Interacção bactéria-hospedeiro na cancerização humana

Transcription

1 Interacção bactéria-hospedeiro na cancerização humana Infecção por Helicobacter pylori e cancro gástrico Céu Figueiredo

2 Gastric carcinogenesis H. pylori Normal Gastric Mucosa Host susceptibility IL1B, IL1RN, TNFA genotypes Chronic Superficial Gastritis H. pylori strain virulence vaca s1m1, caga+ Machado JC et al, Gastroenterology 2001 Machado JC et al, Gastroenterology 2003 Gastric Carcinoma Figueiredo C et al, Am J Pathol 2001 Figueiredo C et al, J Natl Cancer Inst 2002

3 H. pylori caga and cag pathogenicity island (cag PAI) HP0520 cag PAI HP0547 caga caga is part of a kb chromosomal region, the cag PAI, present in some but not all H. pylori strains The cag PAI encodes a type IV secretion system (T4SS) responsible for the translocation of bacterial molecules into the host cell caga positive H. pylori strains are associated with more severe histopathologic features of chronic gastritis and increase the risk for gastric carcinoma development Montecucco & Rappuoli, Nat Rev Mol Cell Biol 2001

4 Role of H. pylori virulence factors on epithelial cell responses and signaling pathways relevant to gastric carcinoma development Invasion Assays Collagen type I Matrigel Cells + H. pylori Cells + H. pylori Collagen type I gel Matrigel

5 No. invasive cells To elucidate the effect of H. pylori on cell invasion * * ** ** 50 0 AGS wt caga cage vaca- Tx30a * Significantly different from untreated cells ** Significantly different from cells infected with H. pylori 60190wt H. pylori strains containing a functional cag pathogenicity island-encoded type IV secretion system (T4SS) stimulate gastric cancer cell invasion

6 Invasion index No. invasive cells To elucidate the signaling pathways involved in H. pylori-induced cell invasion AGS + non-silenc. sirna * * * AGS + sirna c-met ** ** ** 0 Control Hp26695 Hp+PD Hp+ZD Hp+NK4 0 Control * Significantly different from untreated cells ** Significantly different from cells infected with H. pylori * Significantly different from untreated cells ** Significantly different from cells transfected with non-silencing sirna H. pylori strains containing a functional T4SS stimulate gastric cancer cell invasion, through a c-met dependent signaling pathway

7 To elucidate the signaling pathways involved in H. pylori-induced cell invasion H. pylori strains containing a functional T4SS stimulate gastric cancer cell invasion, through a c-met dependent signaling pathway

8 To elucidate the signaling pathways involved in H. pylori-induced cell invasion * Significantly different from untreated cells ** Significantly different from cells infected with H. pylori 60190wt H. pylori strains containing a functional T4SS stimulate gastric cancer cell invasion, through a c-met dependent signaling pathway, and involving an increase in MMP2 and MMP9 activity

9 Conclusions H. pylori strains containing a functional T4SS stimulate gastric cancer cell invasion, through a c-met dependent signaling pathway, and involving an increase in MMP2 and MMP9 activity These findings may implicate H. pylori at later stages of gastric carcinogenesis If this is true, H. pylori eradication treatment should also be given to patients with dysplasia and early cancer

10 FP6, Integrated project INCA The role of chronic infections in the development of cancer WP Leader: José Carlos Machado ERA-NET Pathogenomics HELDIVNET Parasite and host genetic diversity in Helicobacter infections WP Leader: José Carlos Machado FP6, INCO Specific Measures CONTENT Evaluation and Control of Neglected Mucosal Enteric Infections in Childhood WP Leader: José Carlos Machado ERA-NET Pathogenomics RNAi-NET A global RNAi approach to unravel eukaryotic host functions that modulate bacterial infections WP Leader: Céu Figueiredo FCT - MCTES Effects of Helicobacter pylori on gastric epithelial cells PI: Céu Figueiredo

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