Loss of two hormones creates a 'recipe for colon cancer'

PHILADELPHIA—New animal studies show that the loss of two hormones plays a significant role in the development of colon cancer. If confirmed, the discovery "converts colon cancer from a genetic disease, which is the way we've all thought about it, to a disease of hormone insufficiency," said senior author Scott A. Waldman, MD, PhD. "It's a completely different way of thinking about the disease."

Dr. Waldman and his colleagues at the Jefferson Medical School of Thomas Jefferson University and the Kimmel Cancer Center at Jefferson, found that guanylyl cyclase C (GCC), a protein receptor on the surface of intestinal epithelial cells, can suppress tumor formation.

GCC is the receptor for guanylin and uroguanylin, two hormones that regulate the growth of the epithelial cells. Early in the development of colon cancer, these two hormones are no longer expressed, which disrupts the functioning of GCC.

The researchers studied the effects of an absence of GCC on colon cancer development in wild-type and GCC-deficient mice that carried the APC gene mutation (mutated in more than 80% of sporadic human colorectal cancers) or that were exposed to a carcinogen, azoxymethane, that produces DNA damage.

Thus, the animal tests mimic the two ways that colorectal cancer develops in humans, Dr. Waldman said. He and his colleagues reported their findings in the August 1 issue of Gastroenterology (133:599-607, 2007).

In the animals with APC mutations, tumors developed in the colon and small intestine as expected, but the GCC-deficient mice had both larger tumors and a greater number of tumors in the large intestine than did the wild-type mice, Dr. Waldman reported.

The absence of GCC receptor activity produced similar results in the mice exposed to the carcinogen.

In both animal models, the mechanism for the increase in tumor number and size was a combination of increased cell proliferation and a loss of genomic integrity resulting from the lack of GCC functioning.

Putting these cancer hits together—exposure to carcinogen or spontaneous APC mutations, plus the loss of GCC signaling—creates "a recipe for colon cancer," he said.

Dr. Waldman and his colleagues hope to advance their finding by conducting human studies to determine whether hormone replacement therapy with oral administration of GCC ligands can be used to prevent or treat colon cancer.

"This study not only gives us a new paradigm in how we think about the disease but also a new paradigm for treating the disease, that is, by hormone replacement therapy," he said.