Helicobacter pylori and gastric cancer: factors that modulate disease risk

Abstract

Helicobacter pylori is a gastric pathogen that colonizes approximately 50% of the world's population. Infection with H. pylori causes chronic inflammation and significantly increases the risk of developing duodenal and gastric ulcer disease and gastric cancer. Infection with H. pylori is the strongest known risk factor for gastric cancer, which is the second leading cause of cancer-related deaths worldwide. Once H. pylori colonizes the gastric environment, it persists for the lifetime of the host, suggesting that the host immune response is ineffective in clearing this bacterium. In this review, we discuss the host immune response and examine other host factors that increase the pathogenic potential of this bacterium, including host polymorphisms, alterations to the apical-junctional complex, and the effects of environmental factors. In addition to host effects and responses, H. pylori strains are genetically diverse. We discuss the main virulence determinants in H. pylori strains and the correlation between these and the diverse clinical outcomes following H. pylori infection. Since H. pylori inhibits the gastric epithelium of half of the world, it is crucial that we continue to gain understanding of host and microbial factors that increase the risk of developing more severe clinical outcomes.

FIG. 1.

Multifactorial pathway leading to gastric carcinoma. Many host, bacterial, and environmental factors act in combination to contribute to the precancerous cascade leading to development of gastric cancer.

FIG. 2.

Relationships between H. pylori, inflammation, and acid secretion. H. pylori infection can reduce acid secretion and increase inflammation via multiple intermediates. Increased production of IL-1β and TNF-α from inflammatory cells inhibits acid secretion from parietal cells. Acid secretion is also inhibited by repression of H⁺K⁺ ATPase α-subunit promoter activity, in addition to VacA-induced proteolysis of ezrin.

FIG. 3.

Pathways involved in regulation of macrophage iNOS synthesis and NO production in response to H. pylori. The translation of iNOS protein depends on the availability of l-arginine (l-Arg). Pathogenic mechanisms that inhibit l-Arg availability for iNOS include (i) the consumption of extracellular l-Arg by H. pylori itself, through its bacterial arginase activity; (ii) the upregulation of macrophage arginase II, which depletes intracellular l-Arg; and (iii) induction of ODC that generates the polyamine spermine, which blocks uptake of l-Arg into macrophages by CAT2. The resulting effect is limitation of iNOS protein synthesis and NO production, despite high levels of iNOS mRNA. Arginase and ODC are novel targets for therapeutic intervention to enhance antimicrobial NO production and hence reduce persistent colonization that leads to chronic inflammation and cancer risk.

FIG. 4.

Mechanism of macrophage apoptosis caused by H. pylori. This pathway is dependent on the activities of the enzymes arginase II, ODC, and SMO. Induction of arginase II enhances synthesis of l-ornithine, which is converted into polyamines by ODC via a process that requires both H. pylori activation of the ODC promoter and c-Myc as a transcriptional enhancer. Production of the polyamine spermine provides a substrate for SMO, which is also upregulated by H. pylori. SMO generates H₂O₂, which causes mitochondrial membrane depolarization, cytochrome c release from mitochondria to the cytosol, and caspase-3 activation, followed by apoptosis. Induction of macrophage apoptosis leads to impairment of mucosal immunity to H. pylori, chronic inflammation, and cancer risk (48, 50, 116).

FIG. 5.

Dysregulation of the apical-junctional complex by H. pylori. H. pylori preferentially adheres to the apical-junctional complex of epithelial cells and alters localization of apical-junctional component proteins, disrupts epithelial barrier function, cell adhesion, and cell polarity, and induces an invasive phenotype. Translocated CagA interacts with PAR1, preventing phosphorylation of PAR1 by blocking PAR1 kinase activity, which culminates in disruption of the tight junction. In addition, functional urease activity can disrupt the tight junction via a mechanism involving MLC phosphorylation, which can be regulated by MLCK and Rho kinase. VacA can also increase tight junction permeability to low-molecular-weight molecules and ions.