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Borniger. J Cancer Metastasis Treat 2019;5:23 I http://dx.doi.org/10.20517/2394-4722.2018.107 Page 9 of 18

gene abnormalities were found in primary patient tumors and noted that all genes (except for clock) were
down-regulated in lung cancer samples.

In a reciprocal set of experiments to those discussed above, Masri & colleagues investigated how tumors
[10]
themselves disrupt host circadian rhythms, independent of the outside environment . In a mouse model
of lung adenocarcinoma, they demonstrated that tumors dysregulated the circadian expression of genes
controlling immunity and metabolism in a distal organ, the liver, without affecting core components of the
circadian clock. This was subsequently confirmed in an additional model of non-metastatic breast cancer,
[6]
as discussed above . These changes were hypothesized to be due (in part) to tumor-induced IL-6 signaling
interfering with insulin-dependent glucose uptake via a SOCS3-regulated mechanism. Experiments like those
discussed above highlight the bidirectional cross-talk among the circadian system (ultimately controlled by
the brain), tumors, and the host. These findings suggest that novel approaches for cancer treatment lie in the
normalization of circadian rhythms via light, nutrition, or clock phase or amplitude-modulating compounds.
[63]
Indeed, a flavonoid found in citrus peel, nobiletin, is a powerful clock-enhancing molecule that shows
promise in the treatment of a variety of cancers [64-66] .

Melatonin
Melatonin is an indoleamine hormone produced and secreted into circulation primarily by the pineal gland
in mammals, where it acts as an endogenous signal of darkness [56,67-70] . Through a poly-synaptic pathway,
the suprachiasmatic nuclei control melatonin production and secretion, rendering the concentrations of this
[71]
hormone sensitive to environmental light input . Because light activates the SCN to cause downstream
inhibition of the pineal gland, darkness induced disinhibition permits melatonin secretion only during the
night.

Melatonin is a pleiotropic immunomodulatory molecule. Broadly, melatonin is immune-enhancing, acting as
a mild anti-inflammatory agent, buffering the immune system against glucocorticoids and reactive oxidative
and nitrosative stress [72-74] . Shift work and transmeridian travel, two behaviors that strongly alter melatonin
rhythms, are associated with cancer incidence. In 2007, the International Agency for Research on Cancer
[75]
classified shift work with circadian disruption or chronodisruption as a probable human carcinogen .
Artificial light at night (e.g., street and house lights), which inhibits pineal melatonin, is associated with
[78]
increased breast cancer prevalence [22,76,77] , although the findings are not universally consistent . The
mechanisms behind these trends are becoming clearer thanks to basic research.

In a clever experimental design, Blask & colleagues investigated the role of melatonin on human breast cancer
[79]
xenograft tumor progression in nude rats . Blood samples were collected from healthy female volunteers
during the day, night, or after 90 min exposure to bright white light at night (to putatively knockdown
circulating melatonin concentrations). Melatonin deficient- (daytime or light at night collected) or sufficient
blood were then perfused into the tumor xenografts. Tumors perfused with daytime or light at night-exposed
blood samples showed high proliferative activity and linoleic acid uptake/metabolism, while those perfused
with melatonin-rich nocturnal blood had markedly reduced proliferative activity. Additionally, exposing
tumor-bearing rats to increasing intensities of artificial light dose-dependently accelerated tumor growth
in tandem with knockdown of circulating melatonin. These results were the first to suggest that light at
[79]
night exerts its pro-tumorigenic effects via its actions on circulating melatonin concentrations . Since the
publication of this study, melatonin has been intensely investigated as an anticancer molecule, particularly in
the context of breast cancer [80,81] . Potential mechanisms for its actions have been uncovered, including anti-
[82]
estrogen, angiogenic, and oxidant pathways . As an ancient and pleiotropic hormone, melatonin is not the
“cleanest” anti-cancer molecule, given its distributed effects on many tissues throughout the body. However,
understanding the mechanisms by which it exerts its anti-cancer effects will likely lead to novel and targeted