Helicobacter pylori infection and gastric cancer: from cause to cure
Session type: Parallel sessions
Leeds Institute for Molecular Medicine, University of Leeds, UK
Epidemiological evidence indicates that Helicobacter pylori has a key role in the development of both intestinal and diffuse type gastric carcinomas. The interaction of H. pylori with gastric epithelial cells and associated changes in epithelial gene expression and function are critical in generation of the inflammatory response and development of chronic gastritis. The risk of developing atrophic gastritis and gastric cancer with H. pylori infection is related to both strain variation and polymorphisms in host inflammatory response genes.
Strains with the cag pathogenicity island (PAI), which encodes a type IV secretory system, are associated with increased risk of atrophic gastritis and intestinal type gastric cancer. The cag PAI translocates peptidoglycan products into gastric epithelial cells which, via cytosolic NOD1, activate NFkB and upregulate proinflammatory genes such as IL-8. The CagA protein is also translocated via the cag PAI into epithelial cells where it is phosphorylated by host cell tyrosine kinases and disrupts epithelial tight junctions.
In addition H. pylori transactivates the epidermal growth factor receptor (EGFR) in epithelial cells. This is dependent on extracellular ADAM17 transmembrane metalloprotease cleavage of pro-heparin binding epidermal growth factor (proHB-EGF) and signalling by mature HB-EGF. Activation of this signalling pathway will promote gastric epithelial cell proliferation and decrease apoptosis. Experimental studies in a gerbil model indicate treatment with an EGFR inhibitor can modify H. pylori-induced gastric pathology and epithelial responses. The over expression of key elements of the EGFR signalling cascade such as HB-EGF and ADAM 17 membrane metalloproteases in patients with gastric cancer suggests the EGFR autocrine/paracrine signalling pathway induced by H. pylori is of pathophysiological relevance.
Recent studies indicate eradication of H. pylori significantly decreases the risk of developing gastric adenocarcinoma in infected individuals without pre-malignant lesions, providing strong evidence that this bacterium influences early stages in gastric carcinogenesis.