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The gastric pathogen Helicobacter pylori (H. pylori) is linked to peptic ulcer and gastric cancer, but the relevant pathophysiological mechanisms are unclear. We now report that H. pylori stimulates the expression of plasminogen activator inhibitor (PAI)-1, urokinase plasminogen activator (uPA), and its receptor (uPAR) in gastric epithelial cells and the consequences for epithelial cell proliferation. Real-time PCR of biopsies from gastric corpus, but not antrum, showed significantly increased PAI-1, uPA, and uPAR in H. pylori-positive patients. Transfection of primary human gastric epithelial cells with uPA, PAI-1, or uPAR promoters in luciferase reporter constructs revealed expression of all three in [H.sup.+]/[K.sup.+]ATPase- and vesicular monoamine transporter 2-expressing cells; uPA was also expressed in pepsinogen- and uPAR-containing trefoil peptide-1-expressing cells. In each case expression was increased in response to H. pylori and for uPA, but not PAI-1 or uPAR, required the virulence factor CagE. H. pylori also stimulated soluble and cell surface-bound uPA activity, and both were further increased by PAI-1 knockdown, consistent with PAI-1 inhibition of endogenous uPA. H. pylori stimulated epithelial cell proliferation, which was inhibited by uPA immunoneutralization and uPAR knockdown; exogenous uPA also stimulated proliferation that was further increased after PAI-1 knockdown. The proliferative effects of uPA were inhibited by immunoneutralization of the EGF receptor and of heparinbinding EGF (HB-EGF) by the mutant diphtheria toxin CRM197 and an EGF receptor tyrosine kinase inhibitor. H. pylori induction of uPA therefore leads to epithelial proliferation through activation of HB-EGF and is normally inhibited by concomitant induction of PAI-1; treatments directed at inhibition of uPA may slow the progression to gastric cancer. gastric cancer; primary gastric epithelial cells; cagE; HB-EGF

Data from epidemiologic, experimental, and animal studies indicate that diet plays an important role in the etiology of gastric cancer. High intake of fresh fruits and vegetables, lycopene and lycopene-containing food products, and potentially vitamin C and selenium may reduce the risk for gastric cancer. Data also suggest that high intake of nitrosamines, processed meat products, salt and salted foods, and overweight and obesity are associated with increased risk for gastric cancer. However, current data provide little support for an association of [beta]-carotene, vitamin E, and alcohol consumption with risk for gastric cancer.

We have characterized the adaptations of Helicobacter pylori to a rarely captured event in the evolution of its impact on host biology--the transition from chronic atrophic gastritis (ChAG) to gastric adenocarcinoma--and defined the impact of these adaptations on an intriguing but poorly characterized interaction between this bacterium and gastric epithelial stem cells. Bacterial isolates were obtained from a single human host colonized with a single dominant strain before and after his progression from ChAG to gastric adenocarcinoma during a 4-year interval. Draft genome assemblies were generated from two isolates, one ChAG-associated, the other cancer-associated. The cancer-associated strain was less fit in a gnotobiotic transgenic mouse model of human ChAG and better able to establish itself within a mouse gastric epithelial progenitor-derived cell line (mGEP) that supports bacterial attachment. Gene-Chip-based comparisons of the transcriptomes of mGEPs and a control mouse gastric epithelial cell line revealed that, upon infection, the cancer-associated strain regulates expression of GEP-associated signaling and metabolic pathways, and tumor suppressor genes associated with development of gastric cancer in humans, in a manner distinct from the ChAG-associated isolate. The effects on GEP metabolic pathways, some of which were confirmed in gnotobiotic mice, together with observed changes in the bacterial transcriptome are predicted to support aspects of an endosymbiosis between this microbe and gastric stem cells. These results provide insights about how H. pylori may adapt to and influence stem cell biology and how its intracellular residency could contribute to gastric tumorigenesis. microbial pathogenesis | intracellular bacteria | genome sequencing | functional genomics | gnotobiotic mice

When cells within the gastric mucosa progress from metaplasia to dysplasia to cancer, they acquire a Fas Ag apoptosis-resistant phenotype. It is unusual to completely abolish the pathway, suggesting other forms of Fas Ag signaling may be important or even necessary for gastric cancer to progress. Little is known about alternate signaling of the Fas Ag pathway in gastric mucosal cells. Using a cell culture model of rat gastric mucosal cells, we show that gastric mucosal cells utilize a type II signaling pathway for apoptosis. Under conditions of low receptor stimulation or under conditions where apoptosis is blocked downstream of the death-inducing signal complex, Fas Ag signaling proceeds toward proliferative signaling. Under conditions favoring proliferative signaling, cFLIP is recruited to the Fas-associated death domain-like interleukin-l[beta]-converting enzyme at the death-inducing signal complex and activates ERK1/2. ERK1/2 in turn activates NF-[kappa]B. ERK1/2 stimulates proliferation, whereas NF-[kappa]B activation results in upregulation of the antiapoptotic protein survivin, further promoting proliferation over apoptosis. These results suggest that factors that inhibit apoptosis confer a growth advantage to the cells beyond the survival advantage of avoiding apoptosis and in effect convert the Fas Ag signaling pathway from a tumor suppressor to a tumor promoter. tumor promoter; cell culture; alternate signaling

Background: A decrease in folic acid and subsequent DNA hypomethylation may be involved in gastric carcinogenesis. Epidemiological and nutritional studies have indicated that folate status modulates the risk of developing [...]