interacção bactéria-hospedeiro na cancerização humana infecção por helicobacter pylori e...
TRANSCRIPT
Interacção bactéria-hospedeiro na
cancerização humana
Infecção por Helicobacter pylori e cancro gástrico
Céu Figueiredo
H. pylori
Chronic Superficial Gastritis
Gastric Carcinoma
Normal Gastric Mucosa
Host susceptibilityIL1B, IL1RN, TNFA
genotypes
Gastric carcinogenesis
H. pylori strain
virulencevacA s1m1, cagA+
Machado JC et al, Gastroenterology 2001Machado JC et al, Gastroenterology 2003
Figueiredo C et al, Am J Pathol 2001Figueiredo C et al, J Natl Cancer Inst 2002
• cagA is part of a 35-40 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
HP0520HP0547
cagA
cag PAI
H. pylori cagA and cag pathogenicity island (cag PAI)
Montecucco & Rappuoli, Nat Rev Mol Cell Biol 2001
Role of H. pylori virulence factors on epithelial cell responses and
signaling pathways relevant to gastric carcinoma development
Invasion Assays
Collagen type I gel
Cells + H. pylori
Matrigel
Collagen type I Matrigel
Cells + H. pylori
AGS 26695 60190 wt 60190 cagA- 60190 cagE- 60190 vacA- Tx30a0
50
100
150
200
250
300
350
400
450
500
No
. in
vasi
ve c
ells
*
**
**
* 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
*
To elucidate the effect of H. pylori on cell invasion
Control Hp26695 Hp+PD Hp+ZD Hp+NK40
1
2
3
4
5
6
7
8
9
10
*
Inva
sion
inde
x
**
* Significantly different from untreated cells** Significantly different from cells infected with H. pylori 26695
H. pylori strains containing a functional T4SS stimulate gastric cancer cell invasion, through a c-Met dependent signaling pathway
Control 26695 60190
**
** **N
o. in
vasi
ve c
ells
0
50
100
150
200
250
300
350
400
450
500
AGS + non-silenc. siRNA
AGS + siRNA c-Met
* Significantly different from untreated cells** Significantly different from cells transfected with non-silencing siRNA
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
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, and involving an increase
in MMP2 and MMP9 activity
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
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
FP6, Integrated projectINCA – The role of chronic infections in the development of cancerWP Leader: José Carlos Machado
ERA-NET PathogenomicsHELDIVNET – Parasite and host genetic diversity in Helicobacter infectionsWP Leader: José Carlos Machado
FP6, INCO Specific MeasuresCONTENT – Evaluation and Control of Neglected Mucosal Enteric Infections in ChildhoodWP Leader: José Carlos Machado
ERA-NET PathogenomicsRNAi-NET – A global RNAi approach to unravel eukaryotic host functions that modulate bacterial infectionsWP Leader: Céu Figueiredo
FCT - MCTESEffects of Helicobacter pylori on gastric epithelial cellsPI: Céu Figueiredo
