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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-35393

Toller, I M; Altmeyer, M; Kohler, E; Hottiger, M O; Müller, A (2010). Inhibition of ADP ribosylation prevents and cures helicobacter-induced gastric preneoplasia. Cancer Research, 70(14):5912-5922.

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Abstract

Gastric adenocarcinoma develops as a consequence of chronic inflammation of the stomach lining that is caused by persistent infection with the bacterium Helicobacter pylori. Gastric carcinogenesis progresses through a sequence of preneoplastic lesions that manifest histologically as atrophic gastritis, intestinal metaplasia, and dysplasia. We show here in several preclinical models of Helicobacter-induced atrophic gastritis, epithelial hyperplasia, and metaplasia that the inhibition of ADP ribosylation by the small-molecule inhibitor PJ34 not only prevents the formation of gastric cancer precursor lesions, but also efficiently reverses preexisting lesions. PJ34 exerts its chemopreventive and therapeutic effects by impairing Helicobacter-specific T-cell priming and T(H)1 polarization in the gut-draining mesenteric lymph nodes. The subsequent infiltration of pathogenic T cells into the gastric mucosa and the ensuing gastric T cell-driven immunopathology are prevented efficiently by PJ34. Our data indicate that PJ34 directly suppresses T-cell effector functions by blocking the IFN-gamma production of mesenteric lymph node T cells ex vivo. Upon exposure to PJ34, purified T cells failed to synthesize ADP-ribose polymers and to activate the transcription of genes encoding IFN-gamma, interleukin 2, and the interleukin 2 receptor alpha chain in response to stimuli such as CD3/CD28 cross-linking or phorbol 12-myristate 13-acetate/ionomycin. The immunosuppressive and chemoprotective effects of PJ34 therefore result from impaired T-cell activation and T(H)1 polarization, and lead to the protection from preneoplastic gastric immunopathology. In conclusion, ADP-ribosylating enzymes constitute novel targets for the treatment of Helicobacter-associated gastric lesions predisposing infected individuals to gastric cancer and may also hold promise for the treatment of other T cell-driven chronic inflammatory conditions and autoimmune pathologies.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research

05 Vetsuisse Faculty > Institute of Veterinary Biochemistry and Molecular Biology
DDC:570 Life sciences; biology
Language:English
Date:July 2010
Deposited On:16 Aug 2010 08:43
Last Modified:05 Dec 2013 22:08
Publisher:American Association for Cancer Research
ISSN:0008-5472
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1158/0008-5472.CAN-10-0528
PubMed ID:20634404
Citations:Web of Science®. Times Cited: 12
Google Scholar™
Scopus®. Citation Count: 14

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