Scientists discover how a high-fat diet leads to the growth of colorectal cancer

While cancer mortality rates are falling overall, doctors have noted a frightening anomaly: deaths from colorectal cancer among people under 55 appear to be increasing. According to the American Cancer Society, deaths of this younger group increased by 1% between 2007 and 2016.

A new study conducted by scientists at the Salk Institute suggests that high-fat diets promote the growth of colorectal cancer by disrupting the balance of bile acids in the intestine and triggering a hormonal signal allowing potentially cancerous cells to develop oneself. The results, which appeared in Cell on February 21, 2019, may explain why colorectal cancer, which can take decades to develop, affects young people growing up at a time when high-fat diets are common.

"This study offers a new way to reduce inflammation, restore bowel health, and dramatically reduce tumor progression," says Professor Ronald Evans, director of the Gene Expression Laboratory, Howard Hughes Medical Institute researcher and associate professor. Salk March of Dimes Chair Developmental Biology.

The research, conducted on a mouse model, suggests the convergence of lifestyles and genetics. The researchers found that animals carrying an APC mutation, the most common genetic mutation in humans with colorectal cancer, developed cancer faster when they were fed with a diet high in fat.

"It may be that when you're genetically predisposed to colon cancer, a diet similar to a high-fat diet is the second success," says study co-author Ruth Yu, a researcher at Gene Expression Laboratory. from Salk.

The intestine and the colon (usually grouped under the name of "gut") are hard-working organs. As you eat, your bowel needs to constantly regenerate its lining to repair the damage caused by digestive acids. To do this, the bowel houses a population of stem cells capable of reconstituting the cells of the mucosa when needed.

Scientists have discovered that colorectal cancers are often caused by mutations in these stem cells. The most common colorectal cancer mutation is in a gene called APC, which normally acts as a "tumor suppressor" gene because it controls how often the cells divide. Mutations in the APC gene can suppress this control and allow cells to divide rapidly and become cancerous.

Over the last four decades, Evans and his colleagues have been studying the role of bile acids. (30 types of bile acids float in the intestine to help digest food and absorb cholesterol, fats and fat-soluble nutrients.) One of the discoveries of the lab was the discovery that Bile acids send hormonal signals to the stem cells of the intestine through a protein called Farnesoid Receptor X (FXR). For this new study, researchers have discovered how high-fat diets affect this hormonal signaling.

The first author of the study, Ting Fu, a postdoctoral researcher at Salk, began by tracking an index in a mouse model carrying an APC mutation. These mice developing early signs of colorectal cancer, so she decided to monitor bile acid levels in mice at the same time. She discovered that the types of bile acids known to interact with FXR increased at the same time as cancer, and that the presence of additional bile acids accelerated the progression of the cancer.

"We have seen a very dramatic increase in cancer growth correlated with bile acid," said Michael Downes, senior scientist at Salk and co-authored author of the study. "Our experiments have shown that maintaining a balance of bile acids is essential for reducing cancer growth."

The researchers showed that feeding these mice with a high-fat diet meant adding fuel to a fire: a high-fat diet increased the levels of two specific bile acids that curbed FXR's activity . The intestine wants to repair itself and FXR keeps the process slow, steady and safe. When bile acids inhibit FXR, a group of stem cells develops rapidly and accumulates damage to the DNA.

"We knew that high fat diets and bile acids were both risk factors for cancer, but we did not expect to find out that they both affected the FXR in intestinal stem cells," states Annette Atkins, researcher at Salk and co-author. of the study.

Mice with APC mutations developed benign growths called adenomas. In humans, adenomas are common in the intestine and are routinely removed during colonoscopies. These growths normally take decades to turn into malignant adenocarcinomas. Yet the adenomas of these mice soon became cancerous when given a high fat diet.

Finally, researchers have discovered a possible cellular mechanism to explain the increase in colorectal cancer deaths among young people. Their theory is that as high fat diets have become more common in the United States, more and more people with an APC mutation are accelerating the growth of their cancer through these diets.

Then the researchers decided to test a new weapon against cancer. They used a molecule called FexD, developed by Salk, to activate FXR in intestinal stem cells. FexD appeared to neutralize the damage caused by unbalanced bile acids in mouse organ models and human colon cancer cell lines.

Although other experiments are needed before FexD is tested on humans, the team says that the drug candidate has promising qualities: it can reach the colon and acts only on the FXR. It should therefore produce fewer side effects than other drugs.

"While colon cancer is considered" incurable, "Ting's work opens up a whole new frontier for understanding and treating the disease," says Evans.

Provided by
Salk Institute