A new study led by researchers at Arizona State University indicates that a diet high in fat can trigger a series of molecular events that can cause intestinal and colon cancer, as published in the journal Cell Reports.
When foods break down and move through the gut, they interact with intestinal stem cells (ISC) along the inner surfaces of the gut. Further, the ISCs reside in a series of regularly folded valleys of the gut, which the researchers call crypts.
ISCs are thought to be the gateway that coordinates intestinal tumor formation during adaptation to high-fat diets, thus elevating the risk of cancer. High-fat sensor molecules lie within the ISCs, which help sense and react to high-fat diet levels in the cells, according to the study.
"We were following up on mechanisms that might be required for stem cells to adapt to the high fat diet—and that's where we came across the [peroxisome proliferator-activated receptors (PPARs)]," said researcher Miyeko Mana in the press release.
She added that PPARs activate a cellular program that increases the risk of cancer. However, the exact mechanisms were unclear because there are multiple types of PPARs and complexities in teasing out their roles, according to the study.
Mana and her team explored the role of individual PPAR delta and alpha using a mouse model that controlled their activity in the cell. The mice were given a long-term fat or normal diet, with the activity of each PPAR carefully monitored to evaluate the effects on cancer risk.
The team first removed the PPAR delta gene, and the team observed the phenotype after removing it from the intestine to analyze whether another PPAR was compensating due to the high-fat diet phenotype within the stem cells, according to the study authors.
Mana and her team continued to test the genetic complex by slowly teasing out the details, including the level of molecular sequencing from individual cells from different areas of the small intestine and colon. They then used mass spectrometry to measure the amounts of different metabolites.
"So, we looked more downstream at what these two factors (PPARs) may target, and that was this mitochondrial protein, Cpt1a," Mana said in the press release. "This is required for the import of long chain fatty acids (LCFAs) into mitochondria for use. The LCFAs are part of the high fat diet."
When the study authors conducted the mouse knockout study of Cpt1a, they found tumor formation could he stopped and the loss of Cpt1a prevented both the expansion and proliferation of the ISCs in the crypts.
"If you remove Cpt1a, you are spared this high fat diet phenotype in the intestinal stem cells," Mana said in the press release. "So, you lower your risk of tumorigenesis at this point."
Some of the findings include that free fatty acids that help stimulate sensors, such as PPARs, activate genes that can break down the fatty acids and the ability of mutations to occur when the ISCs numbers expand, leading to colon cancer.
"The idea is that this larger pool of cells remain in the intestine and accumulate mutations, and that means they can be a source of mutated cells leading to transformation and tumor initiation," Mana said in the press release. "We do think that is a likely possibility when there are conditions that expand your stem cell pool."
The team also discovered that consuming a high fat diet dramatically accelerated mortality in this model compared with the control condition by accelerating tumorigenesis, according to the study.
"The levels of these fats that you can get through your diet are going to impact your stem cells, probably in a fairly direct way," Mana said in the press release. "I think one of the surprising things we are finding in our studies is that fatty acids can have such a direct effect. But you can remove these PPARs, you can remove CPT1a, and the intestine is fine."
The team hopes that this new evidence can help to expand future work for human colon cancers.
"These studies have all been in these mouse models to date," Mana said in the press release. "One idea we started with was to understand the metabolic dependencies of the tumors that can arise in a natural or pharmacological context and then target these metabolic programs to the detriment of the tumor but not the normal tissue. We are making progress with the high fat diet model. Ultimately though, the goal is to eliminate or prevent colorectal cancer in humans."
Study shows new links between high fat diets and colon cancer. EurekAlert! Published June 9, 2021. Accessed June 11, 2021. https://www.eurekalert.org/pub_releases/2021-06/asu-ssn060921.php