Jefferson researchers find protein signpost may indicate esophageal and stomach cancer

March 26, 2002

A protein marker whose presence is thought to indicate the return of colorectal cancer may also be a sign of the development of esophageal and stomach cancer.

Researchers at Jefferson Medical College have shown for the first time that the protein, GCC, is present in a condition known as intestinal metaplasia, which may lead to both cancers, and in turn, is also present in those cancers.

The work, led by Stephanie Shulz, Ph.D., assistant professor of medicine at Jefferson Medical College of Thomas Jefferson University in Philadelphia, and Jason Park, an M.D./Ph.D. student at Jefferson Medical College, has implications for the development of improved methods of diagnosing and treating both types of cancer.

She reports her team's findings March 26 at the meeting of the American Society for Clinical Pharmacology and Therapeutics in Atlanta. GCC, or guanylyl cyclase C, is a member of a family of seven proteins expressed only by intestinal cells and colorectal cancer cells. It's vital to cellular communications, transmitting signals from outside to inside the cell. Most sporadic colorectal cancers originate in the cells that line the intestine - cells that normally make GCC. When the cells become cancerous, they continue to make GCC.

Several years ago, Scott Waldman, M.D., Ph.D., Samuel M.V. Hamilton Family Professor of Medicine and director of the Division of Clinical Pharmacology at Jefferson Medical College of Thomas Jefferson University, and his co-workers found that GCC allows the detection of cells having spread to other areas of the body. GCC can be used as a diagnostic tool to stage patients and to follow them after their surgery to see if their cancer has returned.

Dr. Schulz and her co-workers had previously shown that Cdx2, a protein involved in the expression of genes in intestinal cells played a role in determining how one of those genes expressed GCC in the intestine. "We wondered, if Cdx2 was present, would it drive GCC expression in intestinal metaplasia as well? And would GCC then be a marker for the condition?"

Intestinal metaplasia is a sometimes precancerous condition in the esophagus and stomach. In fewer than 10 percent of cases, intestinal metaplasia leads to a cancer, adenocarcinoma, of the esophagus and stomach.

Their findings indicate the answer is yes to both questions.

The team looked at the presence of GCC in 18 patients with adenocarcinoma of the stomach and esophagus. They detected GCC genetic material - mRNA - in five of five cases of esophageal cancer and eight of nine cases of stomach cancer. Not only that, GCC mRNA was found in three of five and six of seven "healthy" tissues adjacent to the esophageal and stomach cancers. The researchers believe this may be a sign of "early molecular changes" associated with the development of cancer. the majority of cases they looked at, GCC was present. What's more, GCC was not present in normal esophagus or stomach.

The results may have important clinical implications. "We think this could not only be a diagnostic marker, but a potential therapeutic target, since you can target antibodies, for example, to GCC, which is a receptor," Dr. Schulz says. She suggests a spray might be used with a toxin attached to an antibody that binds to GCC. "You could deliver therapeutics and perhaps use it for diagnostics."

Next, she says, she and her team would like to study GCC expression in a larger number of patients. They are also working to develop an antibody to better detect GCC's presence.

Thomas Jefferson University

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