Oncology and circadian rhythms
Why disrupted body clocks trigger liver cancer
DRINKING too much and eating too much are both good ways of getting liver cancer. But there is a third. The disrupted circadian rhythms caused by working shifts or crossing time zones also seem to induce the disease. Precisely how and why meddling with day and night cycles has such a dire effect on the liver remains an enigma, but a study just published in Cancer Cell by Loning Fu and David Moore at the Baylor College of Medicine, in Texas, sheds some light on the matter.
Among the liver’s many jobs is making bile, a substance secreted into the intestine to break down the fats and oils in food. One of bile’s main components is bile acid, a derivative of cholesterol. Dr Fu and Dr Moore knew from their previous research that disrupting the circadian rhythms of mice causes the rodents’ livers to overproduce this substance. They also knew that liver cancer commonly appears in mice engineered to lack certain genes required for the management of day-night cycles. This led them to suspect a link between liver cancer and too much bile acid. To take a closer look, they set up an experiment.
Working with a team of colleagues, the two researchers studied mice that had had their day-night cycles disrupted. A group of 80 of the animals which had previously lived on a cycle of 12 hours in light and 12 hours in darkness had the lights kept on, on one occasion, for 20 hours, instead. Three days later they were again subjected to four hours of darkness rather than 12. This alternation, at three-day intervals, was then kept up for 30 weeks. A group of 110 mice, meanwhile, were maintained on a constant 12-hour cycle as a control.
After 12 weeks, and again after 30 weeks, the team killed some of the rodents in order to look at their livers. They found that the livers of animals on the disrupted schedule had accumulated fat and showed evidence of damage. In particular, they overproduced bile acid. Eventually, after 90 weeks, they killed and examined the remaining animals. Just under 9% of the cycle-disrupted mice, they discovered, had developed liver cancer. None of the control mice had done so.
In need of regeneration
The probable cause of these differences emerged when the researchers ran two similar follow-up experiments using genetically engineered mice. Some of the mice lacked the gene needed to make the constitutive androstane receptor (CAR), a molecule involved in clearing away bile acid. This gene is activated when levels of bile acid get too high. CAR molecules help liver tissue to regenerate, since excess acid damages tissue, inhibiting regeneration. However, the cellular proliferation associated with regeneration is the sort of thing that can sometimes get out of hand and lead to cancer.
Other mice Dr Fu and Dr Moore looked at lacked a different gene, for a receptor molecule called FXR. This keeps bile-acid production under control in the first place.
In their experiment the researchers found that in mice lacking the gene for CAR, neither those with disrupted day-night cycles nor those used as controls developed liver cancer. In contrast, even if their day-night cycles were uninterrupted almost 30% of mice lacking FXR developed liver cancer. Among those with interrupted cycles the figure was above 60%. On the basis of these results Dr Fu and Dr Moore suggest that developing either a drug that blocks the activity of CAR, to stop cell proliferation, or one that activates FXR, to decrease bile-acid production, could save shift workers and frequent flyers from the threat of liver cancer.