Helicobacter pylori and gastric cancer: state of the art.

An international meeting on He!icobacter py!ori and gastric cancer was held February 23-24, 1996, in the Edwin-ScharffHaus in New Ulm, Germany. G. Adler and G. Bode (University of Ulm, Ulm, Germany) served as meeting organizers, with the scientific advice of P. Malfertheiner (University of Magdeburg, Magdeburg, Germany) and M. Stolte (Klinikum Bayreuth, Bayreuth, Germany) in cooperation with the European He!icobacter py!ori Study Group. G. Adler, Dean of the Ulm Medical School, welcomed the participants and reminded them of the pivotal robe played by Ulm University in organizing the Second European He!icobacter Meeting in 1989, which had great influence on research on the subject in Germany in particular and Europe in general. The meeting this year was organized to address both the basic science and the clinical aspects of H. py!ori infection. M. Blaser (Vanderbilt University, Nashville, TN) delivered the State of the Art lecture. He depicted H. py!ori as a “slow” bacterium, which through evolution has become exquisitely adapted to the human host; it is able to persist for most of the life of the host, maintaining active replication and inducing disease, although not inevitably, decades after the initial infection. It has been estimated that about one-half of the population of the world harbors the infection: 70% in the developing world and 30% in the developed world. It is suspected that this group of bacteria has been present since before we were humans. The stomach itself, the target organ, has been present in animals for approximately 4 X 108 years. The inflammatory response by the host is practicably always present after H. py!ori infection, but it varies considerably in type and intensity. It would appear that the bacteria induce inflammation to seek a favorable environment (including access to nutrients and pH optimization) and the host strives to down-regulate the inflammatory response to minimize tissue damage. In collaboration with Denise Kirschner, Blaser has developed a mathematical model of cobonization in which a steady state may be achieved by balancing forces represented by the peristaltic loss of the “floating” bacterial subpopubation and the small but critical proportion of bacteria adhering to the gastric epithelium. The various outcomes of infection may be the result of host, bacterial, and environmental factors, such as strain virulence, genetic susceptibility, age of acquisition of the infection, and nutrition. The interplay of the above factors may determine such diverse outcomes as the atrophy, gastric ulcer, and cancer nosobogical complex (early acquisition of infection), as contrasted with the duodenal ulcer (a disease of civilization) resulting from ecological changes in the human habitat that result in late acquisition of the infection. The role of the CagA gene encoding the CagA protein was discussed in some detail. It appears to be a marker for the presence of a “pathogenicity island” in the bacterial genorne, which involves approximately 20 genes such as picB (permits induction of cytokines). The presence of this island appears to greatly influence the capacity of the bacteria to induce damage in the gastric mucosa. The gene (VacA) encoding the vacuolating cytotoxin is present in all H. py!ori strains, but only some strains express the toxin in vitro; expression is largely but not absolutely linked to CagA status. Two sessions on pathogenesis covered several areas briefly summarized below. J. Telford (IRIS-Chiron Biocine, Siena, Italy) described the mouse model of H. pv!ori infection in which several groups of investigators collaborate and hope to develop a vaccine against the infection. Bacteria that have CagA and that are toxigenic (Type I) induce damage to the murine gastric mucosa that resembles the human histopathological changes. Bacteria lacking such genes (Type II) induce much milder histopathobogical lesions. VacA toxin has a major direct role in ulcerogenesis. Whole bacterial extracts, as well as purified antigens (urease, CagA, and VacA), in combination with LT (heat-labile toxin from E. co!i) convey 70-90% protection against infection after challenge. Vaccines containing more than one antigen (e.g., urease + VacA) convey 100% protection. Several trials in this model have shown that immunization regimes can also cure active infection. Recombinant VacA with a modified LT adjuvant (suitable for use in humans) effectively eradicates existing infection. These studies raise the possibility of using vaccines to cure human infection. J. Crabtree (University of Leeds, Leeds, United Kingdom) discussed the chemokine responses to H. py!ori infection. Among this complex family of cytokines, 1L8 appears especially relevant to H. py!ori infection. Strains carrying the CagA gene strongly induce 1L8 response from epithebial cells, which results not only in polymorphonuclear infiltrate but also in atrophy and intestinal metapbasia. 1L8 in gastric juice is minimal at low pH because of proteobytic degradation, but gastric concentration of this chemokine is elevated at higher pH, even in H. py!ori-negative patients, probably resulting from stimulation by other bacteria. G. Bode illustrated the structure of the nucleoli and discussed the increase in size and number of.silver-stained nudeobar organizers in H. py!ori infection, both in antrab and oxyntic gastric mucosa especially with CagA + stains. Electron microscopy techniques demonstrate compacted and fractionated granular components in CagA + infected mucosa and in gastric carcinoma cells. These studies show that CagA + strains affect the cell cycle of epithelial cells. The robe of apoptosis in gastrointestinal pathology was discussed by P. M#{246}ller (University of Ulm), using the large bowel glandular crypt model. Several agents may induce apoptosis in this model. Apoptosis induced by Apo-llFas antibodies is paralleled by loss of the normal anchorage of the epithelial cells to the glandular base-