Chronic jet lag leads to human liver cancer in a mouse model

When asked what could cause cancer, people probably think of chemicals like tobacco or radiation like UV rays from the sun, but chronic jet lag probably doesn’t come to mind. Human epidemiological studies have linked chronic jet lag, also known as chronic circadian dysfunction, to an increased risk of liver cancer. However, direct evidence that this leads to liver cancer is lacking.

A recent study led by researchers at Baylor College of Medicine and published in the Journal of Hepatology is the first to demonstrate experimentally that chronic circadian dysfunction is indeed carcinogenic to humans.

“We worked with a humanized mouse model developed by co-author Dr. Karl Dmite Bissig of Duke University,” said senior corresponding author Dr. Loning Fu, associate professor of medicine-gastroenterology. and a member of the Dan L Duncan Comprehensive Cancer Center. at Baylor. “This animal model contains both human and mouse liver cells in the animals’ livers, which allows us to study the effect of circadian rhythm disruption on cancer development in human cells.”

The circadian rhythm is our brain’s internal 24-hour timer that regulates cycles of alertness, sleepiness, and virtually all body functions by being in sync with the planet’s day and night cycle. Recent studies have found that when the internal clock is out of sync, disease is more likely to develop.

Humanized mice were exposed to two different conditions. A group of animals was kept in synchronization with the natural day and night cycle. For the other group, the researchers changed the periods of light and darkness the animals were exposed to, to create the equivalent of the changes a person experiences on a round-trip flight from San Francisco to London every week for several weeks.

Chronic circadian dysfunction is carcinogenic to humans

“We found that compared to mice kept in normal light and dark cycles, mice in the jet lag group had a shorter lifespan as well as an increase in cirrhosis, jaundice (when the skin or whites of eyes turn yellow) and also developed cancer in mouse and human liver cells,” Fu said. “Importantly, chronic jet lag also induced metastases from humanized livers.”

Blood tests and microscopic studies of the livers revealed multiple commonalities between humanized mice and liver cancer patients, including glucose intolerance, abnormal accumulation of fat in the liver, inflammation and fibrosis. This confirms the validity of this model for studying the human condition.

“We show that as the tumor progresses, the biomarker profile and gene expression patterns in the cells change,” Fu said.

Chronic jet-lagged humanized mice spontaneously developed liver cancer in human liver cells following the same process and molecular pathways as those in humans. Gene expression studies reveal that spontaneous cancer development in this model is driven by changes in the expression of thousands of genes that depend on cell type, timing, and stage of disease.

“One of the important findings of the paper is that once tumors grow spontaneously in response to chronic circadian disruption, returning mice to a normal circadian clock slows tumor development and prevents metastasis.” , said co-corresponding author Dr. David Moore, professor. and Director of the Department of Nutritional Sciences and Toxicology at the University of California, Berkeley. “When animals return to a normal circadian rhythm, the pattern of gene expression is restored to what it was before.”

“I am delighted that our results have significant implications at the clinical level,” Fu said. “This work provides new knowledge that can promote the development of improved therapies for this cancer and better understand the mechanisms of carcinogenesis.”

“Our work shows that circadian influences on cancer cannot be underestimated: chronic circadian dysfunction is carcinogenic to humans,” Moore said. “The findings raise awareness of the increased risk of cancer in people working night shifts for an extended period of time or regularly traveling across multiple time zones, and our humanized mouse model provides a valuable tool to study this disease for which there is no treatment effective.”

Jennifer Padilla, Noha M. Osman, Beatrice Bissig-Choisat, Sandra L. Grimm, Xuan Qin, Angela M. Major, Li Yang, Dolores Lopez-Terrada, Cristian Coarfa, and Feng Li also contributed to this work. The authors are affiliated with one of the following institutions: Baylor College of Medicine, Duke University, or University of California, Berkeley.