gozal, chairman of pediatrics at the University of Chicago Medicine and a sleep physician. "The take-home message is to take care of your sleep quality and quantity like you take care of your bank account."
Part of immune system
TLR4 is found in immune cells that are part of the innate immune system — the biological system that is primed to defend the body against foreign agents, such as bacteria and viruses. The immune system also fights cancer, but not always effectively, partly because it often fails to identify cancerous cells as foreign.
Immune cells called tumor-associated macrophages, which cluster at the site of tumors, are hallmarks of the immune system's response to cancer. But they can respond in different ways, depending on the biological signals they get. Some, labeled M1, promote a strong immune response and can eliminate tumor cells. Others, known as M2, suppress the immune response and instead promote the growth of new blood vessels, which encourages tumor growth.
In the laboratory experiments conducted by Gozal and his team, mice whose sleep was disrupted had predominantly M2 cells, along with high levels of TLR4.
The researchers divided their study animals into two groups. The control group was allowed to sleep undisturbed from 7 a.m. to 7 p.m. (mice mostly sleep during the day). The mice in the experimental group had their sleep disrupted every two minutes by a quiet, motorized brush that swept through their cages.
After a week in this setting, both groups of mice were injected with cancer cells. All the animals developed palpable tumors within nine to 12 days. Four weeks after inoculation, the researchers evaluated the tumors.
"Lo and behold — to our surprise — the tumors were growing much faster and becoming much bigger in the sleep-disturbed mice," said Gozal. "We tried a different type of cancer. Same thing. Not only were they growing bigger and faster, but they were also more aggressive." Tumor cells injected into thigh muscles, which normally should help contain their growth, invaded bone and other surrounding tissue in the mice whose sleep was disrupted.
The difference between the tumors in the mice who slept and those who were continually awakened appeared to be related to tumor-associated macrophages, or TAMs.
Well-rested mice had primarily M1-type TAMs, concentrated in the core of the tumors. Sleep-disrupted animals had primarily M2-type TAMs, concentrated more at the edges of the tumor. The M2 cells in the sleep-deprived mice also had higher levels of TLR4.
To test that hypothesis, the researchers injected cancer cells into mice that were genetically incapable of producing TLR4. Taking TLR4 out of the picture resulted in major curtailment of tumor growth. "The differences between undisturbed and sleep-fragmented mice disappeared," said Gozal.
"Poor sleep affects the innate immune response," he explained. "It makes TAMs be more supportive of the tumor rather than fight it. It tips the balance in favor of the tumor, so the host is losing the battle."
More work to be done
Much more work lies ahead.