Abstract | OBJECTIVE: DESIGN: We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of H. pylori-induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of Egfr (EfgrΔepi mice) were also used. RESULTS: In C57BL/6 mice, gefitinib decreased Cxcl1 and Cxcl2 expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by H. pylori infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected EgfrΔepi versus Egfrfl/fl control mice. In H. pylori-infected transgenic insulin- gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked H. pylori-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from EfgrΔepi versus Egfrfl/fl mice. Epithelial EGFR activation persisted in humans and mice after H. pylori eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics. CONCLUSIONS: These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in H. pylori-infected individuals.
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Authors | Johanna C Sierra, Mohammad Asim, Thomas G Verriere, M Blanca Piazuelo, Giovanni Suarez, Judith Romero-Gallo, Alberto G Delgado, Lydia E Wroblewski, Daniel P Barry, Richard M Peek Jr, Alain P Gobert, Keith T Wilson |
Journal | Gut
(Gut)
Vol. 67
Issue 7
Pg. 1247-1260
(07 2018)
ISSN: 1468-3288 [Electronic] England |
PMID | 28473630
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/. |
Chemical References |
- Antineoplastic Agents
- Quinazolines
- ErbB Receptors
- Gefitinib
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Topics |
- Animals
- Antineoplastic Agents
(therapeutic use)
- Cell Culture Techniques
- Epithelial Cells
- ErbB Receptors
(antagonists & inhibitors)
- Gastritis
(microbiology, pathology)
- Gefitinib
- Gerbillinae
- Helicobacter Infections
(pathology)
- Helicobacter pylori
- Mice
- Mice, Inbred C57BL
- Quinazolines
(therapeutic use)
- Stomach Neoplasms
(microbiology, pathology, prevention & control)
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