Sleep Disorders and Cancer: State of the Art and Future Perspectives - Beyond the Abstract

There is a two-way connection between sleep and cancer; however, the specific associations between individual sleep disorders and particular cancers are not very clear.

According to the World Health Organization (WHO), cancer is one of the most common causes of death, with almost seven million deaths worldwide each year. Data updated to 2019 shows that 24.6 million people are affected by cancer, with 16 million new cases expected in 2020 and 10 million deaths from cancer per year. According to the World Health Organization - International Agency for Research on Cancer (WHOIARC), lung cancer is the most widespread in the world for incidence (2.1 million) and mortality (1.8 million); prostate cancer is the second most common in men (with approximately 1.3 million new cases/year).

An accurate assessment of sleep disturbances in patients with cancer helps improving patient health, survival, response to therapy, quality of life, reduction of comorbidities and complications. Indeed, recent scientific evidence supports that understanding and managing sleep disorders offer interesting therapeutic perspectives for better treatment of cancer.

Most sleep disturbances in patients with cancer are connected to the activation of the inflammatory response, even during chemotherapy: cytokines activate microglia, which in turn can induce a neurotoxic reaction of astrocytes. Tumors produce interleukin-1 beta (IL-1 b) in high quantities, which inhibits REM sleep, promotes non-REM sleep, and affects numerous neurotransmitters involved in sleep (adenosine, prostaglandins, nitric oxide, GABA); also interleukin-6 (IL-6), produced in high quantities in prostate cancer, appears to reduce REM sleep and increase slow-wave sleep; tumor necrosis factor alpha (TNF-a) seems to play the same role. Also, hormones are definitely involved in the close connection between sleep and tumors: ghrelin, related to an increase in tumor progression and survival, could act on orexin neurons by activating them; leptin (produced in breast, prostate, pancreatic, ovarian, lung, and colorectal cancer), involved in increasing the proliferation of cancer cells, can induce the production of IL-6 and TNF-a, also appears to activate hypothalamic neurons, which in turn are linked with orexin neurons.

Melatonin is known to play a fundamental role in regulating the sleep-wake rhythm; however, it is also involved in many other biological mechanisms, playing an important role in inflammatory, metabolic and neoplastic processes. In fact, the mechanisms through which melatonin has an antitumor effect seem to be many: it has an antioxidant effect that protects against DNA damage, acts as a scavenger of reactive oxygen species (which undermine genomic stability), stimulates the repair mechanisms of the DNA, improves the functioning of the mitochondrial respiratory chain and inhibits mitochondrial mitophagy and telomerase activity. It also acts on the metabolism of estrogens (i.e. breast cancer) by binding to the estrogen receptor to inhibit its stimulating effect, inhibiting the steroid synthesis of the gonads and downregulating the synthesis of enzymes such as aromatase, involved in the production of androgens. Furthermore, melatonin increases the expression of the p53 protein, induces its phosphorylation, inhibiting cell proliferation, promotes apoptosis, reduces the levels of vascular endothelial growth factor and endothelin-1, essential for tumor growth and the formation of metastases, reduces inflammatory and migratory processes, and inhibits hypoxia by acting on the ERK / Rac1 pathway. Finally, a reduction in the production of melatonin has been observed in some cancers (breast and prostate).

The use of melatonin also has implications for cancer prevention - in particular prostate, mammary, ovarian, colorectal, and gastric - and promising in vivo studies have been reported on melanoma, leiomyosarcoma, and leukemia, indicating also an improvement in patients' sleep quality and life, as well as many other in vitro studies.

In subjects on night shift, an increased risk of prostate, bladder, and non-Hodgkin lymphoma, as well as colorectal and pancreatic cancer has been shown. The circadian genes identified as being involved in prostate carcinogenesis were: NPAS2, ARNTL, CRY1, CRY2, PER1, PER2, PER3, CSNK1, TIMELESS, MTNR1A, and MTNR1B; however, it was not possible to draw firm conclusions about the association between circadian rhythm disorders and prostate cancer, as there were conflicting views across the various studies. Insomnia is a risk factor for a wide range of cancers, particularly prostate, bladder, and kidney, among many others. A study that included a 10-year observation period revealed a very high risk of nose and prostate and, to a lesser extent, bladder cancer in patients with obstructive sleep apnea syndrome.

Many studies have confirmed the presence of orexin at the peripheral level, especially in the gastrointestinal system (colon and Langerhans cells of the pancreas), but also in the kidney, adipose tissue, and reproductive system (testes and prostate). Stimulation of orexin receptors induces an increase in intracellular calcium, activating various pathways: cAMP, MAPK-Erk 1/2, PI3KAkt, and JNK. A possible therapeutic role of orexin manipulation in some types of tumors might be predicted, through the use, for example, of double orexin receptor antagonists, such as almorexant and suvorexant, approved by the Food and Drug Administration for the treatment of insomnia.

From the literature review of the last 10 years, a growing interest in sleep disorders in oncology has emerged, especially in the light of the evidence formulated by IARC on the possible onset of tumors in subjects with circadian rhythm disorders; Many studies have therefore been carried out, most of which very heterogeneous with respect to both sleep disorders and the type of neoplasm. This could explain the conflicting and often inconclusive data reported in the literature. This review is probably the first that has only evaluated studies that have diagnosed different sleep disorders through ICSD-3 criteria in different types of cancer, depending on their anatomical location.

The importance of evaluating sleep disorders in patients with cancer is therefore unquestionable and the introduction of the figure of the sleep expert in the oncology team would be appropriate to optimize the therapeutic response from the early stages of the disease. Indeed, treatment of sleep disorders, with drugs or non-drug interventions such as CBT, has been shown to be important for the response to cancer therapy. Another aspect of fundamental importance is the consideration of the treatment of sleep disorder as a therapeutic in the oncology field: promising studies on chronotherapy have been underway for several years which, through the evaluation of the circadian rhythms of the different types of cancer cells, allows to optimize the therapeutic result by minimizing side effects.

This review also shows that most sleep disturbances may represent a risk factor for the onset of different types of cancers; therefore, preserving the quality of sleep and properly managing its disorders is very important for cancer prevention. With regard to prevention, it must also be considered that the treatment of sleep disorders can guarantee an adequate production of endogenous melatonin, a hormone with anti-tumor and anti-inflammatory functions; the antitumor effect of melatonin has in fact led to the use of this hormone in association with radiochemotherapy treatments, resulting in an improvement in the patient's response, accompanied by lower toxicity.

Sleep interventions can also prove cost-effective, reducing comorbidities and mortality, resulting in reduced care costs.

Written by: Maria Paola Mogavero, MD, Istituti Clinici Scientifici Maugeri, IRCCS, Pavia, Italy; Lourdes DelRosso, MD, MEd, Pulmonary and Sleep Medicine, University of Washington, Seattle Children's Hospital, Seattle, Washington; Francesco Fanfulla, MD, Department of Developmental and Social Psychology, Sapienza University, Rome, Italy; Oliviero Bruni, MD, and Raffaele Ferri, MD, Oasi Research Institute IRCCS, Troina, Italy

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