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Obesity and colorectal cancer

Link between obesity and colorectal cancer found

(Credit: Blausen Medical Communications, Inc.)
Their experiments demonstrated that obese mice, compared to lean mice, were much more likely to silence the hormone and its receptor

Researchers led by investigators at Thomas Jefferson University has revealed the biological connection, and in the process, has identified an approved drug that might prevent development of the cancer. In their study, Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin–GUCY2C Paracrine Signaling Axis. published in Cancer Research, the investigators found that a high caloric diet turned off expression of a key hormone in the intestine, which led to deactivation of a tumour suppressor pathway. However, genetic replacement of that hormone turned the tumour suppressor back on and prevented cancer development, even when mice continued to eat excess calories.

These findings position the use of the pill linaclotide (Linzess), which is structurally related to the lost hormone, as a therapeutic approach to preventing colorectal cancer in obese patients, explained the study's senior author, Dr Scott Waldman, Chair of Pharmacology & Experimental Therapeutics at Sidney Kimmel Medical College of Thomas Jefferson University. The FDA approved linaclotide in 2012 to treat irritable bowel syndrome with constipation, as well as chronic idiopathic constipation (chronic constipation from unknown causes).

"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," explained Waldman. "These findings came as a surprise - we and many other researchers worldwide have been trying to disentangle obesity from development of colorectal cancer. 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.

Scott Waldman (Credit: Kimmel Cancer Center)

The risk of developing colorectal cancer in obese persons is about 50 percent greater, compared to risk in lean people. Scientists had thought the issue was one based on the amount of fat tissue and the associated unknown metabolic processes (excess calories that fuel cell energy and growth), but that did not turn out to be the case.

The research team, which includes investigators from Harvard and Duke Medical Schools, used genetically engineered mice on different diets to conduct their investigation. They found that obesity (either from excess fat or carbohydrate consumption, or both) is associated with loss of the hormone guanylin, which is produced in the intestine's epithelium -the cells lining the organ. The hormone turns on its receptor, guanylyl cyclase C (GUCY2C), which regulates processes underlying regeneration of the intestinal epithelium.

Deactivation of the guanylin gene is common in colorectal cancers in both humans and animals, and morbidly obese patients exhibit an 80 percent decrease in guanylin gene expression compared to lean people. They found that the guanylin hormone receptor acts as a growth-controlling tumour suppressor, and without the hormone, the receptor is silenced.

"This happens extremely early in development of the cancer," said Waldman. "When the receptor is silenced, the epithelium becomes dysfunctional, setting up the conditions for cancer development. Even in the setting of excess calories, from any diet source, tumours don't develop.”

Their experiments demonstrated that obese mice, compared to lean mice, were much more likely to silence the hormone and its receptor.

"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 tumour development. These findings suggest that a drug like linaclotide, which acts like guanylin, can activate GUCY2C tumour-suppressing receptors to prevent cancer in obese patients," he said. "The challenges of lifestyle modification notwithstanding, our observations suggest that calorie restriction can reconstitute guanylin expression. This may be an effective strategy to prevent colon cancer in the obese."

He added 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, However, investigators do not yet know the precise molecular mechanism that turns off hormone production.

"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," he concluded. "Now we finally have a big clue as to the origin of colorectal cancer in obese individuals and perhaps in other people as well.”

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