The cellular and molecular mechanisms by which infection with the pathogen Helicobacter pylori results in the development of gastric cancer are being investigated. In vivo infection studies with isogenic mutant strains are evaluating the pathogenic role of bacterial virulence factors associated with induction of oncogenic signalling responses. The mechanism by which H. pylori transactivates the epidermal growth factor receptor (EGFR) in gastric epithelial cells is being investigated. Our earlier studies demonstrated that H. pylori induced EGFR transactivation is dependent on extracellular metalloprotease cleavage of pro-heparin binding epidermal growth factor (HB-EGF) and signalling by mature HB-EGF. The role of ADAM metalloproteases in this process is being examined, as well as ADAM expression in gastric cancer and gastric cancer pre-cancer lesions. On going studies are examining the effects of tyrosine kinase inhibitors (TKI) on H. pylori-induced signalling responses in vitro, and the chemopreventative effects of TKI on H. pylori-induced pathology and gene expression in an in vivo model.
In developing countries H. pylori infection rates are high and infection is acquired in the first two years. The CONTENT EU Framework 6 project, coordinated by Leeds together with Trinity College Dublin, examines the impact of H. pylori infection on childhood growth, diarrhoeal disease and iron deficiency in field populations in Latin America. Parallel studies using in vivo models are being undertaken in Leeds to examine the role of H. pylori infection on iron deficiency. Research is funded by the European Commission Framework 6 INCA and CONTENT projects and Leeds Teaching Hospital Trust.
Potential vicious cycle induced by childhood H. pylori infectionin developing countries. H. pylori infection and hypochlorhydria results in development of iron deficiency and acquistion of other enteric infections, promoting a vicious cycle of malnutrition and growth impairment. Polymorphisms in IL-1β gene cluster may control extent and duration of hypochlorhydria with initial H. pylori infection. From Windle et al ,Pediatrics 2007; 119, E754 - 759.
Windle HJ, Kelleher D, Crabtree JE. Childhood Helicobacter pylori infection and growth impairment in developing countries: a vicious cycle? Pediatrics 2007; 119, E754 - 759.
Wilson KT, Crabtree JE . Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies. Gastroenterology 2007; 133, 288 - 308.
Du Y, Danjo K, Robinson PA, Crabtree JE. In-Cell Western analysis of Helicobacter pylori induced phosphorylation of extracelluar-signal related kinase via the transactivation of the epidermal growth factor receptor. Microbes and Infection 2007, 9, 838 – 846.
Robins G, Crabtree JE, Bailey A, Forman D. International Variation in Helicobacter pylori Infection and Rates of Oesophageal Cancer. European Journal of Cancer 2008, 44, 726-732.
Lee G, Cama V, Gilman RH, Cabrera L, Saito M, Checkley W, the CONTENT Investigators. Comparison of two types of epidemiological surveys aimed at collecting daily symptoms in community-based longitudinal studies. Annals of Epidemiology 2010, 20, 151-158.