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For life or death?
Helicobater pylori infection leads in some individuals to the development of gastric cancer.1 Because both H pylori infection and gastric cancer are relatively common worldwide, this association has spurred considerable interest into determining whether gastric cancer can be prevented by the eradication of H pylori and into investigating the mechanisms by which this extracellular bacterium and its associated inflammatory response promote carcinogenesis. In this regard, H pylori may provide important clues for the pathogenesis of other tumours associated with chronic inflammatory states.
Despite the fact that H pylori does not invade epithelial cells, it has important and profound effects on the gastric epithelial cell, which include provoking a state of chronic epithelial hyperproliferation that has long been recognised as a precursor of malignancy in the stomach as it has in many other cancer prone organs. How does H pylori induce proliferation? A considerable amount of evidence from cell culture and animal models implicates apoptosis as the primary response of gastric epithelial cells to H pylori, with epithelial hyperproliferation as a secondary, presumably compensatory, occurrence.2 The attachment of H pylori is generally thought to be necessary for the induction of apoptosis in gastric cells, based on experiments in co-culture systems. However, the downstream pathways involved in the transduction of proapoptotic signals triggered by H pylori remain to be clarified.
In general, two major pathways of apoptosis have been implicated in H pylori induced apoptosis—the death receptor pathway and the death receptor independent “stress” or mitochondrial pathway. In support of the Fas–Fas ligand death receptor pathway, the use of antagonistic anti-Fas antibodies has been shown to block the apoptosis induced by H pylori in gastric3 and intestinal epithelial cells4 and in T cells.5 In addition, the lack of functional Fas ligand impairs the epithelial response to Helicobacter felis in a mouse model.6 In contrast, transfecting the vacA vacuolating cytotoxin of H pylori into HEp-2 cells resulted in vacA translocating to the mitochondria and releasing mitochondrial cytochrome c,7 indicating that the mitochondrial pathway may be involved in H pylori induced apoptosis. This is consistent with observations that the expression of the proapoptotic Bcl-2 family members, Bak and Bax, confirmed releasers of mitochondria cytochrome c, is increased during the induction of apoptosis by H pylori.8,9 Recently, further strong support for the mitochondrial pathway being the dominant proapoptotic pathway activated by H pylori has been provided by a series of carefully conducted experiments using a defined wild-type H pylori strain and several isogenic mutants co-cultured with gastric cells. In these studies, Maeda et al have shown that during apoptosis induced by H pylori the death receptor pathway and its downstream effectors, including caspases 8, 3, and 7 were indeed activated, but inhibiting this pathway with antagonistic anti-Fas antibody did not influence apoptosis.10 Furthermore, H pylori was found to stimulate mitochondrial cytochrome c release accompanied by the translocation of Bax from cytosol to the mitochondrial membrane during H pylori induced apoptosis.
The second major finding in this paper by Maeda and colleagues was the intriguing observation that at the same time as inducing apoptosis, H pylori also had an anti-apoptotic effect, via the activation of the nuclear factor κB (NF-κB) transcription factor. This effect was revealed by transiently transfecting a kinase deficient IκB construct to inhibit NF-κB activation. In many respects, the demonstration of this antiapoptotic effect of H pylori was not surprising because it is well established that contact between H pylori and gastric cells results in the activation of NF-κB.11,12 Although NF-κB may behave as a positive regulator of apoptosis in some contexts, in most situations NF-κB activation by—for example, tumour necrosis factor α, chemotherapeutic drugs, or ionising radiation—protects against apoptotic cell death.13 Candidate downstream molecules involved in NF-κB mediated protection against H pylori stimulated apoptosis include the mitochondial membrane stabilising proteins Bcl-xl and Blf-1, the caspase inhibitors cIAP1/cIAP2 and XIAP, the tumour necrosis factor receptor associated TRAF1 and TRAF2 molecules, and the cell cycle regulatory protein cyclin D1.13 However, quite a different conclusion regarding the role of NF-κB in H pylori induced apoptosis has been reached by Gupta et al, who reported that the upregulation of NF-κB by H pylori could induce apoptosis and that the apoptosis can be suppressed by activation of the peroxisome proliferator activated receptor γ.14 An easy explanation for these discrepant results is not immediately obvious, but it may reflect differences in the experimental methods used because the precise co-culture conditions and approaches frequently vary widely between groups of investigators in this field, and some of the model systems may only poorly reflect the interactions that take place in the gastric mucosa.
The activation of apoptosis by H pylori is probably important in the stimulation of the compensatory epithelial hyperproliferation seen in chronic gastritis and in the aetiology of the tissue damage occurring in gastroduodenal ulceration as a result of H pylori. Is the activation of antiapoptotic pathways by H pylori also relevant to clinical conditions? Conceivably, the induction of antiapoptotic pathways by H pylori may provide explanations for several interesting phenomena. For example, Mongolian gerbils experimentally infected by H pylori exhibit increased cell turnover early after infection but later display evidence of an adaptive decrease in apoptotic and proliferative cell numbers.2 Moreover, we have described how the repeated addition of H pylori to epithelial cells in vitro can induce or select for gastric epithelial cells that exhibit an apoptosis resistant phenotype, characteristic of the apoptosis resistant cells found all too frequently in human gastric cancer.15 Thus, in some situations the stimulation of survival pathways by H pylori may be more important than its ability to promote apoptosis in the gastric epithelium.
In part, the effect of H pylori on epithelial cell cycle events may relate to the virulence of the infecting strain. The ability of H pylori to activate NF-κB is known to be dependent on genes within the cag pathogenicity island of H pylori. However, this relation does not exclude the possibility that cag negative strains can activate other epithelial survival pathways, such as those regulated by cyclooxygenase 2.
The demonstration that H pylori can promote both apoptosis and cell survival simultaneously is novel, but should not really surprise us. If there is one lesson we have learned from this organism, it is to expect the unexpected.
For life or death?