Research gives hope to obese cancer patients

High calorie foods like this can lead to colorectal cancer in obese people. By Jasminee Sahoye
High calorie foods like this can lead to colorectal cancer in obese people.
By Jasminee Sahoye

Researchers have found a biological connection associated with obesity and an increased risk of colorectal cancer that was not understood until now.
And that’s not all. They also identified an approved drug that might prevent development of the cancer.
Investigators at Thomas Jefferson University found that a high caloric diet turned off expression of a key hormone in the intestine of mice, which led to deactivation of a tumor suppressor pathway.
Genetic replacement of that hormone turned the tumor 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, said 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,” Waldman said.
He added that “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.
“Now we finally have a big clue as to the origin of colorectal cancer in obese individuals and perhaps in other people as well,” he said.
The risk of colorectal cancer in obese persons is about 50% 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, Waldman said.
He is already involved in a multi-site clinical study testing dose and side effects of linaclotide use in healthy volunteers with investigators from the National Cancer Institute, Mayo Clinic, and Fox Chase Cancer Centre.
In the 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,” Waldman said.
Deactivation of the guanylin gene is common in colorectal cancers in both humans and animals. In that regard, morbidly obese patients exhibit an 80% decrease in guanylin gene expression compared to lean people, he said.
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,” Waldman said.
“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. Even so, investigators don’t yet know the precise molecular mechanism that turns off hormone production.
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,”Waldman said. “This may be an effective strategy to prevent colon cancer in the obese.”