The emerging link between cancer, metabolism, and circadian rhythms

Abstract

The circadian clock is a complex cellular mechanism that, through the control of diverse metabolic and gene expression pathways, governs a large array of cyclic physiological processes. Epidemiological and clinical data reveal a connection between the disruption of circadian rhythms and cancer that is supported by recent preclinical data. In addition, results from animal models and molecular studies underscore emerging links between cancer metabolism and the circadian clock. This has implications for therapeutic approaches, and we discuss the possible design of chronopharmacological strategies.

Figure 1. The mammalian circadian clock.

An overview of rhythmic functions which are critically controlled by the human circadian pacemaker are outlined. Time of day is indicated for peak endocrine functions, deepest sleep, metabolic control, immune responses, alertness, and cardiovascular parameters over the 24-hour cycle. Information was adapted from several references^–.

Figure 2. The Molecular Components of the Mammalian Circadian Clock.

The circadian transcriptional/translational feedback loop occurs within a period of 24-hours. The core circadian transcriptional machinery consists of the bHLH DNA-binding transcription factors, CLOCK and BMAL1^,, which bind E-Box sequences to control the rhythmic expression of ~1015% of genes^,–. CLOCK:BMAL1-dependent transcription of core clock and clock-controlled genes (CCGs) peaks during the day, while transcription is inhibited by the circadian repressors, Period (PER) and Cryptochrome (CRY), at night^–. An additional level of circadian regulation exists with the nuclear receptors RORa and REV-ERBa that activate and repress transcription of the Bmal1 gene, respectively^,.

Figure 3. Circadian regulation of tumor initiation and progression.

During tumorigenesis, several aspects of altered circadian control have been described at the stages of initiation and progression. These include genetic disruption of the canonical circadian transcriptional machinery and changes in epigenetic control mechanisms that regulate circadian gene expression, steps which are likely more implicated in tumor initiation. Subsequent deregulation of metabolism could further drive tumor progression, both in a cell autonomous manner and circadian metabolic changes that influence tumor/host interactions.

Figure 4. Tumor/host communication involving circadian metabolic tissues.

The tumor macroenvironment, comprised of inflammatory cytokines, chemokines, glycolytic byproducts, and other tumor-derived waste is secreted into the blood. Emerging evidence now suggests that metabolic waste byproducts, such as lactate, can potentially be utilized as carbon sources to satisfy the demand of rapidly proliferating cells. The circulating tumor macroenvironment has been described to rewire circadian metabolism at a distance^,. Target metabolic tissues include the liver, but likely extend to the pancreas, adipose tissue and skeletal muscle as shown. In addition, the role of peripheral tissues in further driving tumorigenesis, by potentially supplying metabolic fuel, emphasizes the significance of the tumor/host interaction.