For decades, doctors and dietitians have urged people to limit their intake 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, dietary components high in saturated fat, such as red meat, are thought to be risk factors for colon cancer. Diet is thought to have a strong influence on the risk of colorectal cancer, and changes in eating habits can reduce up to 70% of this cancer burden.
Other known epidemiological risk factors are family history, inflammatory bowel disease, smoking and type 2 diabetes.
But out of all the risk factors that raise colon cancer risk, diet is the environmental and lifestyle factor that is perhaps the easiest to control ̵
“There is epidemiological evidence for a strong link between obesity and increased tumor risk,” said School of Life Sciences assistant professor Miyeko Mana. “And in the gut, the stem cells are the probable origin cell for cancer. So what’s that connection? Well, diet is something that feeds into that cycle of obesity and colorectal cancer.”
Now, a new ASU study led by Mana and her team has shown in more detail than ever before how a high-fat diet can trigger a molecular cascade of events leading to bowel and colon cancer. The study was published in the journal Cell reports.
Tales from the crypts
When food is broken down and finds its way through the gut, it interacts with intestinal stem cells (ISCs) located along the inner surfaces of the gut. These ISCs are located in a series of intestinal valleys that are called regularly, called crypts.
ISCs are thought to be the gateway that coordinates the formation of intestinal tumors as they adapt to low-fat diets and increase the risk of cancer. Within the ISCs are high-fat sensor molecules that sense and respond to high-fat levels in the cells.
“We followed up on mechanisms that may be necessary for stem cells to adapt to a high-fat diet – and this is where we came across PPAR,” said Mana. These peroxisome proliferator-activated receptors (or PPARs) trigger a cellular program that raises the risk of cancer, but the exact mechanisms were unclear because there are several types of PPARs and the complexity of teasing their roles.
“There is a family of 3 PPARs called delta, alpha and gamma. At first I thought just PPAR delta was involved, but to see if this gene is really responsible for the phenotype, you need to remove it.”
Mana’s team was able to explore and unmask the role of individual PPAR delta and alpha using a mouse model that controlled their activity in the cell. In her team’s study, mice were given a long-term low-fat or normal diet, and the activity of each PPAR was closely monitored to investigate the effects on cancer risk.
In their knockout study, they first removed the PPAR delta gene.
“But when we removed it from the gut, we were still observing the phenotype. So we were wondering if maybe another PPAR compensated, and this is where we thought of PPAR alpha. Both of these (PPAR delta and PPAR alpha) look appear to be necessary for this high fat phenotype within the stem cells. “
This was frustrating for Mana because she immediately knew that the development of a potential therapeutic agent to offset the PPARs had just become a much higher task.
“When you think about this therapeutically, if you incorporate a lot of fat into your diet and you want to reduce your risk of colon cancer, it’s more challenging to target two different factors, so if you are only targeting one.”
Looking further down the river
To further tease the genetic complexity, Mana then turned his attention downstream to the PPARs.
From their studies and using new trading tools, they were able to slowly tease the details out – down to the level of performing molecular sequencing from individual 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 for measuring the carbon flow.
Their first major clue came from the metabolic analysis. The high-fat diet found in the ISC crypt cells isolated them, increasing the metabolism of fats while decreasing the breakdown of sugar.
“So we looked more downstream at what these two factors (PPARs) can target, and it was this mitochondrial protein, Cpt1a,” Mana said. “This is necessary for the import of long chain fatty acids (LCFAs) into mitochondria for use. The LCFAs are part of the high fat diet.”
And when they performed the mouse’s knockout study of Cpt1a, they found that they could stop tumor formation in its tracks. The loss of Cpt1a prevented both expansion and proliferation of the ISCs in the crypts.
“If you remove Cpt1a, you will be spared this fat type with high fat content in the intestinal stem cells,” Mana said. “So you lower your risk of tumorigenesis at this point.”
A new model emerges
From their data, Mana’s team was able to track the development of cancer, from diet all the way to tumor formation.
First, fat is broken down into free fatty acids. The free fatty acids then stimulate sensors such as PPARs and turn on genes that can break down the fatty acids.
The excess free fatty acids are then transported to the mitochondria, which can burn them up by oxidation to get more energy to feed the stem cells, which multiply, grow and regenerate intestinal tissue. However, as ISC numbers expand, there is a greater likelihood that mutations can occur – simply because of random mutations and a large number of cells – leading to colon cancer.
“The idea is that this larger pool of cells remains in the gut and accumulates mutations, and that means they can be a source of mutated cells leading to transformation and tumor initiation,” Mana said. “We think it’s a likely option when there are conditions that expand your stem cell pool.”
Mana’s group also found that feeding a high-fat diet dramatically accelerated mortality in this model compared to the control condition by accelerating tumorigenesis.
“The level of these fats that you can get through your diet will affect your stem cells, probably in a pretty direct way,” Mana said. “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 these 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 colon cancer in humans.
“These studies have so far been in these mouse models,” Mana said. “An idea we started with was to understand the metabolic dependencies of tumors that can occur 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 content “Ultimately, however, the goal is to eliminate or prevent colorectal cancer in humans.”
Study examines how low-fat diet affects colon cancer
Miyeko D. Mana et al., Low fat diet-activated fatty acid oxidation mediates intestinal strain and tumorigenicity, Cell reports (2021). DOI: 10.1016 / j.celrep.2021.109212
Provided by Arizona State University
Citation: Study Shows New Relationships Between High Fat Diets And Colon Cancer (2021, June 9) Retrieved June 10, 2021 from https://medicalxpress.com/news/2021-06-links-high-fat-diets-colon.html
This document is subject to copyright. Except for any fair trade for the purpose of private investigation or research, no parts may be reproduced without written permission. The content is provided for informational purposes only.