Reporting August 1, 2007 in the journal Gastroenterology, clinical pharmacologist Scott Waldman, M.D., Ph.D., professor and chair of pharmacology and experimental therapeutics at Jefferson Medical College of Thomas Jefferson University, and his co-workers showed that GCC - guanylyl cyclase C, a protein receptor on the surface of intestinal epithelial cells for two hormones, guanylin and uroguanylin, can suppress tumor formation. These hormones regulate the growth of intestinal epithelial cells.
But early in colon cancer development, these growth-controlling hormones are "lost" and not expressed, disrupting GCC's activity, and, Dr. Waldman believes, contributing to tumor formation. Using two separate mouse models that mimic the development of colon cancer in people, his team showed that GCC signaling blocks such tumors from forming.
According to Dr. Waldman, the group found that GCC stops tumors from forming through two different mechanisms. In one case, it controls cell growth, while in the other, it maintains "regulation of genomic integrity."
In one mouse cancer model, the animals carried mutations in the APC gene, which causes colon polyps that frequently lead to colon cancer. Mice in the other cancer-development model were exposed to a commonly used experimental cancer-causing agent, azoxymethane. "We modeled both ways that humans develop colon cancer, and studied the effects of a lack of GCC on the incidence of colon cancer development," he explains.
"We found that in animals that have APC mutations, tumors developed in the colon and small intestine, which is expected," Dr. Waldman says. "A lack of GCC resulted in both larger tumors and a greater number of tumors in the large intestine." In the carcinogen model, the absence of GCC caused an increase in both tumor number and size also.
The findings indicate that the mechanism of the increase in tumor development through loss of GCC expression was a combination, in both models, of a loss of genomic integrity and an increase in cell growth. "When you eliminate GCC from cells, they develop a level of genomic instability, where they start accumulating more mutations and lose pieces of genetic material," he explains.
"Putting those pieces together - exposure to carcinogen or spontaneous mutations in APC - which happens to almost every colorectal cancer patient, and the loss of GCC signaling brought on by a loss of the two hormones in one of the earliest events that occurs in tumor development in the intestine," he notes, "and it's a recipe for colon cancer."
The finding "converts colon cancer from a genetic disease, which is the way we've all thought about it, to a disease of hormone insufficiency," Dr. Waldman says. "It's a completely different way of thinking about the disease.
"Not only does this give a new paradigm in how we think about the disease, but it gives us a new paradigm for treating the disease - that is, by hormone replacement therapy.
Essentially, this takes the genetic disease and converts it to an endocrine disease, with a hormone solution." The researchers would like to extend these studies to show that by treating patients with hormone replacement therapy, intestinal cancer formation can either be prevented or treated.