Studies have discovered a new link between a high-fat diet and colon cancer

A new study found that a high-fat diet can trigger molecular cascade events that lead to the gut and colon. cancer..

The results of this research were published in the magazine “Cell Reports”.

For decades, doctors and nutritionists have urged people to limit their intake. Ingestion of high-fat foodsIt lists links to poor health 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 ingredients high in saturated fat, such as lean meat, are considered risk factors for colon cancer. Diet is thought to have a strong impact on the risk of colorectal cancer, and changes in eating habits can reduce the burden of this cancer by up to 70%.

Other known epidemiological risk factors include family history, inflammatory bowel disease, smoking, and type 2 diabetes.

However, of all the risk factors that increase the risk of colon cancer, diet is one of the environmental and lifestyle factors, and knowing the exact relationship can only change people’s behavior and eating habits. , May be the easiest to control. “There is epidemiological evidence that there is a strong link between obesity and increased tumor risk,” said Miyeko Mana, assistant professor of life sciences.

“In the gut, stem cells are the cells that are more likely to cause cancer, so what’s the relationship? Well, diet nourishes that cycle of obesity and colorectal cancer. It’s a thing. “

A new Arizona State University study, led by Mana and her team, shows in more detail than ever that a high-fat diet can cause molecular cascade events that lead to gut and colon cancer.

As food breaks down and passes through the intestine, they interact with intestinal stem cells (ISCs) that lie along the inner surface of the intestine. These ISCs reside in a series of regularly folded intestinal valleys called crypts.

The ISC is thought to be a gateway that regulates intestinal tumorigenesis and increases the risk of cancer when adapting to a high-fat diet. Within the ISC are high-fat sensor molecules that sense and respond to intracellular high-fat diet levels.

“I came across PPAR while following up on the mechanisms that stem cells need to adapt to a high-fat diet,” says Mana. These peroxisome proliferator-activated receptors (or PPARs) trigger cellular programs that increase the risk of cancer, because there are multiple types of PPARs and their role is complex to elucidate. The exact mechanism was unknown.

“There are three families of PPARs, delta, alpha, and gamma. At first I thought that only the PPAR delta was involved, but to see if that gene is really involved in the phenotype. You need to get rid of it. “

The mana team was able to investigate and elucidate the role of individual PPAR deltas and alphas using a mouse model that controls intracellular activity. In her team’s study, mice were fed a long-term high-fat or normal diet, and the activity of each PPAR was carefully monitored to study its effect on cancer risk.

In their knockout study, they first deleted the PPAR delta gene.

“But when we removed it from the gut, we still observed the phenotype, so I wondered if another PPAR might be compensating, so I thought about PPAR alpha. Both of them ( PPAR delta and PPAR alpha) are the phenotypes of this high-fat diet within stem cells, “Mana said.

Mana was frustrated by the fact that he quickly realized that developing a potential remedy to offset PPAR would be a much more difficult task.

“If you think of this therapeutically, if you want to include more fat in your diet and reduce your risk of colon cancer, targeting two different factors is more difficult than targeting just one. “Mana added.

To further elucidate the genetic complexity, Mana then turned his attention to the lower reaches of PPAR.

From their studies, and using new tools in the trade, they were able to slowly derive details: molecular sequencing, mass spectrometry from individual cells from different regions of the small intestine and colon. To the level, the amount of various metabolites for measuring the flow of carbon, and the radioactivity-labeled isotopes of the fuel source.

Their first big clue came from metabolic analysis. The high-fat diet found in the ISC crypto cells they isolated increased fat metabolism and at the same time reduced sugar breakdown.

“So we looked further downstream on what these two factors (PPARs) might be targeting, and it was this mitochondrial protein Cpt1a,” Mana said. Required for uptake into mitochondria for use with long-chain fatty acids (LCFA). LCFA is part of a high-fat diet. “

Then, when we conducted a mouse knockout study of Cpt1a, we found that tumor formation could be stopped prematurely. Loss of Cpt1a prevented both ISC dilation and proliferation in the crypts.

“Removing Cpt1a can avoid this high-fat diet phenotype in intestinal stem cells,” says Mana. “That is, at this point you can reduce the risk of tumorigenesis.”

From their data, Mana’s team was able to track the development of cancer from diet to tumorigenesis.

First, fat is broken down into free fatty acids. Free fatty acids then stimulate sensors such as PPAR to turn on genes that can break down fatty acids. The excess free fatty acids are then carried to the mitochondria, where they are burned by oxidation to produce more energy. Stem cells that proliferate, grow, and regenerate intestinal tissue. However, as the number of ISCs increases, mutations are more likely to occur, and random mutations and very large numbers of cells are more likely to lead to colon cancer.

“The idea is that this large cell pool stays in the intestine and accumulates mutations, which means that these cells can be the source of mutant cells that lead to transformation and tumor development,” Mana said. Says. “If there are conditions to expand the stem cell pool, we think it is likely.”

The mana group also found that feeding a high-fat diet dramatically accelerated mortality in this model compared to control conditions by accelerating tumorigenesis.

“The levels of these fats we can get from our diet will probably affect stem cells in a fairly straightforward way,” Mana said. “One of the amazing things we know in our study is However, these PPARs can be removed, CPT1a can be removed, and the intestines are normal. “

New evidence from this study hopes that one day their study will be applied to human colon cancer.

“All of these studies have been done on these mouse models so far,” says Mana.

“One of the ideas we started with was to understand the metabolic dependence of tumors that can occur in natural or pharmacological situations, and to damage these metabolic programs to tumors rather than normal tissues. The goal was to set a goal, which is a dietary model, but ultimately the goal is to eradicate or prevent human colon-rectal cancer, “Mana concludes.

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