Earlier this month two Australian researchers won the Nobel Prize for Physiology or Medicine for discovering a bacterium that can cause gastric inflammation, ulcers, and stomach cancer. The Nobel committee honored Drs. Barry Marshall and Robin Warren for persuading skeptics two decades ago that peptic ulcers are an infectious disease.

A link between bacteria and ulcers was initially dismissed because in the early 1980s medical dogma held that ulcers were caused by "stress" and poor diet. But the evidence, including an experiment in which Dr. Marshall swallowed the bacteria himself and became ill, was irrefutable.

Today, most peptic ulcers are treated with antibiotics, and the association between the bacterium, Helicobacter pylori, and stomach ailments is well documented. Stomach cancer has become a model for researchers investigating connections among infection, inflammation, and cancer.

CCR Grand Rounds October 25: Dr. Angela Brodie, Professor of Pharmacology and Experimental Therapeutics, Department of Pharmacology, University of Maryland School of Medicine; "Aromatase Inhibitors and Breast Cancer: Concept to Clinic" November 1: Dr. Sriram Subramaniam, Chief, Biophysics Section, Laboratory of Cell Biology, CCR, NCI; "From Molecules to Tissues: Bridging the Imaging Gap with 3D Electron Microscopy"

"Inflammation is being recognized as an important feature of more and more types of cancer, and it is likely a component of the causes," notes Dr. Charles Rabkin of NCI, who has helped identify genetic differences associated with variation in the body's response to H. pylori infection.

Although inflammation is a common reaction to H. pylori infection, individuals who are genetically predisposed to have severe immune responses are thought to be at higher risk of developing stomach cancer. The virulence of the infecting strains and the stomach environment also play a role in determining the outcome of an infection.

"There's a consensus that, in general, the genetic variation that confers the greatest degree of inflammation is associated with the greatest risk of stomach cancer and its precursors," says Dr. Rabkin. This could help explain why a minority of infected individuals progress to cancer, although half the world's population carries the bacterium.

Dr. Rabkin and many others have identified variants of proteins called cytokines that promote inflammation and are likely to stimulate the disease process. Identifying genes involved in regulating the inflammatory process could reveal molecular targets for intervening in the disease process.

Last year, a new model of stomach cancer challenged the conventional wisdom about the disease process. Using mice infected with a cousin of H. pylori, researchers at the University of Massachusetts, Worcester, traced the origins of stomach cancer to stem cells from bone marrow.

The researchers hypothesized that bone marrow stem cells migrated to the damaged areas of the stomach to help repopulate the tissue, but the cells could not develop normally in the presence of inflammation, according to findings in the November 26 Science.

"We believe that if carcinogens such as H. pylori are not eradicated they will eventually cause the death of stem cells in the stomach, and these will be replaced by bone marrow stem cells," says Dr. Timothy C. Wang, who co-led the study and is now at Columbia University Medical Center.

The big question now, according to Dr. Wang, is "How can one confirm these results in the human model?" In theory, stem cells have the potential to form any tissue of the body, and they have been implicated in some cancers. But the cells themselves are rare and extremely difficult to find in adult tissue.

Dr. JeanMarie Houghton of the University of Massachusetts, who co-led the study, says a goal of future research is to identify the molecular signals that are calling the bone marrow stem cells to the site of inflammation and helping them to remain there.

"The research is a good demonstration of how the continued presence of inflammation and the toxic factors associated with this state harmed cells that were repopulating the stomach lining, leading to their mutation," comments Dr. Rabkin.

Whether the model turns out to be true in humans and in other types of cancer, it offers an alternative way of looking at the origins of cancer, says Dr. Houghton, adding: "This can help us shake off beliefs we held previously and may lead to new approaches for treatment."

Response to the theory has been unexpectedly positive, although many researchers are awaiting confirmation by other studies. "We've come a long way since poor Barry Marshall had to swallow a culture of bacteria to prove they cause ulcers," Dr. Houghton says.

By Edward R. Winstead