Molecular Link Between Obesity and Increased Risk of Colon Cancer Uncovered

Molecular Link Between Obesity and Increased Risk of Colon Cancer Uncovered

Thomas Jefferson University researchers have found the molecular connection between obesity and an increased risk of colorectal cancer, while also identifying an FDA-approved drug that could prevent the cancer from developing. The study, “Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin–GUCY2C Paracrine Signaling Axis,” was published in the journal Cancer Research.

Obesity is a well-known risk for colorectal cancer, and obese people have a 50 percent greater risk of developing this type of malignancy when compared to leaner people. Researchers studied the link between obesity and the suppression of a specific receptor that regulates regeneration of the intestinal epithelium — the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs as a result of the loss of guanylin. This suppression happens in the development of colon cancer both in humans and animals and contributes to the progression of tumors.

Using genetically engineered mice on high- and low-calorie diets, scientists observed that a high caloric intake, which led to obesity, turned off guanylin in the colon, resulting in the silencing of the receptor GUCY2C, along with epithelial dysfunction and the formation of tumors. Restoring guanylin in intestinal epithelial cells also restored GUCY2C signalling and eliminated intestinal tumors associated with a high-calorie diet.

Researchers demonstrated that calorie-related silencing of the guanylin–GUCY2C signalling pathway links obesity to the shutdown of an essential tumor suppressor pathway in colorectal cancer. They also showed that restricting calories could reconstitute hormonal expression, reversing these harmful effects. Scientists are still researching the exact mechanism that increases the incidence of colon cancer in the obese.

“The beauty of our findings is that while we know the hormone is lost in the obese mice, its receptors are just sitting there waiting to be switched on. And this study demonstrates that if you can prevent hormone loss, you can also prevent tumor development,” senior author Scott Waldman, M.D., Ph.D., said in a press release. “These findings suggest that a drug like linaclotide, which acts like guanylin, can activate GUCY2C tumor-suppressing receptors to prevent cancer in obese patients.”

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