Chronic inflammation caused by too little stomach acid leads to gastric cancer

Genetically engineered mice will help U-M scientists decipher signals that trigger gastric cancer in humans

When it comes to gastric cancer, too little stomach acid can be just as dangerous as too much, according to scientists at the University of Michigan Medical School. Both extremes create inflammatory changes in the stomach lining and a condition called chronic atrophic gastritis, which over time often leads to cancer.

In research published in the March 31 issue of Oncogene, U-M scientists demonstrated that chronic gastritis progresses to gastric cancer in mice with abnormally low levels of gastrin – a hormone that stimulates stomach lining cells called parietal cells to secrete hydrochloric acid. Other researchers have shown that over-production of gastrin in mice stimulates uncontrolled growth of cells in the stomach lining and the development of gastric tumors.

Most physicians are aware of the association between chronic inflammation and gastric cancer. They also know that infection with a bacterium called Helicobacter pylori, if left untreated, can cause stomach cancer. But the fact that lower-than-normal acidity can trigger pre-cancerous changes in the stomach lining is not well-known.

“Our study shows that inflammation, regardless of the cause, is the key to the development of gastric cancer,” says Juanita L. Merchant, M.D., Ph.D., a U-M professor of internal medicine and of molecular and integrative physiology. “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, meaning they develop in epithelial cells lining the stomach. 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.”

Merchant has spent years studying pre-cancerous physical and molecular changes in epithelial cells lining the stomach wall. Now, she has a new research partner – a line of genetically engineered mice that secrete abnormally low amounts of hydrochloric acid, because they lack the gene required to produce gastrin. The mice were generated in the laboratory of Linda C. Samuelson, Ph.D., a professor of molecular and integrative physiology in the U-M Medical School.

The gastrin-deficient mice are especially 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, the 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 says. “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, Ph.D., a U-M research investigator and first author of the Oncogene paper. “RUNX3 is a stomach-specific tumor suppressor gene whose deletion in mice has been shown to result in gastric cancer,” Zavros explains. “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 adds. “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.”

Merchant and Zavros believe that suppression of RUNX3’s apoptosis-stimulating signal may be key to the development of gastric cancer, at least in the antrum. They examined gastric tissue from mice in their study using an assay called TUNEL, which detects cells in the process of undergoing apoptosis.

“We found striking differences in the apoptotic rates of parietal cells in the fundus, or upper compartment of the stomach, compared to the antrum where the tumors were developing,” Merchant says. “The antrums we studied had a 50-percent to 75-percent decrease in the cell death rate. Rates of cell growth and reproduction were about the same in both stomach compartments.

“So we think that gastric cancer, at least in the antrum, appears to be caused by suppression of the normal rate of apoptosis, rather than by cells growing wildly out of control,” Merchant says. “This is a question we will explore in more depth as our research continues.”