The relationship between sleep deprivation and cancer: Dispatches from the apartheid state

More dispatches from Israel,  the apartheid state. Cutting edge research from an Israeli Arab doctor, Fahed Hakim has the potential to change the way we view sleep.  Hakim is a Christian Arab-Israeli pediatrician and pediatric pulmonologist at the Rambam Medical Center in Haifa. He was born, raised and lives in Nazareth. He is a married to a dentist and has two sons, 11 and 7 and has worked at Haifa’s Rambam Center since the completion of his medical degree in 2000.

Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling.

Hakim F, Wang Y, Zhang SX, Zheng J, Yolcu ES, Carreras A, Khalyfa A, Shirwan H, Almendros I, Gozal D.

Cancer Res 2014 Mar 1;74(5):1329-37. doi: 10.1158/0008-5472.CAN-13-3014. Epub 2014 Jan 21.

Sleep fragmentation (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and mortality. In this study, we examined the hypothesis that sleep fragmentation promotes tumor growth and progression through proinflammatory TLR4 signaling. In the design, we compared mice that were exposed to sleep fragmentation one week before engraftment of syngeneic TC1 or LL3 tumor cells and tumor analysis four weeks later. We also compared host contributions through the use of mice genetically deficient in TLR4 or its effector molecules MYD88 or TRIF. We found that sleep fragmentation enhanced tumor size and weight compared with control mice. Increased invasiveness was apparent in sleep fragmentation tumors, which penetrated the tumor capsule into surrounding tissues, including adjacent muscle. Tumor-associated macrophages (TAM) were more numerous in sleep fragmentation tumors, where they were distributed in a relatively closer proximity to the tumor capsule compared with control mice. Although tumors were generally smaller in both MYD88(-/-) and TRIF(-/-) hosts, the more aggressive features produced by sleep fragmentation persisted. In contrast, these more aggressive features produced by sleep fragmentation were abolished completely in TLR4(-/-) mice. Our findings offer mechanistic insights into how sleep perturbations can accelerate tumor growth and invasiveness through TAM recruitment and TLR4 signaling pathways.

And in plain English, via Israel 21 C:

"We knew from epidemiological studies that people whose Circadian rhythm is disrupted – like night-shift workers – have a higher incidence of cancer," says Hakim.

"We also knew that sleep apnea sufferers, who snore and wake up dozens of times a night, have a higher tendency to cancer. In other words, the more hypoxic a person is – the lower the levels of his oxygen – the more he is disposed to cancer. Studies on this emerged just when we began to think about our next research project. So we decided to ask how it happens and why."

Hakim and his research team experimented on two groups of mice. The control group was allowed to sleep normally. The other group was wakened repeatedly. After a week, cancerous tumor cells were injected into all the mice.

Within four weeks, the volume of the tumors – as well as the amount of cancer cells — in the mice whose sleep had been interrupted was double that in the mice that slept soundly.

And the tumors in the sleep-disrupted mice were more invasive; they spread into the adjacent tissue, muscles and bones. The tumors in the mice that had slept better, meanwhile, were better contained.

"To understand why, we looked at the tumor micro-environment," says Hakim.

"When you have an invader in your body, your immune system tries to attack it. The cells that eat invaders, like bacteria, are called microphages

Hakim's team discovered that these M-2s were sitting on the edges of the tumors and calling other macrophages to the area by sending messages to the TLR4 receptor –a protein that activates the immune system.

"What we found was that the TLR4 in the sleep-deprived mice was highly activated,"Hakim says. "So we decided to knock out the TLR4. And we discovered that the tumors in the mice in which we knocked out the TLR4 did not grow as quickly."

Arab doctors are doing innovative cutting edge scientific research in Israeli hospitals. Just another in a long series of apartheid fails, from the only democracy in the Middle east.