Obesity linked with colorectal cancer risk: study

Obesity can lead to an increased risk of colorectal cancer, say scientists who have found that the risk may be reversed through lifestyle modification or use of an approved drug.
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 shown the biological connection, and in the process, has identified an approved drug that might prevent development of the cancer.
In mice, researchers 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.

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, researchers said.

"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," said Scott Waldman from Thomas Jefferson University in US.

The risk of developing colorectal cancer in obese persons is about 50 per cent greater, compared to risk in lean people.
Scientists had thought the issue was 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, researchers said.
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," said Waldman.
"Deactivation of the guanylin gene is common in colorectal cancers in both humans and animals. In that regard, morbidly obese patients exhibit an 80 per cent decrease in guanylin gene expression compared to lean people," he added.
In this study, researchers discovered the consequences of that loss. 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. When the receptor is silenced, the epithelium becomes dysfunctional, setting up the conditions for cancer development," said Waldman.

The study was published in the journal Cancer Research.