High Fat Diets And Colorectal Cancer Risk – Recent Study Finds Link
High Fat Diets and Colorectal Cancer Risk – Recent Study Finds Link | Photo credit: Pixabay
Washington: A new study has discovered how high fat diets can trigger a molecular cascade of events that lead to bowel and colon cancer. The conclusions of the study were published in the journal Cell Reports entitled “Fatty Acid Oxidation Activated by High Fat Diet Mediates Gut Strain and Tumorigenicity”. For decades, doctors and dieticians have urged people to limit their consumption of high-fat foods, citing links to poor health outcomes and some of the leading causes of death in the United States, such as diabetes. , heart disease and cancer.
According to the Centers for Disease Control and Prevention, food components high in saturated fat like red meat are considered risk factors for colon cancer. Diet is thought to strongly influence the risk of colorectal cancer, and changes in eating habits could reduce this cancer burden by up to 70%. Other known epidemiological risk factors are family history, inflammatory bowel disease, smoking, and type 2 diabetes. But of all the risk factors that increase the risk of colon cancer, diet is the most common. one environmental and lifestyle factor that may be easiest to control — simply by changing people’s behavior and eating habits —- if we knew the exact connections.
“There is epidemiological evidence for a strong link between obesity and an increased risk of tumor,” said Miyeko Mana, assistant professor in the School of Life Sciences.
Mana added, “And in the gut, stem cells are probably the original cancer cell. So what is this link? Well, diet is something that fuels this cycle of obesity and colorectal cancer.
The new ASU study led by Mana and his team has shown in more detail than ever how high-fat diets can trigger a molecular cascade of events that lead to bowel and colon cancer.
Tales of the Crypts
As food is broken down and passes through the intestine, it interacts with intestinal stem cells (ISCs) that are found along the internal surfaces of the intestine. These ISCs reside in a series of regularly folded valleys of the intestine, called crypts. ICSs are thought to be the gateway that coordinates the formation of intestinal tumors as they adapt to high-fat diets and increase cancer risk. Within ISCs are fat-rich sensor molecules that sense and respond to high-fat diet levels in cells.
“We were tracking the mechanisms that might be needed for stem cells to adapt to the high fat diet — and that’s where we stumbled upon PPARs,” Mana said. These peroxisome proliferator-activated receptors (or PPARs) trigger a cellular program that increases cancer risk, but the exact mechanisms were not clear as there are several types of PPARs and complexities in determining their roles.
“There is a family of 3 PPARs, named delta, alpha and gamma. At first I thought only PPAR delta was involved, but to see if this gene is really responsible for the phenotype you have to remove it,” added Mana. .
The Mana team was able to explore and unmask the role of individual delta and alpha PPARs using a mouse model controlling their activity in the cell. In his team’s study, the mice were given a high-fat or normal long-term diet, and the activity of each PPAR was carefully monitored to study the effects on cancer risk. In their knockout study, they first removed the PPAR delta gene.
“But when we took it out of the gut, we still saw the phenotype. So we wondered if another PPAR maybe compensated and that’s where we thought about PPAR alpha. Both (PPARs) delta and PPAR alpha) appear to be necessary for this high fat diet phenotype in stem cells, ”Mana said.
It was frustrating for Mana because she knew right away that developing therapeutic potential to compensate for PPARs was becoming a much longer task.
“When you think about it therapeutically, if you incorporate a lot of fat in your diet and want to lower your risk of colon cancer, targeting two different factors is more difficult than if you only target one,” added Mana.
Look further downstream
To better understand the genetic complexity, Mana then turned his attention downstream to PPARs. From their studies and using new tools of the trade, they were able to slowly unravel the details — down to the level of molecular sequencing from single cells from different areas of the small intestine and colon, Mass spectrometry to measure the amounts of different metabolites and radiolabeled isotopes of fuel sources to measure carbon flux. Their first big clue came from metabolic analysis. The high-fat diet found in the ISC crypt cells they isolated increased fat metabolism, while decreasing the breakdown of sugars.
“So we looked further downstream what these two factors (PPARs) might target, and that was this mitochondrial protein, Cpt1a,” Mana said. “This is necessary for the importation of long chain fatty acids (LCFA) into the mitochondria for use. LCFAs are part of the high fat diet.”
And when they did the Cpt1a mouse knockout study, they found they could stop tumor formation in its tracks. The loss of Cpt1a prevented both expansion and proliferation of ISCs in the crypts.
“If you remove Cpt1a, you are spared this high fat diet phenotype in gut stem cells,” Mana said. “So you lower your risk of tumorigenesis at this point.”
A new model emerges
Using their data, the Mana team was able to trace the development of cancer, from diet to tumor formation. First, fats are broken down into free fatty acids. The free fatty acids then stimulate sensors such as PPARs and activate genes that can break down fatty acids.
Then the excess free fatty acids are transported to the mitochondria, which can burn them by oxidation to produce more energy to nourish the stem cells, which multiply, grow and regenerate the intestinal tissue. But when the numbers of SAIs are increased, there is a greater likelihood that mutations can occur — just from random mutations and a large number of cells — that lead to colon cancer.
“The idea is that this larger pool of cells stays in the gut and accumulates mutations, which means they can be a source of mutated cells leading to transformation and tumor initiation,” Mana said. . “We think that’s a likely possibility when there are conditions that are expanding your stem cell pool.” Mana’s group also found that a diet high in fat significantly accelerated mortality in this model compared to the control condition, by accelerating tumorigenesis.
“The levels of these fats that you can get from your diet are going to impact your stem cells, probably in a fairly direct way,” said Mana. “I think one of the surprising things we find in our studies is that fatty acids can have such a direct effect. But you can remove those PPARs, you can remove CPT1a, and the gut is fine.”
With the new evidence from the study, the hope is one day to apply their work to human colon cancers.
“These studies have all been done in these mouse models to date,” Mana said.
“One idea we started with was to understand the metabolic dependencies of tumors that can occur in a natural or pharmacological setting and then target those metabolic programs at the expense of the tumor but not normal tissue. fat diet model. Ultimately, however, the goal is to eliminate or prevent colorectal cancer in humans, ”Mana concluded.