While cancer rates are dropping in general, colorectal cancer is becoming more common in people under the age of 55. The American Cancer Society estimates that between 2007 and 2016, the rate went up by one percent in that group. New work led by researchers at the Salk Institute has indicated that diets rich in fat contribute to the growth of cancer by disrupting bile acids in the gastrointestinal tract; that initiates a hormonal signal that allows cells that might be cancerous to continue growing. The research has been reported in Cell and may help explain why a cancer that typically takes decades to form is cropping up in younger people, who may currently be exposed to more high-fat diets.
"This study provides a new way to lower inflammation, restore intestinal health and to dramatically reduced tumor progression," said Professor Ronald Evans, director of the Gene Expression Laboratory and Howard Hughes Medical Institute investigator.
Bile acids aid in digestion, and have been found to work with the Farnesoid X receptor (FXR) in disease development. The first author of the study, postdoctoral fellow Ting Fu, determined that bile acid levels went up when cancer started growing. With the addition of more bile acids, there was an increase in the progression of cancer. "We saw a very dramatic increase in cancer growth correlated to bile acid," said Michael Downes, a senior staff scientist at Salk and co-corresponding author of the study. "Our experiments showed that maintaining a balance of bile acids is key to reducing cancer growth."
The research showed that diets high in fat increase the levels of two bile acids, which suppress FXR activity. FXR should be keeping cell growth in the gut slow and steady, but the bile acids impair that process, leading to rapid cell division and DNA damage.
The researchers used a mouse model to explore the impact of a high-fat diet while mutations in a gene called APC exert an influence. The most common gene mutation in people with colorectal cancer is in the APC gene. Animals with that mutation got cancer more quickly when they also consumed a high-fat diet.
"It could be that when you're genetically prone to get colon cancer, something like a high-fat diet is the second hit," said study co-author and Salk staff researcher Ruth Yu.
APC is known as a tumor suppressor gene; it helps control cell division. Mutations in the gene disrupt that control and can lead to the unchecked growth that’s characteristic of cancer.
In mice with APC mutations, a high-fat diet caused benign intestinal growths called adenomas to become cancerous.
"We knew that high-fat diets and bile acids were both risk factors for cancer, but we weren't expecting to find they were both affecting FXR in intestinal stem cells," noted Annette Atkins, a staff researcher at Salk and co-author of the study.
The scientists also tested a molecule they created at Salk, FexD, as an FXR activator in intestinal stem cells. FexD seemed to undo the negative impacts that bile acid imbalances have on mouse models and cancer cell lines. More work will be needed to evaluate this molecule.
"While colon cancer is considered incurable, Ting's work opens up an entirely new frontier in the understanding and treatment of the disease," added Evans.