Cancer and Sleep - Chicken or the egg?

Cancer patients have idiopathic sleep problems that are strongly associated with decreased quality of life and subsequent mortality. Why? This is a complicated question to tackle, as there are many different kinds of cancer, cancer treatments, patient populations, and lifestyle factors that all contribute to disrupted sleep. Additionally, we have a 'chicken or the egg' problem, where it is unclear whether poor sleep promotes cancer growth, or if cancer (or cancer treatment) promotes poor sleep. Substantial evidence exists for the former claim, as chronically truncated or fragmented sleep is consistently associated with higher cancer risk and tumor progression. However, less is known about the mechanisms that govern this relationship, and whether cancer itself can communicate with the brain to alter sleep. 

Survival in breast cancer patients stratified by high efficiency (blue) and low efficiency (red) sleepers. (Image Credit:  Palesh et al., 2014 ).

Survival in breast cancer patients stratified by high efficiency (blue) and low efficiency (red) sleepers. (Image Credit: Palesh et al., 2014).

My goal is to use state-of-the-art tools to investigate exactly how cancer in the periphery (e.g., the breast) communicates with the brain, and reciprocally, how the brain responds to this input. In this way, I hope to uncover novel pathways that may be manipulated to improve the quality of life and reduce mortality for cancer patients.

Recently, we tackled this question in a mouse model. We discovered that non-metastatic breast tumors alter the endocrine and immune systems; a signal that the brain picks up on. In mice with tumors, lateral hypothalamic orexin/hypocretin neurons (HO; which are essential for stabilizing wakefulness) were overactive, likely leading to sleep disruption. These cells also modulate glucose metabolism via sympathetic connections to the liver. We tried blocking inflammatory signaling (via anti-IL-6 antibodies), but were unable to stop the sleep and metabolic problems from progressing. Alternatively, we observed that inhibiting the signaling of HO neurons improved sleep quality and rescued metabolic problems induced by the tumor.  

The work by Borniger and Walker et al.(Borniger et al., 2018) is essential reading for those interested in finding answers to these questions by combining experimental approaches from diverse fields of research, and for those who
appreciate that cancer can only be understood by studying both the tumor and the host.
— Tobias Janowitz, Cell Metabolism

This was the first study to manipulate neuromodulator signaling (HO) to rescue tumor-induced impairments in health. In the future, targeting these neuromodulator populations may be a viable strategy to improve quality of life and reduce mortality in cancer patients. Indeed, further strides have been made by manipulating ventral tegmental area (VTA) dopamine neurons (which are powerful regulators of wakefulness) to slow tumor growth. Uncovering additional neuromodulator pathways that can alter peripheral metabolism or immunity will lead to novel strategies to target cancer.

Tumors alter leptin/ghrelin signaling, which results in aberrant activation of hypothalamic hypocretin/orexin neurons. This promotes poor sleep, and changes in glucose metabolism via the sympathetic nervous system. (from:    Borniger et al., 2018   )

Tumors alter leptin/ghrelin signaling, which results in aberrant activation of hypothalamic hypocretin/orexin neurons. This promotes poor sleep, and changes in glucose metabolism via the sympathetic nervous system. (from: Borniger et al., 2018)

Banner image: REM sleep wavelet during optogenetic stimulation of lateral hypothalamic GABA neurons (JCB).

All rights reserved: Jeremy Borniger, PhD