Researchers investigate why obesity can trigger bowel cancer

Behind the Headlines

Tuesday January 19 2016

Obesity has been linked to several different cancers

A high-calorie diet may cause cell damage

"Excess calories 'turn off a hormone in the intestine that blocks colon cancer'," the Mail Online reports.

Obesity is a known risk factor for bowel cancer (also known as colorectal cancer). There is evidence that a diet rich in processed meats, which contain the potentially cacogenic compound nitrates, increases bowel cancer risk. However, it is unclear why other high-calorie diets also increase risk.

This latest study, conducted in genetically engineered mice, found that obesity caused by a diet rich in fats or carbohydrates "silenced" a hormone called guanylin. This, in turn, led to the turning off of a receptor called guanylyl cyclase C (GUCY2C) found on cells that line the bowel. Receptors are specialised structures designed to respond to specific chemical signals.

Turning off this receptor was associated with tumour growth, as the GUCY2C receptor, when working properly, is designed to prevent abnormal cell growth. Further study confirmed this by showing that using a drug to increase production of guanylin reversed the effects of the high-calorie diet and prevented tumour growth.

The obvious question is: could a similar drug be effective in obese humans thought to be at high risk of developing bowel cancer? The simple answer is: we just don't know yet.

It is unwise to assume that the results of an animal study will transfer over to people; we are not biologically identical.

However, the study does provide a route – looking at ways to activate the GUCY2C receptor in humans – for further, hopefully fruitful, research in the area.


Where did the story come from?

The study was carried out by researchers from Thomas Jefferson University, Duke University and Harvard Medical School, and was funded by the Harvard Digestive Diseases Center, the PA Department of Health and Targeted Diagnostic and Therapeutics, Inc, which is a biotech company.

Some of the study authors have financial interests in, and/or are employed by, Health and Targeted Diagnostic and Therapeutics, Inc.    

The study was published in the peer-reviewed medical journal Cancer Research.

The Mail Online's reporting of the study is accurate and contains an interesting interview with one of the authors of the study. However, its coverage could have made it clearer the study was in mice, not humans, as this fact was only mentioned once, halfway down the page.


What kind of research was this?

This was an experimental study in mice aiming to explore the effect of diet-induced obesity on bowel cancer (health professionals often prefer the term colorectal cancer, as the cancer can also develop outside of the bowel, such as in the rectum).

In general, it is known that being obese is linked with increased risk of colorectal cancer in humans. However, the precise biological mechanism by which obesity or high-calorie intake increases risk is poorly understood.

This animal research aimed to explore this by building on the knowledge that dysfunction of a particular receptor in the cells lining the bowel – GUCY2C receptors – is associated with colorectal cancer development in a range of animal species. In particular, loss of the bowel hormone guanylin has been observed in cases of bowel cancer, and loss of this molecule "silences" the receptor, stopping it working.  

The results of such animal studies are useful for investigating links that can then be explored further. However, the results may not be directly transferable to humans.


What did the research involve?

The research involved genetically engineered mice with either a functioning or non-functioning GUCY2C receptor. At four weeks old, they were fed one of three diets:

  • lean diet (3.0 kcal/g, 12.7% from fat and 58.5% from carbohydrate)
  • high-fat diet (5.1 kcal/g, 61.6% from fat and 20.3% from carbohydrate)
  • high-carbohydrate diet (3.8 kcal/g, 10.2% from fat and 71.8% from carbohydrate)

At six weeks of age, lean mice were administered a cancer-causing chemical called azoxymethane. The resulting tumours were counted and their sizes quantified at eight weeks.

High-fat mice were given tamoxifen, an artificial hormone, every four weeks, starting at four weeks of age, to make them produce guanylin. They also received six doses of azoxymethane weekly, starting at five weeks of age. Tumours were counted and their sizes quantified at 22 weeks of age.

High-carbohydrate mice were given azoxymethane at six weeks old, every week for six weeks. Tumours were counted and their sizes quantified 12 weeks after the last azoxymethane dose.


What were the basic results?

In the mice with an intact GUCY2C receptor on their colon cells, a high-fat diet reduced the levels of guanylin hormone. This led to GUCY2C receptor silencing and allowed increased DNA damage, leading to rapid cell formation and cancer formation.

The researchers suggest that these findings show the production of tumours is associated with diet-induced obesity effects. However, a high-carbohydrate diet that increased calorie intake by approximately 40% without any weight gain also led to reduced guanylin with associated receptor dysfunction and increased cancer formation – similar to that of the high-fat diet.

The study also found that by preventing the loss of guanylin and maintaining GUCY2C receptor function, the production of tumours in the intestines almost completely stopped.


How did the researchers interpret the results?

The researchers conclude that the findings show excess calories are able to suppress the GUCY2C receptor and this links obesity to the tumour pathway in colorectal cancer. The researchers go on to suggest this may provide an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the drug linaclotide.

Linaclotide is currently licensed in the UK to treat constipation in cases of irritable bowel syndrome. It is known to increase levels of guanylin.



This was an experimental animal study aiming to explore the possible biological mechanism by which obesity may be associated with the development of bowel cancer. The findings suggest it may be down to silencing a particular receptor – GUCY2C – located on the cells lining the bowel.

The study found that excessive consumption of fat or carbohydrate in mice was associated with loss of the guanylin hormone responsible for turning on the GUCY2C receptor. Silencing this receptor led to tumour development.

Further study confirmed this by showing that using a drug to increase production of guanylin reversed the effects of the high-calorie diet and prevented the mice developing tumours.

The findings of this study are of interest and further our understanding of a possible mechanism by which obesity and high-calorie diets may be associated with the development of bowel cancer. However, caution should be taken in transferring these results to people, as we are not biologically identical to mice.

It is also not possible to say at this stage whether, as the researchers suggest, providing a drug that activates the GUCY2C receptor could be effective in the treatment of bowel cancer in humans. However, the study does provide a route for further research in the area.

Looking at the anti-constipation drug linaclotide, known to increase the production of guanylin, would seem an obvious first step. 

Analysis by Bazian. Edited by NHS Choices. Follow NHS Choices on TwitterJoin the Healthy Evidence forum.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

How overeating gives you CANCER: Excess calories 'turn off a hormone in the intestine that blocks colon cancer'. Mail Online, January 18 2016

Links to the science

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. Published online January 15 2016


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