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Carcinogenesis Advance Access originally published online on September 10, 2008
Carcinogenesis 2008 29(12):2400-2405; doi:10.1093/carcin/bgn218
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Outer membrane vesicles enhance the carcinogenic potential of Helicobacter pylori

Kenny Chitcholtan1, Mark B. Hampton2 and Jacqueline I. Keenan1,*

1 Department of Surgery
2 Department of Pathology, University of Otago Christchurch, PO Box 4345, Christchurch 8140, New Zealand

* To whom correspondence should be addressed. Tel: +64 3 3640 570; Fax: +64 3 3641 427; Email: jacqui.keenan{at}otago.ac.nz

Chronic Helicobacter pylori infection is associated with an increased risk of gastric carcinogenesis. These non-invasive bacteria colonize the gastric mucosa and constitutively shed small outer membrane vesicles (OMV). In this study, we investigated the direct effect of H.pylori OMV on cellular events associated with carcinogenesis. We observed increased micronuclei formation in AGS human gastric epithelial cells treated with OMV isolated from a toxigenic H.pylori strain (60190). This effect was absent in OMV from strain 60190v:1 that has a mutant vacA, indicating VacA-dependent micronuclei formation. VacA induces intracellular vacuolation, and reduced acridine orange staining indicated disruption in the integrity of these vacuoles. This was accompanied by an alteration in iron metabolism and glutathione (GSH) loss, suggesting a role for oxidative stress in genomic damage. Increasing intracellular GSH levels with a GSH ester abrogated the VacA-mediated increase in micronuclei formation. In conclusion, OMV-mediated delivery of VacA to the gastric epithelium may constitute a new mechanism for H.pylori-induced gastric carcinogenesis.

Abbreviations: AO, acridine orange; BrdU, 5-bromo-2'-deoxyuridine; GSH, glutathione; OMV, outer membrane vesicles; PBS, phosphate-buffered saline

Received June 26, 2008; revised September 3, 2008; accepted September 6, 2008.


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