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

Abstract

Objective Gastric 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. 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.

Helicobacter: Inflammation, immunology, and vaccines

“…18 This year, the Wilson group also showed that treatment of H. pylori-infected INS-GAS mice or Mongolian gerbils with the EGFR inhibitor gefitinib resulted in (a) reduced activation of MAPK1/3 and activator protein 1 in GECs, (b) inhibition of chemokine synthesis by the gastric mucosa, (c) a decrease in myeloperoxidase-positive inflammatory cells, and (d) a marked reduction of gastric dysplasia and carcinoma. 19 Of particular interest, similar data were obtained in mice with epithelial cell-specific deletion of Egfr (Egfr Δepi ) and key findings were recapitulated using culture of primary GEC monolayers of WT and Egfr Δepi mice. Altogether, these data prove that the recruitment of myeloperoxidase-positive inflammatory cells to the infected gastric mucosa is orchestrated by epithelial EGFR.…”

Pathogenesis of Helicobacter pylori infection

“…showed that gefitinib, a specific EGFR inhibitor, was able to decrease the epithelial DNA damage induced by H. pylori infection in C57BL/6 mice. Furthermore, it blocked H. pylori ‐induced activation of MAPK1/3 and AP‐1 in gastric epithelial cells and markedly reduced dysplasia and carcinoma in infected INS‐GAS mice and gerbils . This suggests that in H. pylori ‐infected individuals, epithelial EGFR blockage may represent a putative cancer preventive strategy.…”

Effect of vitamin D on Helicobacter pylori infection and eradication: A meta‐analysis

“…Previous study demonstrated that the CagA of H pylori activated various intracellular signaling pathways, including the NF‐κB pathway and MAP kinases via EGFR activation . In vitro, Sierra et al showed that a specific EGFR inhibitor was able to decrease the epithelial DNA damage induced by H pylori infection. It can be seen that EGFR plays a key role in the process of H pylori infection.…”