Internal Clock Disruptions Increase Colon Cancer Risk in Mice

Recommendable! Cancer is history (soon)!

More evidence that stressful lives and/or disruptive live styles likely promote cancer especially among younger people.

"... 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,” ...
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. ...

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. ..."

From the abstract:

"An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk factors of young onset CRC include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock. We find that both genetic disruption and environmental disruption of the circadian clock accelerate Apc-driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving Apc loss of heterozygosity, which hyperactivates Wnt signaling. This up-regulates c-Myc, a known Wnt target, which drives heightened glycolytic metabolism. Using patient-derived organoids, we show that circadian rhythms are lost in human tumors. Last, we identify that variance between core clock and Wnt pathway genes significantly predicts the survival of patients with CRC. Overall, our findings demonstrate a previously unidentified mechanistic link between clock disruption and CRC, which has important implications for young onset cancer prevention."

Internal Clock Disruptions Increase Colon Cancer Risk in Mice | The Scientist Magazine® Disturbing circadian rhythms in organoids and mice increases intestinal tumor growth, findings that may explain a recent rise in colon cancer among young adults, the researchers behind the work say.

Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer (open access)

Fig. 1. Disruption of circadian clock accelerates intestinal tumorigenesis in vivo