A multidisciplinary perspective on the complex interactions between sleep, circadian, and metabolic disruption in cancer patients

Abstract

Sleep is a basic need that is frequently set aside in modern societies. This leads to profound but complex physiological maladaptations in the body commonly referred to as circadian disruption, which recently has been characterized as a carcinogenic factor and reason for poor treatment outcomes, shortened survival, and reduced quality of life in cancer patients. As sleep and circadian physiology in cancer patients spans several disciplines including nursing science, neurology, oncology, molecular biology and medical technology, there is a lack of comprehensive and integrated approaches to deal with this serious and growing issue and at best a fractionated understanding of only part of the problem among researchers within each of these segments. Here, we take a multidisciplinary approach to comprehensively review the diagnosis and impact of sleep and circadian disruption in cancer patients. We discuss recent discoveries on molecular regulation of the circadian clock in healthy and malignant cells, the neurological and endocrine pathways controlling sleep and circadian rhythmicity, and their inputs to and outputs from the organism. The benefits and drawbacks of the various technologies, devices, and instruments used to assess sleep and circadian function, as well as the known consequences of sleep disruption and how sleep can be corrected in cancer patients, will be analyzed. We will throughout the review highlight the extensive crosstalk between sleep, circadian rhythms, and metabolic pathways involved in malignancy and identify current knowledge gaps and barriers for addressing the issue of sleep and circadian disruption in cancer patients. By addressing these issues, we hope to provide a foundation for further research as well as better and more effective care for the patients in the future.

Keywords: Cancer; Circadian clock; Metabolism; Patient care; Sleep; Treatment.

Fig. 1

Vicious circle underlying sleep disruption in cancer patients. Poor sleep due to shift work, jet lag, anxiety, restlessness, and light pollution is associated with increased HO-neuron activity during the night and increased MCH-neuron activity during the day. This leads to increased cortisol and reduced melatonin secretion, as well as dietary mis-synchronization, which increase the risks of cancer, tumor growth, metastasis, and treatment failure. Cancer-associated mutations in clock proteins and low-grade inflammation, as well as pain and nausea which are also common side effect of chemotherapy, lead to deregulated cytokine production. Increased IL1β, IL6, and TNFα during the day are associated with daytime sleepiness, and increased IL4, IL10, and TGFβ during the day are associated with insomnia. These inflammatory factors also lead to BBB-disruption and disrupted regulation of sleep centers in the brain

Fig. 2

Circadian and metabolic crosstalk in cancer cells. The core clock factors Bmal1, Npas2, Clock, Hif1a, Per1-3, and Cry1/2 are required at oscillating concentrations during the day and night to maintain circadian homeostasis. Activators (Bmal1, Npas2, Clock, Hif1a) bind E-boxes/hypoxia-responsive elements (HRE) sequences in the promoter region to induce glycolysis during the day. Repressors (Per1-3 and Cry1/2) inhibit this during the night, allowing oxidative metabolism. Expansion of daytime metabolism due to deletion of Per, or Sirt1 (proteins important for stabilization of clock rhythmicity), increased glycolytic flux leading to elevated NUC-Glc-NAc, increased levels of FAD and SAM, or stabilization of HIF1a, results in persistent expression of glycolytic enzymes (Glut1, HK2, Aldoa, Eno2) and thereby maintained glycolysis during the night