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  MAY 7, 2019 by APRIL McCARTHY
Disruptions In Our Internal Body Clock Increase Cancer Risk


While it's reported that chronic disruptions of circadian rhythms, or internal body clocks, can lead to an increased risk of cancer, the underlying mechanisms by which the disturbances promote tumor growth had been largely unknown until now.


This internal clock, or circadian rhythm, controls when we sleep and wake and plays a role in other biological processes as well, such as temperature regulation and hormone production. Some people have internal body clocks that run longer than 24 hours, or at the very least have slower adapting mechanisms to the traditional daily cycle.

Agrarian cultures built their societies around sunlight, waking up with the sun to toil in the field and heading home as the sun lowered beneath the horizon. But the Industrial Revolution, and electricity in particular, brought the freedom to unshackle us from nature's clock.

In a study published in the journal PLOS Biology, researchers at Penn Medicine show circadian disruptions trigger an increase in cell proliferation that, ultimately, shifts the cell-cycle balance and stimulates the growth of tumors in mice.

The findings also suggest that "chronotherapy"--the delivery of treatment timed to the host's circadian rhythm--can improve disease outcomes that inhibit tumor growth in mice. Chronic circadian disruption--which researchers achieved by simulating frequent jet-lag--reduced the efficacy of the therapy in human cultured cells, a finding that was validated in mice.

"We suggest that chronic disruption of the normal circadian rhythm tips the balance between tumor-suppressive and tumor-progressive gene expression to favor tumor growth," said senior author Amita Sehgal, PhD, a professor of Neuroscience and director of Penn's Chronobiology Program. "Better understanding the molecular effects of jet lag, shift work, and other sources of chronic disruption may lead to strategies to minimize the increased cancer risk associated with these behaviors, as well as to better treatment strategies, including timing delivery of cancer therapy for maximum benefit."

To identify the cellular and molecular mechanisms driving this change, researchers used the hormone dexamethasone to chronically advance daily rhythms in human cultured cells, mimicking frequent jet-lag. They found the treatment altered expression of multiple genes, and increased expression of a cell-cycle control protein called cyclin D1. Cyclin D1, in turn, activated cyclin D-dependent kinase 4/6 (CDK4/6), proteins that are a part of a cell-cycle regulatory pathway. In this case, CDK4/6 halted the cell from growing larger and caused it to synthesize new DNA, which led to accelerated cell division rates.

"Our findings strongly indicate that environmental or physiological disturbances of circadian rhythms such as shift work, abnormal sleep timing, or irregular psycho-sociological stresses can affect variability in both cancer growth and response to cancer drugs," said first author Yool Lee, a research associate in the Sehgal Lab. It may be reasonable to expect that resetting of the body clock by scheduled light-exposure, meal-times, or exercise may address the body's response to better adapt to immune responses related to cancer.


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