A recent study reported new insights into the observed link between obesity and an increased colorectal cancer risk, and proposed that approved drugs like linaclotide, as well as lifestyle changes, could limit a person’s likelihood of developing this cancer. The study, “Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis” was published in Cancer Research.
Excess body fat can have harmful consequences as it may alter hormones and growth factors, which, in turn, could change the way cells function. Obesity has long been linked to colorectal cancer, with obese patients found to be at a 50 percent greater risk of developing this cancer than lean individuals. However, the precise process through which obesity influences the cancer’s development is less unclear.
Researchers performed a set of experiments on genetically engineered mice under various diets, and found that a high caloric diet induced a loss of the hormone guanylin. This hormone normally binds to a receptor called guanylyl cyclase C (GUCY2C) to regulate processes related to the regeneration of intestinal lining.
“The lining of the intestines is very dynamic and continuously being replaced, and GUCY2C contributes to the choreography of the key processes needed for this regeneration,” said the study’s senior author, Dr. Scott Waldman with Thomas Jefferson University, in a news release.
In turn, loss of this hormone silences the receptor and induces a dysfunction in the intestinal lining. When compared to lean mice, obese mice have a higher chance of turning off both the hormone and its receptor, becoming more susceptible to growing tumors.
“We believe that if colorectal cancer is going to develop, it will be through this silencing mechanism — and that it will happen much more frequently in the obese,” Dr. Waldman said.
When researchers genetically restored guanylin in the mice, they noticed that colorectal cancer was prevented even though the mice continued on a diet with excess calories. Further, because linaclotide (Linzess) has a similar structure to guanylin, the researchers proposed that this drug could be a therapeutic approach to keeping the hormone active and preventing its loss.
“Our study suggests that colorectal cancer can be prevented in obese individuals with use of hormone replacement therapy — much as other diseases associated with hormone deficiency, such as loss of insulin in diabetes, can be treated,” said Dr. Waldman.
The researchers also found that the effect of excessive calorie consumption can be reversed through calorie restriction, even in mice that were obese.
The findings demonstrated that loss of guanylin in obese mice is linked to the development of colorectal cancer. This outcome could be prevented by restoring the hormone, either through the administration of drugs like linaclotide or lifestyle modification through calorie restriction, or both. The team is now testing linaclotide on healthy volunteers to determine its optimal dosing levels and side effects.
“These findings came as a surprise — we and many other researchers worldwide have been trying to disentangle obesity from the development of colorectal cancer,” concluded Dr. Waldman. “Calories sit in the middle of these two conditions, but the question of what they were doing has been one of the most perplexing and provocative questions in cancer research. (…) Now we finally have a big clue as to the origin of colorectal cancer in obese individuals and perhaps in other people as well.”