Silja Wessler, PhD
Professor for Microbiology
Department of Biosciences
University of Salzburg
H. pylori in Inflammation and Cancer
Infections with the human pathogen and class-I carcinogen Helicobacter pylori (H. pylori) are strongly associated with the development of gastric cancer and lymphoma of the mucosa-associated lymphoid tissue (MALT) system. The knowledge of cellular and molecular mechanisms leading to carcinogenesis is still incomplete. The healthy and intact epithelium represents a functional barrier against pathogens. However, H. pylori developed fascinating strategies to depolarize the epithelium deregulating cancer-associated signal transduction pathways. Hence, our research is focused on the investigation of the interference of H. pylori with the complex signal transduction network in gastric epithelial and non-gastric host cells. Special emphasis lies on the experimental study of bacterial virulence factors that selectively interfere with the function of distinct signal transduction cascades and thus lead to (i) the loss of intercellular adhesion, (ii) enhanced epithelial cell motility, and (iii) deregulation of target genes with critical functions in the development and progression of gastric cancer and MALT lymphoma.
More than 70% of gastric cancer diseases are attributable to infections with the bacterial class-1 carcinogen Helicobacter pylori (H. pylori). Generally, a healthy epithelium is characterized by a complex architecture and forms an important protective barrier with tumor suppressive functions. However, H. pylori developed fascinating strategies to disrupt the epithelial barrier and consequently, to control cancer-associated signal transduction pathways. Hence, main focus of our research is the investigation of the cellular and molecular mechanisms of the sophisticated pathogen-host interaction that originate at the cell surface and deregulate intracellular signal transduction pathways, which result in a drastic depolarization of H. pylori-infected host cells. Special emphasis lies on the experimental study of bacterial virulence factors that selectively interfere with the function of distinct signal transduction cascades and thus lead to (i) the loss of intercellular adhesion, (ii) enhanced epithelial cell motility, and (iii) deregulation of target genes with critical functions in the development and progression of gastric cancer.
The H. pylori-secreted serine protease HtrA (high temperature requirement A) is a novel bacterial factor, which directly cleaves off the ectodomain of the cell adhesion protein E-cadherin and causes the loss of intercellular adhesions. Since E-cadherin also acts as an important tumor suppressor, our research focus lies on the functional consequences of HtrA-mediated E-cadherin cleavage and on pharmacological intervention strategies. Further, H. pylori expresses a type IV secretion system that injects the bacterial effector CagA (cytotoxin-associated gene A) into the host cytoplasm where it is phosphorylated by activated non-receptor tyrosine kinases of the Src and Abl families. This leads to drastic cell morphological changes and motility of epithelial cells, which also might contribute to the poor prognosis of the highly metastasizing gastric cancer.
Hoy B, Löwer M, Weydig C, Carra G, Tegtmeyer N, Geppert T, Schröder P, Sewald N, Backert S, Schneider G, Wessler S. Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep, 2010, 10: 798-804. IF: 7.8
Kwok T, Zabler D, Urman S, Rhode M, Hartig R, Wessler S, Misselwitz R, Berger J, Sewald N, König W, Backert S. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature, 2007, 449: 862-866. IF: 42.3
Hoy B, Geppert T, Böhm, M, Reisen F, Plattner P, Gadermaier G, Sewald N, Ferreira F, Briza P, Backert S, Schneider G, Wessler S. Distinct roles of secreted HtrA proteases from Gram-negative pathogens in cleaving the junctional protein and tumor suppressor E-cadherin. J Biol Chem, 2012, 287: 10115-10120. IF: 4.8
Schneider S, Carra G, Sahin U, Hoy B, Rieder G, Wessler S. Complex cellular responses of Helicobacter pylori-colonized gastric adenocarcinoma cells. Infect Immun, 2011, 79: 2362-2371. IF: 4.1
Helicobacter pylori – Signal Transduction in Inflammation and Cancer