Chronic inflammation, whether associated with excessive or deficient amounts of stomach acid, seems to cause chronic atrophic gastritis that can progress to stomach cancer, according to an article in the March 31st issue of Oncogene.

In the current study, American researchers demonstrated that chronic gastritis progresses to gastric cancer in mice with abnormally low levels of gastrin. Previous studies had found that overproduction of gastrin in mice stimulates uncontrolled growth of cells in the stomach lining and development of gastric tumors.

“Our study shows that inflammation, regardless of the cause, is the key to the development of gastric cancer,” said Juanita L. Merchant, MD, PhD. “We’re finding that there are many mechanisms, in addition to gastrin hypersecretion and H. pylori infection, capable of producing the chronic inflammatory changes that lead to cancer.”

Most gastric cancers are adenocarcinomas. The American Cancer Society estimates that, in 2005, there will be 21,860 new cases of gastric cancer reported in the United States and 11,550 deaths from the disease.

“It’s a fairly deadly type of cancer and difficult to treat, especially in advanced stages,” according to Merchant. “Our goal is to identify genetic and molecular changes that occur early ? for example, during the inflammatory process before cancer develops ? and then see if it is possible to reverse those changes.”

A strain of mice genetically engineered to be gastrin-deficient has proven valuable, because the progression of cell changes leading to gastric cancer in these mice matches changes seen in the development of human gastric cancer. In both species, the process begins with chronic gastritis, which leads to atrophy of the stomach lining, followed by abnormal tissue changes and, finally, development of malignant cells.
“Now we have a mouse model that we can use to isolate the different genetic steps in human gastric cancer,” Merchant said. “We’ve identified certain molecular changes and are in the process of testing these molecules to see how each contributes to the transformation of normal mucosa into gastric cancer.”

Three genes of particular interest are RUNX3, TFF1 and STAT3, according to Yana Zavros, PhD, first author of the paper. “RUNX3 is a stomach-specific tumor suppressor gene whose deletion in mice has been shown to result in gastric cancer,” Zavros explained. “TFF1 appears to have a protective effect on the gastric mucosa. STAT3 is a gene that mediates inflammatory signals and has been linked to the development of cancer.

“We are especially interested in RUNX3, because its activity is suppressed in mouse and human gastric cancers,” Zavros added. “Other researchers have shown that RUNX3 stimulates apoptosis or programmed cell death. We hope to learn how the inflammatory process suppresses this critical gene, and subsequently suppresses apoptosis, as well.”