A team of pharmacologists has shown how obesity increases an individual’s risk for developing colorectal, or bowel, cancer and unveiled the potential of a hormone therapy in preventing the disease in obese individuals.
Researchers, led by Scott Waldman, chair of the department of pharmacology and experimental therapeutics at Thomas Jefferson University in Philadelphia, Pennsylvania, note that although obesity is a known risk factor for colorectal cancer, the precise molecular mechanism of how obesity causes the cancer remains unclear.
Waldman and colleagues used genetically engineered mice fed different diets and found that an obesity-inducing or high-caloric diet in the mice led to the loss of the hormone guanylin in the gut. The loss of guanylin in turn led to an attenuation of guanylin’s receptor guanylyl cyclase C (GUCY2C) — a protein expressed selectively in intestinal epithelial cells. Subsequently, epithelial dysfunction and formation of tumours in the colorectal region were noted in the mice.
“Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response [a cellular stress response] in intestinal epithelial cells,” the researchers say.
The researchers assessed their findings in transgenic mice that maintained a specific expression of guanylin and thereby did not allow attenuation of GUCY2C; in those mice, tumours did not develop, despite being fed a high caloric diet.
“Here, we link the over-consumption of calories, a key mechanism in obesity, with the loss of the paracrine hormone guanylin in the colorectum,” says Waldman, who points out that in intestinal cells guanylin binds to the receptor GUCY2C, a known tumour suppressor.
“Loss of guanylin induced by calories silences the GUCY2C tumor suppressor, creating one concrete mechanism linking obesity to colorectal cancer,” notes Waldman. “In fact, mice genetically engineered to express guanylin in intestine that cannot be suppressed by calories resist developing obesity-associated colorectal cancer.”
The study, published in Cancer Research
(online, 15 January 2016), suggests that obesity-related colorectal cancer could be prevented by oral GUCY2C ligand replacement, he adds. “In that context, there is a commercially available ligand for GUCY2C called linaclotide, used to treat chronic constipation, which could be immediately translated into clinical trials for colorectal cancer prevention.”
The researchers also showed that the effects of excess calorie consumption can be reversed by restricting calories, even in obese mice. “The challenges of lifestyle modification notwithstanding, our observations suggest that calorie restriction can reconstitute guanylin expression,” Waldman says. “This may be an effective strategy to prevent colon cancer in the obese.”
Shuji Ogino, a pathologist at Dana-Farber Cancer Institute in Boston, Massachusetts, who was not involved in the study, describes the work as “an important contribution” in the development of a therapy targeting the GUCY2C-related pathway. He adds that evidence of the link between obesity and colorectal cancer is “very convincing”, but that it is still a challenge to develop intervention measures for the prevention of obesity-induced cancer.
 Lin JE, Colon-Gonzalez F, Blomain E et al. Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin–GUCY2C Paracrine Signaling Axis. Cancer Research 2016. doi: 10.1158/0008-5472.CAN-15-1467-T.