- A new study from the University of Arizona (USA) 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.
Wednesday 16 June 2021
The study, published in the journal Cell Reports, assumes that, according to the Centers for Disease Control and Prevention, the components of diet high in saturated fat, like red meat, are considered risk factors for colon cancer. In fact, diet is believed to heavily influence colorectal cancer risk, and changes in eating habits could reduce this incidence by as much as 70 percent.
“There is epidemiological evidence of a strong relationship between obesity and increased tumor risk,” said Miyeko Mana, an adjunct professor at the Faculty of Life Sciences of the university. “And in the gut, stem cells are the probable cell of origin of cancer. So what is that connection? Well, diet is something that fuels that cycle of obesity and colorectal cancer,” he explained.
As food breaks down and makes its way through the intestine, it interacts with intestinal stem cells found along the interior surfaces of the intestine. These cells reside in a series of regularly folded valleys in the intestine, called crypts.
Intestinal stem cells are believed to be the gateway that coordinates the formation of intestinal tumors when adapted to high-fat diets, and increases the risk of cancer. Within these cells are high-fat sensor molecules that detect and react to diets high levels in cells.
“We were investigating the mechanisms that might be necessary for stem cells to adapt to a high-fat diet, and that’s where we found peroxisome proliferator-activated receptors (or PPARs), which trigger a cellular program that elevates blood risk of cancer. But the exact mechanisms were not clear because there are multiple types of PPAR, and it is complex to decipher their functions “, has indicated the leader of the work.
“There is a family of 3 PPARs, called delta, alpha and gamma. At first, we thought that only the delta PPAR was involved, but to see if that gene is really responsible for the phenotype, we have to eliminate it,” he explains. Mana’s team was able to explore and unmask the role of individual delta and alpha PPARs using a mouse model that monitored their activity in the cell. In his team’s study, mice were given a high-fat or normal diet long-term, and the activity of each PPAR was carefully monitored to study its effects on cancer risk.
In their knockout study, they first removed the PPAR delta gene. “But when we remove it from the gut, we keep looking at the phenotype. So we wondered if maybe another PPAR was compensating and that’s where we thought about PPAR alpha. Both (PPAR delta and PPAR alpha) seem to be necessary for this high diet phenotype. fats within stem cells, “says Mana, who comments that she knew immediately that the development of a possible therapy to counteract PPARs became a much more difficult task. “When you think about this therapeutically, if you are incorporating a large amount of fat in your diet and you want to reduce the risk of colon cancer, targeting two different factors is more difficult than targeting just one,” he said. she is an expert.
To further unravel the genetic complexity, Mana turned her attention down to the PPARs. From their studies and, using new working tools, they were able to unravel little by little the details, down to the level of molecular sequencing of individual cells from different areas of the small intestine and colon, mass spectrometry to measure the amounts of different metabolites and radiolabeled isotopes from fuel sources to measure carbon flux.
The first big clue came from the metabolic analysis. The high-fat diet found in the crypt cells of the intestinal stem cells they isolated increased fat metabolism, while at the same time, decreased the breakdown of sugars. “So we looked further down to see what these two factors may be targeting, and it was this mitochondrial protein, Cpt1a,” Mana said. “This is necessary for the importation of long-chain fatty acids (LCFAs) into the mitochondria for use. LCFAs are part of the high-fat diet.”
And when they did the Cpt1a knockout study in mice, they found that they could stop tumors from forming in their tracks. The loss of Cpt1a prevented both the expansion and proliferation of intestinal stem cells in the crypts. “If Cpt1a is eliminated, this phenotype of a high-fat diet is avoided in intestinal stem cells,” Mana detailed. “So the risk of tumorigenesis is reduced at this point.”
With their data, Mana’s team was able to trace the development of cancer, from diet until tumor formation. First, fats are broken down into free fatty acids. The free fatty acids then stimulate sensors like PPARs and turn on genes that can break down fatty acids.
The leftover free fatty acids are then transported to the mitochondria, which can burn them through oxidation for more energy and feed the stem cells, which multiply, grow, and regenerate intestinal tissue. But when the number of intestinal stem cells expands, there is a greater chance of mutations that lead to colon cancer.
“The idea is that this greater number of cells remain in the intestine and accumulate mutations, and that means that they can be a source of mutated cells that lead to the transformation and initiation of a tumor,” explained the main author of the study. “We think it is likely when there are conditions that expand your stem cell pool,” he adds.
More mortality on a high-fat diet
Mana’s group also found that feeding a high-fat diet dramatically accelerated mortality in this model compared to the control group by accelerating tumorigenesis. “The levels of these fats that can be obtained through the diet are going to have an impact on stem cells, probably in a fairly direct way,” he explains. “I think one of the surprising things that 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 gut is fine,” he adds.
With the new evidence from the study, the hope is to one day apply his work to human colon cancers. “To date, all of these studies have been carried out in these mouse models,” Mana details. “One of the ideas we started with was to understand the metabolic dependencies of tumors that can arise in a natural or pharmacological context and then direct these metabolic programs to the detriment of the tumor but not of normal tissue. We are moving forward with the model of high-fat diet. Ultimately, however, the goal is to eliminate or prevent colorectal cancer in humans. “