Mouse Trial Sets Basis To Test Progressive Risks Of <I>H. Pylori</I> Colonizing H. Pylori Colonizing ">From Minor Irritation To Lethal Cancer

Mouse Trial Sets Basis To Test Progressive Risks Of H. Pylori Colonizing Stomach Lining

By David N. Leff

There's good news and bad news about stomach cancer.

Two generations ago, in the 1930s, gastric carcinoma was the leading cause of death among men in the U.S. Today it ranks eighth, with almost the lowest mortality in the world.

The bad news for Americans is that stomach cancer still strikes several thousand people a year in the U.S. (24,000 in 1994), and fewer than a fifth of these are alive five years after diagnosis.

In Japan and China, the stomach-cancer news is all bad. It's the leading cause of death in both countries. Areas elsewhere in the world share this mortality statistic with lung cancer.

Until the 1980s, the news about ulcers was pretty bad, though less dire than cancer. People with stomach ulcers were condemned to a lifetime of bland, alcohol-free diets, bed rest, sedatives, tranquilizers, antacids and psychotherapy.

Then, 14 years ago, Australian scientists discovered that a key culprit in ulcers was not a nervous-tension psychosis, but a bacterium, Helicobacter pylori. It's the only microorganism that populates the harsh, acidic environment of the human stomach, and can be controlled to some extent by antibiotic therapy. (See BioWorld Today, Feb. 7, 1996, p. 1)

"Half the world's population," observed molecular biologist Jeffrey Gordon, "is colonized by H. pylori at some time in their lives. Most people," he added, "establish a cordial relationship with this microorganism, which can typically last for decades, or life."

But Gordon made the point that "the prevalence of stomach cancer correlates with areas of the world where Helicobacter pylori infection is endemic. We don't know precisely how this organism causes cancer, but it's rather remarkable that a bacterium is associated with the development of neoplasia."

Between a mild, transient gastritis and full-blown gastric carcinoma occur a slow crescendo of increasingly serious attacks by H. pylori on the stomach lining, notably peptic ulcers, and atrophic gastritis. Key constituents of this inner epithelial wall are the parietal cells, which secrete the acids of digestion.

"Look into the stomach of an infected person who has severe gastritis or ulcers," Gordon observed, "and you'll see H. pylori associated with cells that line the stomach. In healthy people, the pathogen floats free in the gastric mucus."

Early in the 1990s, scientists discovered that H. pylori can attach to a human blood-group antigen called Lewis b (Leb) on stomach-lining cells.

Gordon, on the faculty of Washington University, in St. Louis, is senior author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated March 31, 1998. Its title: "Epithelial attachment alters the outcome of Helicobacter pylori infection."

He told BioWorld Today, "We wanted to test the hypothesis that if the bacterium is able to attach to a host's stomach-lining cells, that puts the person in jeopardy for more severe pathology. So we had to identify a host receptor for the bacteria."

Transgenic Mice, Peruvian Patients Test Hypothesis

To begin with, Gordon recounted, "We genetically engineered production of human Leb blood-group epitopes in a strain of mice by transgenic technology. It caused the animals no ill effects on their overall health, ability to absorb nutrients, or life span."

The co-authors then turned to a cohort of chronic gastritis patients in Lima, Peru, seeking H. Pylori bacteria that could bind to a known host receptor, namely, Leb.

"Leb is a very common blood group in Peru," Gordon pointed out.

Biopsies of the patients' stomach linings allowed them to isolate H. pylori strains and confirmed that they were Leb-positive.

One unexpected finding: "The particular strains of H. pylori that we used," Gordon recounted, "coming from this Peruvian Lewis-B world, so to speak, produced a type of carbohydrate structure on their surfaces that happened to resemble a structure normally generated in the parietal cells of this strain of mice that we employed.

"The implication of that," he continued, "was, we had an example of the bacteria having molecules that resemble molecules on the host. The immune response those animals mounted was in part to those bacterial structures. And because the host itself had similar structures, when teh bacteria attached to the stomach lining, the antibodies cross-reacted with their own cells, in autoimmune fashion. And that immune response by the bacteria ultimately destroyed the acid-forming parietal cells on the hosts' stomach lining. The risk factor in developing an autoimmune response is attachment.

"Loss of those parietal cells," Gordon pointed out, "could lead to atrophic gastritis and put the host at risk of cancer. We think that this may be a relatively common theme in patients with H. pylori infection."

On the basis of this picture, Gordon proposed "prospective studies to look at the frequency of circulating antibodies against parietal cells and other gastric cell types in infected patients."

Pathogens Run Infection Lottery In People

He described the PNAS paper's finding as "the first demonstration that a genetically engineered receptor for a bacterium was not only functional, but also markedly affected the outcome of a bacterial infection. It's a rather extraordinary example," he added, "of a bacterium that can be relatively harmless in some people and cause cancer in others."

The clinical payoff, he suggested, is to identify populations of patients harboring this pathogen-colonization testable risk factor, "who may be candidates for more aggressive antibacterial therapy, including even vaccination against H. pylori. An analysis of the genes that are turned on or off in the bacteria and in the host as a consequence of attachment may yield new and important therapeutic targets," Gordon said, " as well as markers, perhaps, in patients at risk for more serious consequences of colonization."

This does not mean, however, routinely blood-testing large populations in high-risk areas for the Leb blood-group antigen, he observered.

"It is probably only one of several devices that the organism can use to attach to its host. We used it only as a model system. And the bacterium itself," he pointed out, "exists in many different genetic variants in a given community, and you as the host are colonized with one or a subset of these strains.

"The question," Gordon concluded, "is whether the match, the relationship, destines a person to a happy, cooperative and long-term peaceful interaction with Helicobacter pylori, or dooms one to strife, chaos, and severe pathology." *

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