Epidemiological studies have revealed that human night-shift workers show an increased risk of breast, colon, lung, endometrial and prostate cancer, hepatocellular carcinoma and non-Hodgkin's lymphoma. Disruption of circadian rhythm increases spontaneous and carcinogen-induced mammary tumors in rodents. Loss of circadian rhythm is also associated with accelerated tumor growth in both rodents and human cancer patients. These findings raise the question of how circadian dysfunction increases the risk of cancers. A new mechanism for how long-term disruption of circadian homeostasis can also increase your risk of developing cancer is currently being debated (Lee et al. 2010).
Circadian rhythms in mammals are generated by an endogenous clock composed of a central clock located in the hypothalamic suprachiasmatic nucleus (SCN) and subordinate clocks in all peripheral tissues. The timing of peripheral oscillators is controlled by the SCN when food is available ad libitum. Time of feeding, as modulated by temporal restricted feeding, is a potent 'Zeitgeber' (synchronizer) for peripheral oscillators with only weak synchronizing influence on the SCN clockwork. When restricted feeding is coupled with caloric restriction, however, timing of clock gene expression is altered within the SCN. The SCN clock responds to external cues--daily resetting of the phase of the clock by light stimuli and metabolic cues--and drives peripheral clocks via circadian output pathways. The components of the circadian timing system can be differentially synchronized according to distinct, sometimes conflicting, temporal (time of light exposure and feeding) and homeostatic (metabolic) cues. Both the central and peripheral clocks are operated by feedback loops of specific temporal expression patterns of circadian genes, including Bmal1, Clock, Period (Per1-3) and Cryptochrome (Cry1 and 2). Bmal1 and Clock encode bHLH-PAS transcription factors that heterodimerize and bind to E-boxes in gene promoters to activate Per and Cry transcription, whereas Per and Cry encode repressors of BMAL1/CLOCK. The alternating activation and suppression of the BMAL1-driven positive loop and the PER/CRY-controlled negative loop result in a circadian oscillation of the molecular clock, allowing them to run autonomously with their characteristic, near-24h period.
Cell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm (Matsuo et al. 2003) and is paced by both central and peripheral clocks. The central clock-controlled mitogenic signals simultaneously activates the cell cycle and peripheral clocks leading to a circadian coupling of cell cycle and tumor suppressor gene expression. Thus these clock genes also function as tumor suppressors during cell cycle control. For example, BMAL1 suppresses proto-oncogene c-myc but stimulates the tumor suppressor Wee1, CRY2 indirectly regulates the intra S-check point, and PER1 directly interacts with ATM in response to γ-radiation in vitro. In mice, mutation in Per2 leads to deregulation of DNA-damage response and increased neoplastic growth. In humans, deregulation or polymorphism of Per1, Per2, Cry2, Npas2 and Clock is associated with acute myelogenous leukemia, hepatocellular carcinoma, breast, lung, endometrial and pancreatic cancers, and non-Hodgkin's lymphoma.
Disruption of circadian rhythm in cell proliferation is frequently associated with tumor development and progression in mammals, due to, at least in part, loss of the homeostasis of cell cycle control. The central clock generates a robust circadian rhythm in SNS signaling via direct and indirect targeting of the presympathetic neurons located in the hypothalamic autonomic paraventricular nucleus [43]. In vivo, the SNS controls all peripheral tissues by releasing the hormones epinephrine and norepinephrine that target adrenergic receptors (ADRs) on the cell membrane [46]. Norepinephrine is directly released from postganglionic sympathetic neurons, whereas epinephrine is released from preganglionic sympathetic neuron-controlled chromaffin cells located in the adrenal medulla. Disruption of circadian rhythm desynchronizes the central clock-SNS-peripheral clock axis, suppresses peripheral clock function and abolishes peripheral clock-dependent ATM activation, leading to myc oncogenic activation and increased incidence of tumors in wild-type mice. Our studies identify a previously unknown molecular pathway that links disruption of circadian rhythm with oncogenesis and demonstrate that tumor suppression in vivo is a clock-controlled physiological process but not a non-clock function of a specific circadian gene. Using the central clock-SNS-peripheral clock axis as a model system, we propose that the central clock-controlled SNS signaling generates a coupled AP1, peripheral clock, and ATM activation. The activation of AP1 leads to myc-induced cell cycle progression, while the activation of the peripheral clock inhibits myc overexpression and is required for ATM activity. ATM then induces p53 to prevent Myc oncogenic signaling by blocking p53-MDM2 interaction. Disruption of circadian rhythm desynchronizes the central clock-SNS-peripheral clock axis which suppresses peripheral clock and peripheral clock-dependent ATM-p53 signaling but has no effect on c-myc activation. Together, these events lead to Myc oncogenic activation that promotes genomic instability and tumor development (Fig. 7i). Our model suggests that the circadian clock plays a dual role in cell cycle control and it suppresses tumor development by controlling the homeostasis but not the inhibition of cell proliferation.
Robin McAllen argues that the evidence for SNS involvement is merely correlative rather than causative--since the endogenous measures used by the paper, catecholamine urine levels and UCP1 expression, are intimately involved in patterns of activity, body temperature and feeding, which also have circadian rhythms that are disrupted by clock gene knockouts and jetlag--and that the authors over-simplify the workings of the SNS--claiming that the specialized sympathetic nerves that innervate different body tissues can be treated as a single entity, bathing all tissues in uniform levels of catecholamine soup.
The paper's authors counter that SNS maintains many homeostatic functions in addition to the flight-or-fight response. The sympathetic tone to all tissues is low during the sleeping phase but increases before waking, which is coupled with the increase in urine volume, rate of heart contraction and body temperature. Such sympathetic control provides one of the key mechanisms that couple various physiological processes with daily physical activity, and our studies clearly show disruption of this control in response to circadian disruption in mice, not just in cultured cells. Finally, and most importantly, the sympathetic target genes found in their in vitro studies are expressed in all tissues following a robust circadian rhythm in vivo that is disrupted in response to SNS dysfunction. They demonstrate that this circadian activation of the p53 tumor suppressor in the thymus is lost in the absence of ATM, which itself is directly regulated by the clock. It is well established that loss of function in some of these genes including Per, Atm and p53 promotes tumor development in mice. Thus, the authors claim that McAllen's conclusion that their studies use a mitogenic function of catecholamines on cells in vitro to explain tumor promotion in vivo is a misunderstanding.
(2003) Control mechanism of the circadian clock for timing of cell division in vivo. Science 302: 255–259.
Lee S, Donehower LA, Herron AJ, Moore DD, Fu L. (2010) Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice. PLoS One 2010 5(6):e10995.
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