Scientists uncover how high-fat diet drives colorectal cancer growth

most common genetic mutation found in humans with colorectal cancer, developed cancer faster when fed 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 coauthor Ruth Yu, a staff researcher in the Gene Expression Laboratory at Salk.

The intestine and colon (commonly lumped together as the ‘gut’) are hard-working organs. As you eat, your gut needs to constantly regenerate its lining to undo the damage done by digestive acids. To do this, the gut houses a population of stem cells that can replenish lining cells when needed.

Scientists have found that colorectal cancers often originate from mutations in these stem cells. The most common colorectal cancer-linked mutation is in a gene called APC, which normally acts as a ‘tumor suppressor’ gene because it controls how often cells divide. Mutations in the APC gene can remove that control and allow cells to divide rapidly and become cancerous.

Over the last four decades, Evans and his colleagues have investigated the roles of bile acids. (30 types of bile acids Àoat around in the gut to help digest food and absorb cholesterol, fats and fat-soluble nutrients.) Among the lab’s discoveries was the revelation that bile acids send hormonal signals to intestinal stem cells through a protein called the Farnesoid X receptor (FXR). For the new study, the researchers uncovered how highfat diets affect that hormonal signaling.

Study ¿rst author Ting Fu, a postdoctoral fellow at Salk, began by following a clue in a mouse model with an APC mutation. These mice develop early signs of colorectal cancer, so she decided to monitor bile acid levels in the mice at the same time. She discovered that types of bile acids known to interact with FXR increased at the same time as cancer initiation — and that the presence of additional bile acids accelerated cancer progression.

“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 researchers showed that feeding these mice a high-fat diet was like adding fuel to a ¿re: High-fat diets increased levels of two speci¿c bile acids that dampen the activity of FXR. The gut wants to repair itself, and FXR keeps the process slow, steady and safe. When bile acids inhibit FXR, a group of stem cells starts growing rapidly and accumulating DNA damage.

“We knew that high-fat diets and bile acids were both risk factors for cancer, but we weren’t expecting to ¿nd they were both affecting FXR in intestinal stem cells,” said Annette Atkins, a staff researcher at Salk and coauthor of the study.

The 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 in these mice quickly turned cancerous when given high-fat diets.

At last, the researchers had found a possible cellular mechanism to explain the rise in colorectal cancer deaths in younger people. Their theory is that as high-fat diets have become more common in the US, more people with an APC mutation are accelerating their cancer growth through these diets.

Next, the researchers decided to test a new cancer-¿ghting weapon. They used a molecule called Fexd, developed at Salk, to activate FXR in intestinal stem cells. Fexd appeared to counteract the damage done by unbalanced bile acids in both mouse organ models and human colon cancer cell lines.

While more experiments need to be done before Fexd is tested in humans, the team said the drug candidate has some promising qualities: It can reach the colon and it only acts on FXR, so it should produce fewer side effects than other drugs.

“While colon cancer is considered ‘incurable,’ Ting’s work opens up an entirely new frontier in the understanding and treatment of the disease,” said Evans.