January 28, 2014
Disrupted Sleep Patterns May Accelerate Tumor Growth
Brett Smith for redOrbit.com - Your Universe Online
A new study from a team of American researchers has revealed that a disrupted sleep pattern can accelerate the progression of cancer.
According to the team’s report published in the journal Cancer Research, fragmented sleep disrupts a cancer-fighting metabolic pathway – a disruption that could be mitigated through drug therapy.
"It's not the tumor, it's the immune system," said study director Dr. David Gozal, chairman of pediatrics at the University of Chicago Comer Children's Hospital. "Fragmented sleep changes how the immune system deals with cancer in ways that make the disease more aggressive."
Gozal said he was inspired by a previous study that found a connection between sleep apnea and increased cancer mortality.
"Fortunately, our study also points to a potential drug target," he said. "Toll-like receptor 4, a biological messenger, helps control activation of the innate immune system. It appears to be a lynchpin for the cancer-promoting effects of sleep loss. The effects of fragmented sleep that we focused on were not seen in mice that lacked this protein."
In the study, the researchers used mice kept in small sets as models of tumor growth. Throughout the day-when mice typically sleep, a muted, motorized brush passed through one half of the enclosures every two minutes, driving those mice to wake up then return to sleep. The remaining mice were not bothered.
After a week of this routine, both sets of mice were injected with cells from one of two tumor varieties, TC-1 or 3LLC. All mice produced conspicuous tumors within 9 to 12 days. One month after inoculation the scientists examined the growths.
They discovered that tumors from mice with disrupted sleep were double the size, for both tumor varieties, compared to those from rodents that had slept normally. A follow-up trial revealed that when tumor cells were incorporated in the thigh muscle, which should naturally contain growth, the tumors were considerably more aggressive and penetrated nearby tissues in mice with fragmented sleep.
"In that setting, tumors are usually encased by a capsule of surrounding tissue, like a scar," Gozal said. "They form little spheres, with nice demarcation between cancerous and normal tissue. 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."
The mechanism behind the difference appeared to be driven by immune system cells called tumor-associated macrophages (TAMs). One type of TAM, called M1, invokes a strong immune response toward combating tumors cells. Another type, known as M2, tamps down the immune response and instead encourages the growth of new blood vessels—which has the unintended effect of spurring tumor growth.
While the rested mice had mostly M1-type TAMs in the core of their tumors, Sleep-disrupted mice had mostly M2-type TAMs. These were plentiful, particularly around the edge of the tumors. The sleep-disrupted mice also had high levels of toll-like receptor 4 (TLR4).
The team theorized that TLR4 and two downstream signals called MYD88 and TRIF were influencing the immune system toward M2. To test their theory, the team placed tumor cells into a series of mice that were engineered not to produce one of these three proteins and subjected them to the disrupted sleep pattern. Cancer growth was slightly lower in mice lacking MYD88 or TRIF, but in mice lacking TLR4, tumor growth was similar to that in mice with undisturbed sleep.
"This study offers biological plausibility to the epidemiological associations between perturbed sleep and cancer outcomes," Gozal said. "The take home message is to take care of your sleep quality and quantity like you take care of your bank account."