Helicobacter pylori: gastric cancer and beyond

Abstract

Helicobacter pylori is the dominant species of the human gastric microbiome, and colonization causes a persistent inflammatory response. H. pylori-induced gastritis is the strongest singular risk factor for cancers of the stomach; however, only a small proportion of infected individuals develop malignancy. Carcinogenic risk is modified by strain-specific bacterial components, host responses and/or specific host-microbe interactions. Delineation of bacterial and host mediators that augment gastric cancer risk has profound ramifications for both physicians and biomedical researchers as such findings will not only focus the prevention approaches that target H. pylori-infected human populations at increased risk for stomach cancer but will also provide mechanistic insights into inflammatory carcinomas that develop beyond the gastric niche.

Western-type CagA proteins contain the phosphorylation motifs EPIYA-A, EPIYA-B and EPIYA-C (pink boxes). Conserved 16 amino acid repeat motifs (FPLKRHDKVDDLSKVG; green boxes) embedded within the 3′ terminus of CagA bind PAR1B and mediate the dimerization of CagA.

Figure 1. Helicobacter pylori VacA structure and functional effects

a | vacA is a polymorphic mosaic gene that arose through homologous recombination. Regions of sequence diversity are localized to the signal (s), intermediate (i) and mid (m) region. The s1 signal region is fully active, but the s2 region encodes a protein with a different signal peptide cleavage site, resulting in a short amino-terminal extension that inhibits vacuolation. The mid region encodes a cell-binding site, but the m2 allele is attenuated in its ability to induce vacuolation. The function of the i region is undefined. b | VacA is secreted as a 96 kDa protein, which is rapidly cleaved into a 10 kDa passenger domain (p10) and an 88 kDa mature protein (p88). The p88 fragment contains two domains, designated p33 and p55, which are VacA functional domains. c | The secreted monomeric form of VacA p88 binds to epithelial cells nonspecifically and through specific receptor binding. Following binding, VacA monomers form oligomers, which are then internalized by a pinocytic-like mechanism and form anion-selective channels in endosomal membranes; vacuoles arise owing to the swelling of endosomal compartments. The biological consequences of vacuolation are currently undefined, but VacA also induces other effects, such as apoptosis, partly by forming pores in mitochondrial membranes, allowing cytochrome c release. VacA has also been identified in the lamina propria, and probably enters by traversing epithelial paracellular spaces, where it can interact with integrin β2 on T cells and inhibit the transcription factor nuclear factor of activated T cells (NFAT), leading to the inhibition of interleukin-2 (IL-2) secretion and blockade of T cell activation and proliferation. AP1, activator protein 1; NF-κB, nuclear factor-κB; P, phosphorylation.

Figure 2. Interactions between pathogenic H. pylori and gastric epithelial cells

Several adhesins such as BabA, SabA and OipA mediate binding of Helicobacter pylori to gastric epithelial cells, probably through the apical surface. H. pylori can also bind to α₅β₁ integrins, which are located on the basolateral surface of epithelial cells. After adherence, H. pylori can translocate effector molecules such as CagA and peptidoglycan (PGN) into the host cell. PGN is sensed by the intracellular receptor nucleotide-binding oligomerization domain-containing protein 1 (NOD1), which activates nuclear factor-κB (NF-κB), p38, ERK and IRF7 to induce the release of pro-inflammatory cytokines. Translocated CagA is rapidly phosphorylated (P) by SRC and ABL kinases, leading to cytoskeletal rearrangements. Unphosphorylated CagA can trigger several different signalling cascades, including the activation of NF-κB and the disruption of cell–cell junctions, which may contribute to the loss of epithelial barrier function. Injection of CagA seems to be dependent on basolateral integrin α5β₁. AJ, adherens junction; CSK, c-src tyrosine kinase; IFN, interferon; IKKε, IκB kinase-ε; IRF7, interferon regulatory factor 7; RICK, receptor-interacting serine-threonine kinase 2; TBK1, TANK-binding kinase 1; TJ, tight junction.

Figure 3. Aberrant activation of β-catenin by Helicobacter pylori

a | Membrane-bound β-catenin links cadherin receptors to the actin cytoskeleton, and in non-transformed epithelial cells β-catenin is primarily localized to E-cadherin complexes. Cytoplasmic β-catenin is a downstream component of the Wnt pathway; in the absence of Wnt (upper panel), cytosolic β-catenin remains bound within a multi-protein inhibitory complex comprised of glycogen synthase kinase-3β (GSK3β), the adenomatous polyposis coli (APC) tumour suppressor protein and axin. Under unstimulated conditions, β-catenin is constitutively phosphorylated (P) by GSK3β, ubiquitylated and degraded. Binding of Wnt to its receptor, Frizzled (FRZ; lower panel), activates dishevelled (DSH) and Wnt co-receptors, low density lipoprotein receptor-related protein 5 (LRP5) and LRP6, which then interact with axin and other members of the inhibitory complex, leading to the inhibition of the kinase activity of GSK3β. These events inhibit the degradation of β-catenin, leading to its nuclear accumulation and formation of heterodimers with the transcription factor lymphocyte enhancer factor/T cell factor (LEF/TCF), resulting in the transcriptional activation of target genes that influence carcinogenesis. b | Injection of CagA results in the dispersal of β-catenin from β-catenin–E-cadherin complexes at the cell membrane, allowing β-catenin to accumulate in the cytosol and nucleus. CagA, potentially by binding MET or other H. pylori constituents such as OipA, VacA and peptidoglycan (PGN) as well as tumour necrosis factor-α (TNFα), which is produced by infiltrating macrophages, can activate PI3K, leading to the phosphorylation and inactivation of GSK3β. This liberates β-catenin to translocate to the nucleus and upregulate genes, leading to increased proliferation and aberrant differentiation; TNFR, TNF receptor.

Figure 4. Transactivation of EGFR by H. pylori and induced cellular consequences with carcinogenic potential

Helicobacter pylori transactivates epidermal growth factor receptor (EGFR) through cleavage, which is dependent on the a disintegrin and metalloproteinase (ADAM) family proteinases, of EGFR ligands, such as heparin-binding EGF-like growth factor (HBEGF) in gastric epithelial cells. One downstream target of EGFR transactivation is PI3K–AKT, which leads to AKT-dependent cell migration, inhibition of apoptosis and β-catenin activation. BAX, BCL-2-associated X protein; GSK3β, glycogen synthase kinase-3β; P, phosphorylation.