Link between obesity and increased risk of colorectal cancer revealed

Obesity has long been associated with increased risk of colorectal cancer, but the link has never been understood. Now, a research team 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. Their study is published in Cancer Research.

In mice, investigators found that a high caloric diet turned off expression of a key in the intestine, which led to deactivation of a pathway. Genetic replacement of that hormone turned the tumor suppressor back on and prevented 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 to preventing colorectal cancer in , says the study's senior author, Scott Waldman, M.D. Ph.D., Chair of Pharmacology & Experimental Therapeutics at Sidney Kimmel Medical College of Thomas Jefferson University.

The U.S. Food and Drug Administration 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," Dr. Waldman says.

"These findings came as a surprise—we and many other researchers worldwide have been trying to disentangle from development of colorectal cancer," he says. "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 .

"Now we finally have a big clue as to the origin of colorectal cancer in obese individuals and perhaps in other people as well," says Dr. Waldman, who is also the Samuel MV Hamilton Professor.

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 here, Dr. Waldman says.

Dr. Waldman is already involved in a multisite clinical study testing dose and side effects of linaclotide use in healthy volunteers. Investigators from the National Cancer Institute, Mayo Clinic, and Fox Chase Cancer Center are participating.

In the present study, 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. "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," Dr. Waldman says.

Deactivation of the guanylin gene is common in colorectal cancers in both humans and animals, he says. In that regard, morbidly obese patients exhibit an 80 percent decrease in guanylin gene expression compared to lean people, he says.

But in this study, the researchers discovered the consequences of that loss. They found that the guanylin hormone receptor acts as a growth-controlling tumor suppressor, and without the hormone, the receptor is silenced. "This happens extremely early in development of the cancer," Dr. Waldman says. "When the receptor is silenced, the epithelium becomes dysfunctional, setting up the conditions for cancer development."

The scientists checked their findings by creating mice that carried a transgene that won't allow the guanylin gene to be shut off. "Even in the setting of excess calories, from any diet source, tumors don't develop," he says.

Their experiments demonstrated that obese mice, compared to lean mice, were much more likely to silence the hormone and its receptor. "We believe that if is going to develop, it will be through this silencing mechanism—and that it will happen much more frequently in the obese," Dr. Waldman says. Even so, investigators don't yet know the precise molecular mechanism that turns off hormone production.

"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. These findings suggest that a drug like linaclotide, which acts like guanylin, can activate GUCY2C tumor-suppressing receptors to prevent cancer in obese patients," he says.

The researchers also showed that the effect of excess calorie consumption can be reversed via calorie restriction, even in obese mice. "The challenges of lifestyle modification notwithstanding, our observations suggest that calorie restriction can reconstitute guanylin expression," Dr. Waldman says. "This may be an effective strategy to prevent colon cancer in the obese."

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More information: Cancer Research,
Journal information: Cancer Research

Citation: Link between obesity and increased risk of colorectal cancer revealed (2016, January 15) retrieved 21 May 2019 from
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Jan 15, 2016
The challenges of lifestyle modification and calorie restriction depend on individuals acting on recommendations. Unfortunately, acting on these depends on their understanding of why and how colo-rectal and liver cancer develop from the amount and selection of food they eat.

Adding liver health education with simple messages about the role liver cells play in converting food into hundreds of live sustaining body functions has shown that individuals are motivated to modify their behaviors.

Millions are being spent after the fact while little is being spent on true preventive education. For quick and easily shared liver health messages visit With 45 years experience as the CEO of ALF and HFI, testing effective ways to motivate changes in behaviors, I can attest to the effectiveness of these messages for adults as well as children.

Thelma King Thiel, RN, BA - BOD Global Liver Institute.

Jan 15, 2016
That said, the most important piece of "preventive education" is this: The surest way to prevent bowel/colorectal cancer is to remove pre-cancerous "polyps" during a colonoscopy.

Jan 16, 2016
I think obesity and colorectal cancer is related due to indigestion problems. Once constipated everything got complicated. So if ever we felt constipated, immediately take this igestic by Mimonis which is a best fighter for constipation problem. I already have proved it when I got constipated and I know it will work to you also.

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