Fractured Sleep Exacts a Heavy Toll

David A. Johnson, MD


February 19, 2014

In This Article

The Toll-like Receptor 4 Pathway

The investigators used a mouse model to study a proinflammatory signaling pathway that has been linked with a variety of cancers. This toll-like receptor 4 (TLR4) pathway has been implicated in several cancers. Colon, gastric, breast, bladder, prostate, and salivary cancers have all been tied to the disruption or upregulation of the TLR4 pathway.

From some elegant work by Maria Abreu and her colleagues[2,3,4,5] at the University of Miami, we know that TLR4 is upregulated in inflammatory bowel disease-related cancers and in adenomatous polyps, the more dysplastic polyps. In fact, in colon cancer in general, TLR4 is upregulated. Why is TLR4 an important factor in these proinflammatory pathways?

TLR4 promotes the immune response, at least in the colon cancer model, by inducing immunosuppressive cytokines and apoptosis resistance. It promotes adhesion of these colon cancer cells, all of which mediate toward a more aggressive cancer as it relates to the potential for angiogenesis factors, which stimulate the TLR4 pathway as well.

Let's get to the present study. This study was looking at a group of mice that included some that were genetically engineered to be TLR4-negative. This sounds like fairly basic science, but it has profound implications. The TLR4 pathway was expressed in some of the mice, and TLR4 was genetically engineered to be negative in others.

Mice are nocturnal animals. To sleep-deprive half of the mice, the investigators put them in cages and ran a brush through the cage every 2 minutes to wake them up. The other group was allowed to sleep undisturbed. After 1 week, they injected both groups of mice with tumor cells.

All of the mice developed cancer within 9-12 days. They restudied the mice within 4 weeks. They found that in the sleep-deprived mice, the tumors were twice as large and far more invasive than they were in the sleep-undisturbed mice. The TLR4 pathway was potentially being upregulated by sleep deprivation.

In the genetically engineered TLR4-negative mice, the tumors were the same size as those in the sleep-undisturbed mice. Without TLR4, sleep deprivation had no effect on tumor growth, and the aggressive features of sleep deprivation were abolished.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: