Researchers, led by Dr. Scott Waldman, PhD, of Thomas Jefferson University in Philadelphia, PA, carried out mouse studies to investigate the link between obesity and colorectal cancer.
They found that obesity, whether from excess fat, carbohydrate consumption or both, is associated with loss of the hormone guanylin. Guanylin is produced in the lining cells, or epithelium, of the intestine.
The lining of the intestines is very dynamic and continuously being replaced. A receptor, guanylin cyclase C (GUCY2C), contributes to this regeneration. Guanylin is the hormone that turns on this receptor.
Findings showed that a high caloric diet turned off the expression of guanylin in the intestine, leading to deactivation of a tumor suppressor pathway.
Low guanylin expression sets the scene for tumors
One feature of colorectal cancer is the deactivation of the guanylin gene. This has been seen in both humans and animals. Morbidly obese patients have an 80% lower guanylin gene expression compared with lean people.
It appears that the guanylin hormone receptor acts as a growth-controlling tumor suppressor. Without the hormone, the receptor is silenced from the early stages of the cancer. This causes the epithelium to become dysfunctional and sets up the conditions for cancer development.
To check their findings, the team genetically created mice with a transgene that stops the guanylin gene from being shut off. By switching the tumor suppressor back on in this way, cancer development was prevented, even when mice continued to eat excess calories.
The experiments showed that the hormone and its receptor were far more likely to be silenced in obese mice than in lean mice.
Dr. Waldman and his team were surprised at the link, which many researchers worldwide have been trying to understand. The team proposes that colorectal cancer could be prevented in obese individuals through hormone replacement therapy, in the same way that diabetes is treated with insulin.
Dr. Waldman says:
“Calories sit in the middle of [obesity and colorectal cancer], 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.”
The team believes that if colorectal cancer is going to develop, it will be through this silencing mechanism; and that it is more likely in people who are obese.
Linaclotide could replace the lost hormone
The findings also suggest that the drug linaclotide (Linzess), which is structurally related to the lost hormone, could be used to prevent colorectal cancer in obese patients.
The US Food and Drug Administration (FDA) approved linaclotide in 2012 to treat irritable bowel syndrome with constipation as well as chronic constipation from unknown causes, known as chronic idiopathic constipation.
The researchers also showed that caloric restriction can reverse the effect of excess calorie consumption and reconstitute guanylin expression, even in obese mice, suggesting a role for lifestyle changes.
Further studies will be needed to identify the precise molecular mechanism that turns off hormone production. Meanwhile, Dr. Waldman is already involved in a multisite clinical study testing dose and side effects of linaclotide use in healthy volunteers.
Medical News Today reported recently on the role of the Sprouty2 gene, normally known to suppress tumors, in enabling the spread of colorectal cancer.