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The circadian clock: pacemaker and tumour suppressor

Nature Reviews Cancer volume 3, pages 350–361 (2003)Cite this article

Key Points

  • The circadian clock is the internal timing machine that can sustain rhythms of about 24 hours in the absence of external cues. The circadian clock is operated by the feedback loops of the circadian genes in the mammalian central pacemaker, as well as in most peripheral tissues.

  • The mammalian central pacemaker is located in the suprachiasmatic nuclei (SCN) of the brain and controls the activity of peripheral clocks through the neuroendocrine and autonomic nervous systems. The circadian clock regulates hundreds of functions in the human body.

  • Disruption of circadian rhythms has been linked to mammalian tumorigenesis and tumour progression, and has been used as an independent prognostic factor of survival time for patients with certain metastatic cancers.

  • Normal and malignant tissues often show asynchronies in cell proliferation and metabolic rhythms. Based on these observations, cancer chronotherapy has been developed to improve the efficacy in cancer treatment and the quality of patients' life.

  • The circadian clock functions in vivo as a tumour suppressor at the systemic, cellular and molecular levels. The central clock is capable of generating 24-hour cell-proliferation rhythms in peripheral tissues through the activity of the neuroendocrine and autonomic nervous systems.

  • Molecular clocks in peripheral tissues control cell-proliferation rhythms by regulating the expression of cell-cycle genes. The core circadian genes are also involved in regulating cell proliferation. The circadian clock in peripheral tissues responds directly to DNA damage and could be important in the control of the cell cycle and apoptosis.

  • The molecular clockworks and cell-cycle clocks in peripheral tissues can be regulated simultaneously by the central clock, through interacting signalling pathways. Further study of the mechanism of the circadian clock in tumour suppression and the DNA-damage response has important implications for cancer therapy.

Abstract

The circadian rhythms are daily oscillations in various biological processes that are regulated by an endogenous clock. Disruption of these rhythms has been associated with cancer in humans. One of the cellular processes that is regulated by circadian rhythm is cell proliferation, which often shows asynchrony between normal and malignant tissues. This asynchrony highlights the importance of the circadian clock in tumour suppression in vivo and is one of the theoretical foundations for cancer chronotherapy. Investigation of the mechanisms by which the circadian clock controls cell proliferation and other cellular functions might lead to new therapeutic targets.

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Figure 1: Mammalian core circadian gene feedback loops.
Figure 2: Circadian regulation of hormones, urine and the immune system.
Figure 3: The circadian clock controls cell proliferation and apoptosis at the systemic level.
Figure 4: A model for the role of Per2 in tumour suppression.
Figure 5: Signalling pathways linking the circadian clock to cell-cycle regulation in peripheral tissues.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Loning Fu & Cheng Chi Lee

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DATABASES

Cancer.gov

acute lymphoblastic leukaemia

breast cancer

colorectal cancer

osteosarcoma

pancreatic cancer

LocusLink

β-catenin

Bcl-xL

Bmal1

Ccna1

Ccna2

Ccnd1

CKIε

Cry1

Cry2

cyclin D3

Fos

Fra1

Gadd45α

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JunB

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Per2

Per3

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Ras

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FURTHER INFORMATION

A time to heal – chronotherapy tunes in to body's rhythms

Biological clocks

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From circadian rhythm to cancer therapy

Glossary

SUPRACHIASMATIC NUCLEI

(SCN). The mammalian master circadian clock. The SCN are small bilateral structures located next to the third ventricle and just above the optic chiasm in mammalian brain. Each SCN nucleus contains about 10,000 neurons that are synchronized to generate coordinated circadian outputs in vivo.

PHASE SHIFT

The displacement of waveform in time. When a waveform is displaced by a complete wavelength, it is described as having a phase shift of 360 degrees. When a waveform is displaced by a half a wavelength, it is described as having a phase shift of 180 degrees.

MELANOPSIN-EXPRESSING RETINAL GANGLION CELLS

A small subset of retinal ganglion cells that are intrinsically photosensitive and express the opsin-like protein melanopsin. These neurons project directly to the suprachiasmatic nucleus of the mammalian central circadian clock, as well as to the intergeniculate leaflet and the olivary pretectal nucleus in the brain. Mice that are deficient in melanopsin show attenuated responses to light stimuli.

PINEALECTOMY

Ablation of the pineal gland. The pineal gland is a cone-shape gland that is located at the posterior end of the third ventricle in the brain. The pineal gland produces melatonin, a hormone that is important for regulating circadian rhythmicity in humans. The level of melatonin rises at night and falls during the day.

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Fu, L., Lee, C. The circadian clock: pacemaker and tumour suppressor. Nat Rev Cancer 3, 350–361 (2003). https://doi.org/10.1038/nrc1072

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