ReviewCircadian effects in cancer-relevant psychoneuroendocrine and immune pathways
Introduction
Every day, as the Earth revolves around its axis, our lives oscillate through a repeating cycle of day and night. Cellular and systemic physiologies are synchronized with circadian cycles. Circadian coordination appears crucial for healthy physical and mental function, while many disease states are marked by disruption of circadian endocrine rhythms (Mongrain and Cermakian, 2009). Such disruption is particularly evident in some cancers including breast cancer. Human and animal evidence demonstrate that circadian disruption worsens as tumors progress. Poorly differentiated, fast growing, or advanced tumors are often accompanied by disrupted endocrine, metabolic, and immune rhythms or alteration of sleep-wake and physical activity cycles (Touitou et al., 1995, Mormont and Lévi, 1997). Circadian disruption may be a reaction of host physiology to tumor presence or a result of endocrine responses to the physical and emotional demands of the disease. Alternatively, rhythm disruption due to genetic, environmental, or behavioral factors may predate the tumor and predispose its development. Data are accumulating to suggest that circadian disruption may be more than a cancer symptom: it may be a risk factor for tumor initiation and may accelerate cancer progression (Fu and Lee, 2003). Previously, our group proposed a model of circadian disruption as a pathway of psychoneuroimmune effects on tumor progression and cancer survival (Sephton and Spiegel, 2003). There has since been an explosion of relevant clinical, systemic, and cellular research. We present an updated review of the literature informing a revised theoretical model (Fig. 1). Because much of the human and animal research has been conducted in the context of mammary tumors, we highlight the relevance of this model for breast cancer.
Physiological rhythms are coordinated by the central clock in the hypothalamic suprachiasmatic nuclei (SCN). The SCN endogenously generates circadian rhythms using an intricate mechanism of feedback loops involving at least eight core circadian genes: CLOCK, ARNTL (formerly BMAL1), period1 (PER1), period2 (PER2), period3 (PER3), cryptochrome 1 (CRY1), cryptochrome 2 (CRY2), and casein kinase 1 epsilon (CSNK1E). Feedback mediated by clock proteins stimulates and suppresses transcription of clock genes. For example, proteins regulated by CLOCK and ARNTL activate rhythms by initiating transcription of proteins period and cryptochrome (Guillaumond et al., 2005). In turn, the master clock can be entrained by external cues such as light and feeding schedules. Light stimulates specialized melanopsin-expressing retinal ganglion cells that transmit signals directly to the SCN via the retinohypothalamic tract (Abrahamson and Moore, 2001).
In addition to the central clock, peripheral cells have their own circadian clocks. In almost every peripheral tissue thus far examined, the eight known clock genes are expressed in a circadian fashion (Yamamoto et al., 2004). Most peripheral cells can sustain cellular rhythms independently (Schibler and Sassone-Corsi, 2002, Nagoshi et al., 2004). A primary function of the central clock, then, is to synchronize peripheral cellular clocks to coordinate systemic physiology with environmental demands. The mechanisms by which the SCN coordinates peripheral tissues are under investigation. They appear to be tissue-specific, multiple, and diverse (Guo et al., 2005). However, autonomic circuits and glucocorticoids are emerging as primary mechanisms whereby the SCN synchronizes peripheral rhythms (Balsalobre et al., 2000, Dickmeis, 2009).
Arrow A in Fig. 1 represents the integration of circadian and endocrine function by which the central circadian clock coordinates peripheral cellular rhythms. SCN neurons project to the hypothalamic paraventricular nucleus (PVN), a control center for both autonomic and HPA function. SCN ablation significantly alters glucocorticoid rhythmicity (Filipski et al., 2002). SCN control of glucocorticoid secretion is mediated partly via sympathetic input to the adrenal gland (Dickmeis, 2009). The adrenal peripheral clock is a necessary partner in generating the robust glucocorticoid rhythms that synchronize peripheral clocks (Son et al., 2008, Dickmeis, 2009). Neuroendocrine signals regulate rhythms of peripheral cellular physiology including cell proliferation, apoptosis, secretion of hormones and cytokines, immune cell trafficking, and cytotoxicity (Fu and Lee, 2003). Glucocorticoids appear to be the principal coordinator of peripheral cell division, an endpoint with enormous relevance to cancer (Dickmeis, 2009, Mongrain and Cermakian, 2009).
Though both are modulated by the SCN, circadian cycles and sleep cycles are somewhat independent phenomena. The most prominent regulator of sleep appears to be homeostatic drive (Kudo et al., 1999); however, sleep is also partly regulated by the lateral hypothalamus, which receives neural projections from the SCN (Green et al., 2008, Murillo-Rodríguez et al., 2009). The SCN also projects to the pineal gland, which releases melatonin in response to retinal signals regarding the onset of darkness. Melatonin peaks in darkness, induces sleepiness, and helps maintain sleep. Melatonin type 2 receptors seem to be involved in sleep onset (Liu et al., 1997). Sleep difficulties are often marked by melatonin suppression (MacFarlane et al., 1984), and administering melatonin can improve sleep duration and efficiency (Zhdanova and Tucci, 2003). Chronic sleep deprivation also activates autonomic and HPA responses (Vgontzas et al., 1999, Sgoifo et al., 2006). Sleep deprivation elevates evening cortisol and flattens its circadian rhythm (Leproult et al., 1997), and advancing the sleep–wake cycle by 8 h shifts the cortisol nadir (Caufriez et al., 2002). Actigraphic recordings from metastatic breast cancer patients indicate nocturnal awakenings are linked with flattened diurnal cortisol rhythms and heightened sympathetic activity. Thus, sleep may be protective of both parasympathetic tone and circadian glucocorticoid rhythms (Palesh et al., 2008). Correlations between sleep and circadian genetic and hormonal variations point to tightly linked and bidirectional systems (Archer et al., 2008). However, changes in cellular physiology related to sleep–wake cycles may be driven by mechanisms somewhat different than those related to circadian rhythms.
The SCN stimulate melatonin release from the pineal in response to light, but in turn, melatonin acts at SCN receptors to synchronize central rhythms with the photoperiod (Dubocovich et al., 1996). Melatonin type 1 receptors seem to be involved in sleep maintenance via SCN suppression (Liu et al., 1997). Effects of glucocorticoids on the central pacemaker are likely indirect since the SCN contains no glucocorticoid receptors (Rosenfeld et al., 1988). While glucocorticoid agonists do not shift the phase of the SCN, they can increase its expression of PER1, PER2, and PER3 (Balsalobre et al., 2000). Elevated glucocorticoids are also associated with impaired sleep (Prinz et al., 2001). HPA activation may specifically disrupt slow-wave sleep by increasing EEG frequency and norepinephrine release from the locus coeruleus (Buckley and Schatzberg, 2005).
Many disorders of both physical and mental health are marked by poor circadian coordination (Mongrain and Cermakian, 2009). Our preliminary model (Sephton and Spiegel, 2003) highlighted research in a rapidly growing area: circadian effects in cancer. Correlational studies had demonstrated circadian alterations in human cancer patients, tumor-bearing animals, and tumor tissue that appeared to differ by aspects of the tumor and to worsen as cancer advanced (Mormont and Lévi, 1997). Among tumor-bearing animals, disrupted cycles of cellular proliferation, hepatic enzymes, corticosterone, and temperature were observed. In turn, tumor tissue cultures demonstrated altered DNA synthetic and cell proliferation cycles (Mormont and Lévi, 1997). Circadian disruption was implicated as a cancer risk factor when long-term night shift work demonstrated prognostic value for breast cancer (Davis et al., 2001, Schernhammer et al., 2001). Speculation that circadian dysregulation might facilitate tumor growth was supported by prospective studies of circadian physiology and tumor progression: flattening of the diurnal cortisol rhythm was found to predict shorter survival in metastatic breast cancer (Sephton et al., 2000), and poorly coordinated rest-activity rhythms were prognostic for early mortality in colorectal cancer (Mormont et al., 2000).
There has recently been an explosion of relevant human and animal research providing evidence that circadian disruption accelerates tumor progression, as represented by Arrow B in Fig. 1. DNA genotyping studies show that variants of the circadian genes PER3 and NPAS2 are associated with increased breast cancer risk (Zhu et al., 2005, Zhu et al., 2008). A genetic variant of NPAS2, one of the genes that coordinate central circadian rhythms, has also recently demonstrated prognostic significance in breast cancer (Yi et al., 2009). New clinical research shows melatonin suppression is associated with increased breast cancer risk (Schernhammer and Hankinson, 2005, Schernhammer et al., 2008). Associations continue to be found between long-term shift work and risk for breast cancer (Schernhammer et al., 2006), while similar associations have emerged for colorectal, endometrial, and prostate cancer (Schernhammer et al., 2003, Kubo et al., 2006, Viswanathan et al., 2007). Comparisons with healthy controls indicate metastatic breast cancer patients have flattened diurnal cortisol rhythms with suppression of the morning cortisol peak and/or elevation of the evening nadir (Abercrombie et al., 2004). Nocturnal melatonin suppression and flattened cortisol rhythms have also been demonstrated in lung cancer patients (Mazzoccoli et al., 2003). Sleep disturbance is reported in approximately 60% of breast cancer patients (Fortner et al., 2002), and actigraphy and polysomnography studies confirm that cancer patients take longer to fall asleep, wake up more often, spend more time in bed, and nap more frequently than healthy individuals (Pati et al., 2007, Parker et al., 2008). Cancer patients also demonstrate poorly differentiated rest-activity rhythms. For example, advancing non-small cell lung cancer is linked with daytime sleep and nocturnal wakefulness (Levin et al., 2005). Metastatic colorectal cancer patients with poorly differentiated rest-activity rhythms show elevation of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and transforming growth factor-α (TGF-α) and suffer early mortality (Rich et al., 2005). An independent international multisite study has recently confirmed the prognostic significance of rest-activity rhythm disruption in colorectal cancer (Innominato et al., 2009).
In recent animal studies, SCN lesions produced disrupted rhythms of corticosterone, temperature, lymphocyte trafficking, and cytotoxic activity, along with accelerated tumor growth, increased tumor weight, and shorter survival (Filipski et al., 2002, Filipski et al., 2006). Repeated 8-h advances of the light–dark cycle also accelerate tumor growth and shorten survival. This intervention down-regulates the tumor suppressor gene, TP53, and up-regulates the protooncogene, MYC (Filipski et al., 2006). These alterations favor the development of tumor cell characteristics, including increased susceptibility to mutation, ability to escape apoptosis, and accelerated proliferation.
Animal and tissue culture studies yield evidence that tumors may suppress peripheral clock genes and become unresponsive to host circadian regulation (You et al., 2005). In some tumors, rhythms of cell division and proliferation are autonomous of host rhythms (Canaple et al., 2003). Human breast tumors in tissue culture demonstrate reduced PER1 and PER2 clock gene expression, and similar reductions are seen in several types of human cancer (Winter et al., 2007, Yang et al., 2009a, Yang et al., 2009b). Down-regulation of these genes in vitro accelerates tumor cell growth (Yang et al., 2009a). Thus, disruption of clock gene function in the tumor may favor more rapid cancer progression.
The central clock synchronizes peripheral cellular clocks, which control cell division. Thus, cellular proliferation is closely synchronized with master circadian rhythms. A study of mouse fibroblast cells demonstrated that circadian rhythms of peripheral cells gate the timing of cell division (Nagoshi et al., 2004). Cell cycle timing is regulated by feedback loops involving cyclins, cyclin-dependent kinases and their inhibitors, and the tumor suppressors, RB1 and TP53 (Canaple et al., 2003). Since peripheral tumor cell proliferation is under similar central circadian control, it follows that central circadian disruption may accelerate tumor progression via dysregulation of tumor cell proliferation cycles.
Peripheral PER1 and PER2 have been highlighted as potential tumor suppressor genes that work in a circadian time-dependent manner to control tumor cell proliferation rates (Fu et al., 2002, Gery et al., 2006, Gery et al., 2007). PER1 appears to gate breast tumor growth, yielding two daily growth peaks (Yang et al., 2009b). In turn, PER2 has been shown to suppress cancer cell growth both in vivo and in vitro. Down-regulation of PER2 doubles proliferation rates of implanted mammary tumors and increases the amplitude of the tumor growth rhythm (Yang et al., 2009a), while up-regulation inhibits growth and enhances apoptosis (Gery et al., 2007). Similar findings have been obtained after manipulation of colon tumor tissue (Gery et al., 2006).
PER2 knockout mice exhibit spontaneous tumor development and decreased tumor cell death in response to gamma radiation (Fu et al., 2002), and PER2 mutations confer susceptibility to the formation of colon polyps (Wood et al., 2008). Knockout or down-regulation of PER2 also interferes with expression of murine tumor cell cycle genes, MYC, CCND1, CCNE1, and WEE1 (Fu et al., 2002, Yang et al., 2009a).
In a recent study of mice implanted with mammary tumors, tumor cells lost daily rhythmic expression of PER1 and PER2 clock genes. Despite this, the animals maintained normal locomotor activity and rhythms of clock gene expression measured in liver. Within the tumor, daily cycles of growth, DNA synthesis, and mitosis were maintained. This suggests that central expression of core clock genes could be sufficient to gate tumor cell proliferation (You et al., 2005). If this is the case, then the implications of central clock dysregulation for tumor growth could be significant.
Growing evidence suggests circadian effects on tumor growth may act at multiple levels. Central circadian disruption can alter the synchronization of peripheral clocks, and in turn, the peripheral clock's gating of tumor cell growth rates (Yang et al., 2009a, Yang et al., 2009b). Alternatively, central host circadian disruption may affect tumor cell proliferation cycles through behavioral, neuroendocrine, and/or immune alterations (You et al., 2005).
Cancer-associated circadian disruption may also reflect tumor effects on peripheral, and perhaps even central, clocks of the host (Arrow B). It has been speculated that growth factors and hormones released by tumors may be capable of altering both peripheral and central circadian rhythms (Mormont and Lévi, 1997). Clock genes and immune cells may also be manipulated by tumors to disrupt host rhythms. Interestingly, cell division can shift the circadian phase: as mitosis ends, PER and CRY proteins are suppressed. It is speculated that reduction of PER and CRY during their descending phase can shorten the cellular circadian cycle, and during their ascending phase, lengthen it (Nagoshi et al., 2004). It seems possible that a tumor that interferes with central circadian regulation of its proliferation cycle, perhaps through suppression of cellular clock genes, could gain an ability to proliferate in a rapid and uncontrolled manner.
Section snippets
Circadian effects in psychoneuroendocrine pathways
Recent reviews present strong evidence that neuroendocrine changes may accelerate cancer progression by promoting tumor cell proliferation, adhesion, migration, invasion, angiogenesis, survival, and immune evasion (Antoni et al., 2006, Miller et al., 2008, Thaker and Sood, 2008, Armaiz-Pena et al., 2009, McGregor and Antoni, 2009). Because autonomic and HPA mediators also convey SCN signals to coordinate peripheral cell rhythms, endocrine stress responses may alter circadian regulatory
Circadian effects in psychoneuroimmune pathways
Effects of circadian disruption in cancer-relevant psychoneuroimmune pathways may hasten tumor growth. Cytokines can be functionally divided into two general groups: pro-inflammatory and anti-inflammatory. Chronic psychological distress and dysregulation of endocrine rhythms may shift immune responses toward an anti-inflammatory TH2-dependent rather than a pro-inflammatory TH1-dependent response, which may favor tumor growth. Dysregulation of immune modulators may further disrupt central
Discussion
Several lines of investigation converge in demonstrating that circadian disruption worsens with advancing cancer. Results distinguish central and peripheral disruption of the host from disruption in the tumor. In cancer patients and tumor-bearing animals, circadian rhythm alterations are evidenced by suppression of clock genes, sleep difficulties, poorly coordinated rest-activity rhythms, and diminished amplitude, phase shifts, period changes, and erratic peaks and troughs in endocrine,
Role of the funding source
Funding for this study was provided by a University of Louisville Graduate Research Fellowship. The University of Louisville Graduate School had no further role in the generation of the model, review of the literature, writing of the report, or the decision to submit the paper for publication.
Conflicts of interest
The authors have no conflicts of interest and declare no financial interests.
Acknowledgements
We would like to thank the Department of Psychological and Brain Sciences and the James Graham Brown Cancer Center at the University of Louisville for supporting the preparation of this manuscript.
References (196)
- et al.
Flattened cortisol rhythms in metastatic breast cancer patients
Psychoneuroendocrinology
(2004) - et al.
Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections
Brain Res.
(2001) The role of pineal gland in breast cancer development
Crit. Rev. Oncol. Hematol.
(2003)- et al.
Neuroendocrine modulation of cancer progression
Brain Behav. Immun.
(2009) - et al.
Inflammation and cancer: back to Virchow?
Lancet
(2001) - et al.
Diurnal cortisol rhythm and fatigue in breast cancer survivors
Psychoneuroendocrinology
(2005) - et al.
Cytokines and psychopathology: lessons from interferon-alpha
Biol. Psychiatr.
(2004) - et al.
Neuroimmunology of the circadian clock
Brain Res.
(2008) - et al.
Pinealectomy inhibits interleukin-2 production and natural killer activity in mice
Int. J. Immunopharmacol.
(1989) - et al.
Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking
Brain Behav. Immun.
(1997)
Diurnal and acute stress-induced changes in distribution of peripheral blood leukocyte subpopulations
Brain Behav. Immun.
The immunobiology of cancer immunosurveillance and immunoediting
Immunity
Systemic stress-induced Th2 shift and its clinical implications
Int. Rev. Neurobiol.
Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease
Trends Endocrinol. Metab.
Neurotransmitter signaling of cells of the immune system: important progress, major gaps
Brain Behav. Immun.
Sleep and quality of life in breast cancer patients
J. Pain Symptom Manage.
The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo
Cell
Inhibition by cortisol of human natural killer (NK) cell activity
J. Steroid Biochem.
The circadian gene Per1 plays an important role in cell growth and DNA damage control in human cancer cells
Mol. Cell
Emotional expression and diurnal cortisol slope in women with metastatic breast cancer in supportive-expressive group therapy: a preliminary study
Biol. Psychol.
Stress-associated immune dysregulation and its importance for human health: a personal history of psychoneuroimmunology
Brain Behav. Immun.
The meter of metabolism
Cell
Human psychoneuroimmunology: 20 years of discovery
Brain Behav. Immun.
Hypnotic efficacy and safety of triazolam administered during the postoperative period
Gen. Hosp. Psychiatr.
Reduction in serum IL-6 after vaccination of breast cancer patients with tumour-associated antigens is related to estrogen receptor status
Cytokine
Understanding the interaction between psychosocial stress and immune-related diseases: a stepwise progression
Brain Behav. Immun.
Expression profiles of 10 circadian clock genes in human peripheral blood mononuclear cells
Neurosci. Res.
Similar profiles in human period1 gene expression in peripheral mononuclear and polymorphonuclear cells
Neurosci. Lett.
Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer
Lancet
Winter depression: integrating mood, circadian rhythms, and the sleep/wake and light/dark cycles into a bio-psycho-social-environmental model
Sleep Med. Clin.
Fatigue, sleep, and circadian rhythms prior to chemotherapy for breast cancer
Support. Care Cancer
Stress and immune responses after surgical treatment for regional breast cancer
J. Natl. Cancer Inst.
The influence of bio-behavioural factors on tumour biology: pathways and mechanisms
Nat. Rev. Cancer
Lymphocyte number and stress parameter modifications in untreated breast cancer patients with depressive mood and previous life stress
J. Exp. Therapeut. Oncol.
Inter-individual differences in habitual sleep timing and entrained phase of endogenous circadian rhythms of BMAL1, PER2 and PER3 mRNA in human leukocytes
Sleep
Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells
J. Immunol.
Resetting of circadian time in peripheral tissues by glucocorticoid signaling
Science
Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity
Int. J. Cancer
Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines and β-adrenoceptors
Neuroimmunomodulation
Cytotoxic T lymphocyte count and survival time in women with metastatic breast cancer
Breast J.
Effects of sleep and circadian rhythm on circulating immune cells
J. Immunol.
Altered cortisol response to psychologic stress in breast cancer survivors with persistent fatigue
Psychosom. Med.
Fatigue and proinflammatory cytokine activity in breast cancer survivors
Psychosom. Med.
Tumors and inflammatory infiltrates: friends or foes?
Clin. Exp. Metastasis
Review: on the interactions of the hypothalamic–pituitary–adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders
J. Clin. Endocrinol. Metab.
Depression and anxiety in women with early breast cancer: Five year observational cohort study
Br. Med. J.
Beta-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines
Int. J. Oncol.
The days and nights of cancer cells
Cancer Res.
Depression in women with metastatic breast cancer: a review of the literature
Palliat. Support. Care
Associations among salivary cortisol, melatonin, catecholamines, sleep quality and stress in women with breast cancer and healthy controls
J. Behav. Med.
Cited by (70)
Electrochemical sensors for cortisol detection: Principles, designs, fabrication, and characterisation
2023, Biosensors and BioelectronicsSleep disturbance is associated with perturbations in immune-inflammatory pathways in oncology outpatients undergoing chemotherapy
2023, Sleep MedicineCitation Excerpt :Once activated, NK cells can produce biochemical signals and cytokines to stimulate adaptive immune responses [58]. As noted in preclinical [59] and clinical [60,61] studies, sleep disturbance was associated with a significant decrease in NK cell counts. This reduction was associated with increases in levels of TNF-alpha, that suppressed the expression of circadian rhythm genes (i.e., PER1, PER2, PER3) in NK cells.
A biobehavioral intervention to enhance recovery following hematopoietic cell transplantation: Protocol for a feasibility and acceptability randomized control trial
2022, Contemporary Clinical Trials CommunicationsCharacterization of basal gene expression trends over a diurnal cycle in Xiphophorus maculatus skin, brain and liver
2018, Comparative Biochemistry and Physiology Part - C: Toxicology and PharmacologyThe influence of cancer on endocrine, immune, and behavioral stress responses
2016, Physiology and Behavior