Mini-reviewCircadian rhythms and tumor growth
Introduction
Changes in the external environment necessitated the evolution of a system that could anticipate and respond to the cues. The earth’s rotation around its axis of about 1 day is thought to have driven the evolution of a daily oscillatory system. The term diurnal was used to describe a daily oscillation and is now generally used to describe a daytime behavior or response, while nocturnal is a nighttime behavior or response. An oscillation that is endogenous and as such is autonomous from an external periodic signal has been termed circadian (circa-about and dies-days) [1]. Circadian oscillations (rhythms) require synchronization (entrainment) from external stimuli. Without entrainment, endogenous rhythms would dissociate from natural cycles. The environmental entrainment agent has been termed Zeitgeber, from German for “time giver,” or “synchronizer”. The light–dark cycle is one of the most powerful stimulants for entrainment. However, food (nutrients and metabolites), hormones, temperature, social interactions, and exercise also play important roles in entrainment [2]. Circadian rhythms are critical to normal behavior and physiology and as such are known to regulate the sleep-wake cycle, core body temperature, hormonal secretion, metabolism, and cell cycle control. Given that hormone secretion, metabolism, and cell cycle control regulate cell proliferation, the connection between cancer and circadian rhythms has garnered recent attention. The focus of this review will be on the control of tumor growth by circadian rhythms.
Section snippets
The circadian clock
The mammalian time keeping system is organized in a manner so that there is central control by a master circadian pacemaker or “clock” located in the brain, and peripheral clocks located in virtually all cells. The master circadian clock is centered in the suprachiasmatic nuclei (SCN), a paired structure in the anterior hypothalamus, each containing approximately 10,000 neurons. The SCN is anatomically located to receive visual input from the light–dark cycle and nonphotic information from
Rhythms and cancer
Less than 10% of gene transcripts from different tissues (e.g. heart, kidney, liver, fat, and brain) are thought to be under rhythmic control. Core components of the clock, metabolic genes, and other tissue specific transcripts have been shown to have rhythmic expression [16]. For example, cell cycle (e.g. myc, p53, and cyclin D1), DNA damage repair (e.g. XPA), and metabolism (e.g. glucose-6-phosphatase, peroxisome proliferator-activated receptor, and nicotinamide phosphoribosyltransferase) are
Experimental disruption of rhythms and tumor growth
Studies in isolated cells, highly proliferative tissues, and regenerating tissues have all demonstrated that cell proliferation is a temporally regulated event and that progression through the cell cycle is controlled by growth factors [42], [43]. Thus, rhythmic control of cell division limits DNA replication to a specific time in the day and may regulate the rate of cell division. In a survey of slow and fast growing tumors, cell cycle rhythm was often preserved in the slow growing tumors
Melatonin
Melatonin is a pineal hormone involved in maintaining the daily clock and the calendar clock. Thus, it is considered to be the body’s chronological pacemaker. Melatonin synthesis and secretion is regulated by the light–dark cycle in most vertebrates and was thought to be an exclusive output of the SCN [64]. However, the observation that restricted feeding can synchronize melatonin synthesis and transcription of arylalkylamine-N-acetyltransferase, the rate-limiting enzyme for melatonin
Signaling pathways regulating tumor growth in desynchronized animals
Studies investigating the mechanistic details by which signaling pathways regulate tumor growth in desynchronized animals suggest that mitogenic and metabolic signaling coupled with circadian clock control plays a critical role in cell cycle progression and energy metabolism. The insulin/IGF-1 signaling pathway best illustrates the dual control of cell cycle progression and energy metabolism (Fig. 1).
IR and IGF-1R are receptor kinases that Tyr phosphorylate a family of molecular docking
Summary
Evidence from population based, in vivo, and in vitro studies have implicated circadian rhythms in the control of cancer and are consistent with the hypothesis that specific components in the host circadian timing system regulate tumor growth. Factors regulating tumor growth share the capacity to modulate peripheral clocks, the cell cycle, and energy metabolism (Fig. 2). A challenge is to determine the relative contribution of peripheral clock setting towards cell cycle and/or energy metabolism
Acknowledgements
Grant support from the Stephan C. Clark Foundation. I thank members of the Greene lab for helpful discussions and Robert Dauchy and Dr. David Blask for their suggestions on the manuscript.
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