Often coming hand in hand, both obesity and a high-fat diet have been linked with an increased risk for several different cancers. While various possible mechanisms have been proposed to explain such associations, scientists have remained in the dark about how these risk factors could drive colon cancer. But a new study finally seems to be offering some answers, finding that a high-fat diet boosts the growth of stem cells in the intestines of mice and may increase the likelihood that others form tumors.
This find actually ties in nicely with earlier work that found these intestinal stem cells (ISCs) represent the population in this area that is most likely to accrue potentially cancer-driving mutations. That observation makes sense, given the fact that stem cells can effectively divide indefinitely, giving rise to lots of different cell types that make up different tissues and organs. So if a mutation takes place in one of these cells, it’s more likely to hang around.
To find out more about their relationship with obesity and colon cancer, researchers in the U.S. kept mice on a long-term high-fat diet consisting of 60 percent fat; Western diets typically consist of around 20 to 40 percent. Described in Nature, not only did these mice gain significantly more weight than their normal chow-fed counterparts, there were also marked differences in their intestines.
Most notably, there was a significant increase in the number of ISCs in the mice on a high-fat diet, despite the fact that there was actually a decrease in the number of specialized cells called Paneth cells, which make up the intestinal lining.
Can high-sugar diets also trigger the same changes? Alexandra Lande/Shutterstock
Next, they wanted to see whether this diet could enhance the regenerative capacity of the intestine, so they removed ISCs from the mice and grew them in a dish. Those obtained from mice on a high-fat diet formed miniaturized versions of intestines much more readily than those taken from the control mice, which the researchers found was down to the activation of a molecule called PPAR-delta.
“PPAR-delta is a master regulator of fatty acid metabolism, enabling cells to use fatty acids to generate energy,” lead researcher Omer Yilmaz from the Massachusetts Institute of Technology told IFLScience. “But what’s really exciting is that in addition to this, we found that PPAR-delta engages a set of genes that are important for stem cell identity.”
As evidence of this, in the mice on a high-fat diet, activation of PPAR-delta in intestinal progenitor cells – daughters of stem cells that are along the road of specialization – caused them to behave like stem cells, increasing their lifespan and endowing them the ability to form mini-intestines in a dish. Importantly, when the team deleted a gene in these cells that’s often mutated in colon cancer, the cells obtained the capacity to form tumors.
“It’s previously been shown that if you delete this gene in stem cells, it gives rise to tumors,” Yilmaz told IFLScience. “But if you delete it in non-stem cells, you rarely get tumors.”
So not only is this high-fat diet increasing the number of stem cells, and therefore the number of target cells that can accumulate cancer-driving mutations, but it also increases the pool of cells that can undergo tumor formation, Yilmaz explained.
While humans and mice aren’t the same, and high-fat diets aren’t the only diets linked with obesity, the work is important nonetheless. Ultimately, it may be possible to target PPAR-delta in tumors in obese patients as a potential therapeutic strategy, something the researchers are actively pursuing.