Troubled by a possible link between sleep apnea and increased cancer mortality, Dr. David Gozal and his colleagues devised a series of experiments to investigate the effects of fragmented sleep on cancer. Poor quality sleep, they soon discovered, can speed cancer growth, increase tumor aggressiveness, and stifle the immune system's ability to eradicate early cancers. "The take home message is to take care of your sleep quality and quantity like you take care of your bank account," said Gozal, an authority on sleep apnea and chairman of pediatrics at the University of Chicago Comer Children's Hospital. The new study appears online in the journal Cancer Research.
Collaborating with colleagues from the University of Chicago and the University of Louisville, Gozal began the series of experiments by housing two groups of mice in separate settings. Knowing mice normally sleep during the day, the researchers set a quiet, motorized brush moving through the cages of one group of mice every two minutes; the mice would waken and then fall back asleep. The second group of mice lodging in isolated cages remained undisturbed in their sleep. After seven days, both groups were injected with cells from one of two tumor types, and within 9 to 12 days, all the mice, no matter which cage they slept in, developed palpable tumors. Four weeks after the inoculation, the researchers evaluated the tumors.
Tumors in the mice with broken sleep, the researchers discovered, were twice as large as those in the mice with undisturbed sleep, with the same being true for both tumor types. "Fragmented sleep changes how the immune system deals with cancer in ways that make the disease more aggressive," Gozal stated in a press release. Next, the researchers conducted a follow-up experiment where they implanted tumor cells in the thigh muscles of each mice. "In [the thigh muscle], tumors are usually encased by a capsule of surrounding tissue, like a scar. They form little spheres, with nice demarcation between cancerous and normal tissue,” Gozal said. “But in the fragmented-sleep mice, the tumors were much more invasive. They pushed through the capsule. They went into the muscle, into the bone. It was a mess."
To gain a more nuanced understanding of the beneficial effects of sleep, Mother Nature's wonder cure, the researchers investigated the immune system and then conducted one final experiment.
The difference, Gozal and his colleagues found after analyzing the tumors, appeared to be driven by cells from the immune system, called tumor-associated macrophages (TAMs), which cluster at the site of tumors. Part of the immune system's response to cancer, TAMs can respond in a variety of ways. Some, for instance, promote a strong immune response and eliminate tumor cells, while others suppress immunity and so encourage tumor growth. Among the well-rested mice, the kind of TAMs that promote a strong immune response were evident. On the other hand, the sleep-fragmented mice showed abundant TAMs encouraging cancerous growth, especially around the periphery of the tumors.
The sleep-disrupted mice also had high levels of toll-like receptor 4, a protein that can activate the immune system. So the researchers conducted another experiment, this time disabling toll-like receptor 4, and they found tumor growth in the sleep-interrupted mice was no greater than in mice with undisturbed sleep. "Toll-like receptor 4, a biological messenger, helps control activation of the innate immune system," Gozal said. "It appears to be a lynchpin for the cancer-promoting effects of sleep loss." Additionally, the co-authors wrote in the study’s conclusion, "Considering the high prevalence of both sleep disorders and cancer in middle age or older populations, there are far-reaching implications.”
The next project on this research team's list is to determine whether sleep also affects metastasis or resistance to cancer chemotherapy. Meanwhile, the current study suggests a potential target — toll-like receptor 4 — for developing a new drug therapy to help prevent the development and spread of cancer in those who suffer sleep problems, an estimated 50 to 70 million American adults, according to the Centers for Disease Control and Prevention, which describes the problem of insufficient sleep as a public health epidemic.
Source: Gozal D, Hakim F, Wang Y, Zhang SXL, Zheng J, Yolcu ES, et al. Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling. Cancer Research. 2014.