Half the population in the world is chronically infected with H.pylori. This infection has been proven to be associated with gastritis, duodenal and gastric ulcers but also with gastric cancer and MALT-lymphoma. The aims of this thesis were to explore some possible mechanisms by which H.pylori may contribute to the onset of gastric cancer.
The first approach was to study whether H. pylori is mutagenic. Three different H.pylori strains (NCTC 11637, Ca 18, 13/12), all cagA and VacApositive, were studied with the Salmonella mutagenicity assay (the Ames test). No dose-response curve and no increase in revertants were seen. These results show that H. pylori is not likely to be mutagenic.
A special feature ofH.pylori gastritis is that it is practically always linked to inflammation with varying degrees of mucosal activity. Neutrophils and monocytes produce and liberate nitric oxide and oxygen radicals, which are capable of inducing mutations of DNA. In order to test if the bacterium alone or together with bile could affect lenkocytes to produce mutagenic substances, some in vitro experiments were performed. The Ames test was used on neutrophils from blood donors. The neutrophils· were exposed to H. pylori and/or bile. A time-dependent response was found, where neutrophils exposed for two hours or more showed significant mutagenic activity in 5 of 19 experiments. The combination with bile gave the highest response. In a follow up of these findings, no mutagenic activity was found in H. pylori-infected mouse mucosa when tested for mutagenic substances with the Ames test.
A second approach was to develop in vivo models of H. pylori gastritis by inoculating Wistar rats and C57BL/6 mice with species-adapted H. pylori strains. An increased cell proliferation was seen in infected animals whereas, the apoptotic rate was unaffected compared with non-infected controls. This different cell response may favour gastric carcinogenesis. Furthermore, H.pylori significantly promoted cell proliferation in rats exposed to bile, and in mice given the combination of MNNG and bile.
A third approach was to study the immunohistochemistry for the expression of the enzyme COX-2 and the protein Bcl-2 in rats receiving different combinations ofH.pylori, MNNG and bile. H.pylori enhanced Bcl-2 expression in antrum mucosa and also increased the COX-2 expression in corpus mucosa. The COX-2 expression correlated with increased cell proliferation in antrum but not with apoptosis. This change in COX-2 and Bcl-2 may also promote the development of neoplasia.
In conclusion, H. pylori may promote gastric carcinogenesis in several ways. Thus neutrophils that are accumulated in H.pylori-infected mucosa, may give rise to mutagenic substances. Moreover, H.pylori infection is associated with increased cell proliferation and unchanged apoptosis, which increases the risk for mitotic errors and mutations from endo- and exogenous carcinogens. The increased cell proliferation may be induced by a simultaneously increased COX -2 expression. The enhanced Bcl-2 expression in antrum that was corrolated to increased cell proliferation, also favours tumour development.
Linköping: Linköpings universitet , 2001. , 88 p.