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Page 8 of 18 Borniger. J Cancer Metastasis Treat 2019;5:23 I http://dx.doi.org/10.20517/2394-4722.2018.107

sleep and cancer, where disrupted arousal influences cancer growth and aberrant neoplasia reciprocally
promotes changes in sleep.

Circadian deregulation
The paired suprachiasmatic nuclei (SCN) are the primary structures responsible for setting circadian rhythms
in physiology and behavior that we observe across most of the phylogenetic tree [50-53] . The SCN receive
photic input from specialized retinal ganglion cells that serve a minimal role in vision. These cells express a
photosensitive protein, melanopsin, allowing them to directly sense light, and are therefore named “intrinsically
photosensitive retinal ganglion cells” (ipRGCs) [54,55] . ipRGCs transduce photic input into a neurochemical one,
with axons traversing the retino-hypothalamic tract and terminating in the suprachiasmatic nucleus. Here,
glutamate-mediated synaptic transmission results in downstream cyclic adenosine monophosphate (cAMP)
accumulation and cAMP response element binding (CREB) phosphorylation. Phosphorylation of CREB
results in it binding the promoters of the core clock genes per and cry. In a transcription-translation loop,
the protein products homo or heterodimerize (e.g., PER::CRY dimers), enter the nucleus, and suppress the
transcription of the positive arms of the circadian clock, the genes arntl1 (bmal1) and clock.

This process takes approximately 24 h to complete, where light-induced gene transcription has a phase-
modulatory effect on the clock. This feedback loop operates in a cell-autonomous manner throughout the
body, with peripheral clocks “set” via neural and humoral routes originating from the SCN [56,57] . Behavioral
and physiological outputs controlled by the clock include sleep-wake cycles, appetite and food intake, mating
and reproductive behavior, rhythms in immune function and glucocorticoid secretion, and stress responses,
among others.

Chronic circadian disruption (e.g., via aberrant light exposure, genetic manipulations, or phase shifting) is
repeatedly associated with spontaneous cancer occurrence in humans and multiple rodent models spanning
a variety of cancer types [2,4,21,58,59] . For example, chronic circadian disruption via repeated inversions of the
light-dark cycle promotes spontaneous tumor development in a mouse model of breast cancer mimicking Li-
[60]
Fraumeni syndrome . This paradigm is known to cause significant disruption of the circadian clock as well
as the sleep-wake cycle. Using a transgenic approach to specifically knockdown the tumor-suppressor p53 in
fl/fl
mammary epithelial cells (WAP-Cre::p53 ), van Dycke and colleagues demonstrated that mice undergoing
the inversion protocol developed mammary tumors ~8 weeks sooner (median; 17% sooner) than their control
counterparts. This was accompanied by increased body mass gain in mice experiencing circadian disruption,
as well as gross increases in sleep throughout the experiment. This was the first study to demonstrate a causal
role for light-induced circadian disruption in the acceleration of spontaneous breast cancer development.

In a similar study, Papagiannakopoulos and colleagues investigated the effects of environmental and
[61]
genetic circadian disruption on lung tumorigenesis . Using a cre-inducible model of lung cancer
[K-ras LSL-G12D/+ ;p53 flox/flox (KP) mice], the authors subjected the mice to a jet-lag circadian disruption schedule
and examined tumor growth, metabolism, and proliferative capacity. Chronic jet-lag accelerated tumor
growth, severity, and mortality upon cre-mediated recombination. A similar phenotype was uncovered when
manipulations consisted of knocking out core clock genes (Per2 or Bmal1 (Arntl1)) in animals that develop
spontaneous cancer (Kras LA2/+ mice). Tumor cells deficient in per2 were also more proliferative in culture, and
mouse embryonic fibroblasts lacking kras and per2 were more sensitive to cellular transformation than their
Per2-intact counterparts. As energy balance is powerfully regulated by circadian rhythms, they investigated
cellular metabolic pathways in Per2 deficient cells. Indeed, cells lacking this core clock gene showed a marked
increase in the excretion of core energy substrates lactate, glucose, and glutamine, indicating a systemic
effect of circadian disruption. Using isotope labeled glucose (U-13Cglucose) and carbon 4 (M4) labeling they
demonstrated that cells with disrupted circadian clocks increased the amount of glucose loaded into the
[62]
tricarboxylic acid cycle, a finding that agreed with prior reports . Finally, they investigated whether clock