According to a new study, high-fat diets can trigger a biochemical chain reaction that leads to intestine and colon cancer. The researchers’ findings were reported in the journal ‘Cell Reports.’ Physicians and dieticians have advised consumers to limit their intake of high-fat meals for decades, noting ties to poor health and some of the most common causes of death in the United States, such as diabetes, heart disease, and cancer.
Dietary components high in saturated fats, such as red meat, are known to be risk factors for colon cancer, according to the Centers for Disease Control and Prevention. Colorectal cancer risk is expected to be substantially influenced by diet, with modifications in eating habits potentially reducing the cancer burden by up to 70%.
Family history, inflammatory bowel disease, smoking, and type 2 diabetes are all recognised epidemiological risk factors. But, of all the risk factors for colon cancer, nutrition is the one environmental and lifestyle component that can be controlled the most easily —- just by changing one’s diet. If we knew the specific links, we could change people’s behaviour and eating patterns.
“Epidemiological research supports a substantial correlation between obesity and increased tumour risk,” said Miyeko Mana, an assistant professor at the School of Life Sciences. Mana said, “And, in the intestine, stem cells are the most likely source of cancer. So, what’s the link here? Diet, on the other hand, contributes to the obesity and colorectal cancer cycle.”
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Mana and her team’s recent ASU study has revealed in greater detail than ever before how high-fat diets might set off a biochemical cascade that leads to intestine and colon cancer. Foods interact with intestinal stem cells (ISC) that line the interior surfaces of the gut as they are broken down and passed through. These ISCs are found in crypts, which are a series of consistently folded troughs in the gut.
When people adapt to high-fat diets and increase their cancer risk, ISCs are thought to be the gateway that coordinates the creation of intestinal tumours. High-fat sensor molecules are found within ISCs, and they detect and react to high-fat food levels in the cells.
“We were looking into pathways that would be required for stem cells to adapt to a high-fat diet —-and that’s where we found the PPARs,” Mana explained. These peroxisome proliferator-activated receptors (or PPARs) initiate a cellular programme that raises cancer risk, but the specific mechanisms are unknown due to the numerous varieties of PPARs and the difficulties in determining their functions.
“There are three types of PPARs: delta, alpha, and gamma. I initially assumed that only PPAR delta was involved, but in order to determine whether that gene is truly responsible for the phenotype, you must first eliminate it “Mana chimed in. Using a mouse model that regulated PPAR delta and alpha activity in the cell, Mana’s team was able to investigate and uncover the role of each PPAR delta and alpha. In her research, mice were fed a high-fat or low-fat diet for a long time, and the activity of each PPAR was closely examined to see how it affected cancer risk.
They initially knocked off the PPAR delta gene in their knockout study. “When we took it out of the gut, however, the phenotype remained. So we wondered if another PPAR was compensating, and that’s when PPAR alpha came into play. Within stem cells, both of them (PPAR delta and PPAR alpha) appear to be essential for this high fat diet phenotype “Mana remarked.
Mana was frustrated because she realised immediately away that building a possible therapy to counteract the PPARs had now become a considerably more difficult undertaking. “When you think about it therapeutically, if you’re eating a high-fat diet and want to lower your risk of colon cancer, treating two separate factors is more difficult than targeting just one,” Mana explained.
Mana then focused her attention downstream of the PPARs in order to elucidate the genetic complexity even more. They were able to slowly tease out the details from their studies, down to the level of doing 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 to measure the carbon flow, using new tools of the trade.
The metabolic study provided their first major hint. The high fat diet reported in the isolated ISC crypt cells boosted fat metabolism while decreased sugar breakdown. “So, we investigated further downstream to see what these two factors (PPARs) might be targeting, and it turned out to be this mitochondrial protein called Cpt1a,” Mana explained. “Long chain fatty acids (LCFAs) must be imported into mitochondria in order to be used. LCFAs are a component of a high-fat diet.”
In a mouse knockout study of Cpt1a, scientists discovered that they could stop tumour growth in its tracks. The absence of Cpt1a prevented the ISCs from expanding and multiplying in the crypts. “You are spared this high-fat diet phenotype in the intestinal stem cells if you remove Cpt1a,” Mana said. “At this time, you’ve reduced your chance of cancer.”
Mana’s team was able to follow the progression of cancer from diet to tumour creation using their data. Fats are broken down into free fatty acids first. The free fatty acids then activate sensors like PPARs, which switch on genes that break down the fatty acids.
The excess free fatty acids are then delivered to the mitochondria, which can oxidise them to provide extra energy to feed the stem cells, which multiply, grow, and rebuild gut tissue. However, when the number of ISCs grows, there is a larger chance that mutations will occur, leading to colon cancer, simply due to random mutations and the sheer number of cells.
“The notion is that this larger pool of cells stays in the intestine and accumulates mutations, making them a source of altered cells that can lead to transformation and tumour start,” Mana explained. “When there are situations that expand your stem cell pool, we believe that is a likely possibility.”
Mana’s team also discovered that, compared to the control condition, feeding a high-fat diet greatly increased mortality in this animal by speeding up carcinogenesis. “The amount of these fats that you can acquire through your diet will probably have a fairly direct impact on your stem cells,” Mana added. “One of the most startling findings from our research is that fatty acids can have such a direct effect. However, you can delete these PPARs and CPT1a and the gut will be alright.”
The goal is that, with the new information from the study, they will be able to extend their findings to human colon cancers one day. “To yet, all of these research have been done in these mouse models,” Mana explained.
“Understanding the metabolic dependencies of tumours that can form in a natural or pharmaceutical context was one of our first ideas, and then targeting these metabolic processes to the tumor’s detriment but not the normal tissue was another. With the high-fat diet concept, we’re making progress. The ultimate goal, however, is to eliminate or prevent colorectal cancer in people “Mana came to a conclusion.
- Source – ANI
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