ABOVE: A normal intestinal organoid (L) and a tumorous one (R). As tumors grow, intestinal organoids lose their structure, becoming a spherical mass of actively dividing cells (red). Scale bars are 20µm MASRI LABORATORY
Genetic and environmental disruptions to circadian clocks accelerate the progression of colorectal cancer in organoids and mice, University of California, Irvine, researchers report in an August 10 paper in Science. This acceleration appears to be driven by an increase in mutations within a tumor suppressor gene.
This link between the body’s natural circadian clock and colorectal cancer, the researchers behind the study say, may explain the alarming rise in young onset colorectal cancer observed over the last two decades. “A majority of these [cases in young adults] are sporadic in nature and not actually linked to genetic predisposition,” says study co-author Selma Masri, a molecular biologist at UCI.
In humans and lots of other creatures, many bodily processes follow hardwired internal rhythms. These built-in circadian clocks can influence everything from energy metabolism to how effective medications are, and studies suggest that if they get thrown out of whack, they can cause or worsen illnesses, including some cancers. Indeed, previous research found that nurses working night shifts have higher rates of breast cancer, so Masri and her colleagues hypothesized that keeping odd hours could also play a role in colorectal cancer.
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To find out, the researchers took healthy mice and deleted the gene Bmal1, which regulates circadian rhythms, preventing the clock from functioning properly in their intestines. They then crossed these clock-deficient mice with ones that are prone to tumors because they carry two mutated copies of their APC gene, which normally acts as a tumor suppressor in colon cancer. The cross resulted in mice with one nonfunctional APC allele and disrupted intestinal clocks.
Intestinal organoids grown from these animals’ stem cells exhibited accelerated development of intestinal tumors compared to organoids grown from animals with a functional circadian clock. Genetic sequencing revealed a high prevalence of mutations to the organoids’ previously functional APC allele. This is known in cancer biology as loss of heterozygosity, and is reported in nearly 80 percent of colorectal cancer cases in humans, the researchers explain in the paper.
The team also took six tumor-prone, APC-mutant mice and changed their sleep-wake cycle every other day in order to model nightshift work three days a week for 10 weeks. The mice with this environmental disruption to their circadian clocks had a higher incidence of colon cancer than tumor-prone mice kept in consistent 12-hour light-dark cycles, and also had significantly larger tumor counts and sizes.
Taken together, the results highlight a fundamental link between internal clock disruptions and colon cancer, Masri says. “We have [a] strong prevalence of night-shift work in many industries like health care. This extended light exposure from working late at night or phones and computers can be disruptive to our circadian clock,” she notes, adding that “we need to now explore this and understand if this also could be a major risk factor for colon cancer progression.”
To Phillip Karpowicz, a biologist at University of Windsor in Canada whose research focuses on the effects of circadian rhythms on intestinal tissue but who was not involved in the work, the study’s data are particularly compelling because they focus on a growing population that is working overnight. If researchers are able to understand how environmental disturbances of the clock are linked with colon cancer, there’s potential to keep these workers healthy. Though, he notes, more work is needed to determine how clock disruptions drive APC mutations so that the findings can better inform our understanding of cancer biology and treatment
Masri agrees, saying she and her team plan to explore other clock-disrupting environmental factors, apart from abnormal light exposure, before delving into the mechanism by which APC mutations arise.
Correction (August 29): This article has been updated to reflect the correct location of the University of Windsor. The Scientist regrets the error.