Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis

• Published in: Gut Vol. 67; no. 7; pp. 1247 - 1260
• Main Authors: Sierra, Johanna C, Asim, Mohammad, Verriere, Thomas G, Piazuelo, M Blanca, Suarez, Giovanni, Romero-Gallo, Judith, Delgado, Alberto G, Wroblewski, Lydia E, Barry, Daniel P, Peek, Richard M, Gobert, Alain P, Wilson, Keith T
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.07.2018
• Subjects: Activator protein 1; Animals; Antibiotics; Antineoplastic Agents - therapeutic use; Breast cancer; Carcinogenesis; Cell Culture Techniques; Chemokines; Clonal deletion; Cytokines; Deoxyribonucleic acid; DNA; DNA damage; Dysplasia; Epidermal growth factor; Epidermal growth factor receptors; Epithelial Cells; ErbB Receptors - antagonists & inhibitors; Gastric cancer; Gastrin; Gastritis - microbiology; Gastritis - pathology; Gastroenterology; Gefitinib; Gene deletion; Gerbillinae; Helicobacter Infections - pathology; Helicobacter pylori; Infections; Inflammation; Insulin; Kinases; Lung cancer; MAP kinase; Mice; Mice, Inbred C57BL; Mucosa; Peroxidase; Phosphorylation; Phylogeography; Protein kinase; Proteins; Quinazolines - therapeutic use; Stomach Neoplasms - microbiology; Stomach Neoplasms - pathology; Stomach Neoplasms - prevention & control; Transgenic mice; United States > US; EPIDERMAL GROWTH FACTOR; CHEMOPREVENTION; CHEMOKINES; GASTRIC CANCER; HELICOBACTER PYLORI
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2016-312888

ObjectiveGastric cancer is the third leading cause of cancer death worldwide and infection by Helicobacter pylori is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the H. pylori-induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis.DesignWe 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.ResultsIn 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.ConclusionsThese findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in H. pylori-infected individuals.