Development of Epstein-Barr virus-associated gastric cancer: Infection, inflammation, and oncogenesis

Figure 3 Interaction of Helicobacter pylori and Epstein-Barr virus in the formation of Epstein-Barr virus-associated gastric cancer. A: Infiltration of Epstein-Barr virus (EBV)-infected B lymphocytes in non-tumor areas of EBV-associated gastric cancer. Numerous CD20-positive B lymphocytes infiltrate the submucosal lesions of atrophic gastritis. CD20 is stained brown and EBV-encoded RNA (EBER) is stained purple. EBER-positive B lymphocytes are indicated by arrows. Chronic gastritis in the background is counterstained by Hematoxylin-Eosin staining; B: Induction of inflammatory cytokine production by bacterial adhesion to epithelial cells and tumorigenesis of EBV-infected epithelial cells. Helicobacter pylori adhesion induces production of inflammatory cytokines from gastric epithelial cells. Inflammation of gastric mucosa leads to an accumulation of various immune cells. EBV-positive B lymphocytes localized in the submucosa are activated by inflammation and transition from latent to lytic EBV infection. The viral particles produced are transferred to gastric epithelial cells, and the infected epithelial cells eventually form tumors; C: EBV transfer infection and tumorigenesis of epithelial cells via activated EBV-positive B lymphocytes. Infectious viral particles produced during inflammation adhere to CD21-positive B lymphocytes and transferred to epithelial cells expressing EBV coreceptors. Thus, gastric epithelial cells infected with EBV form Epstein-Barr virus-associated gastric cancers over time. EBV: Epstein-Barr virus; EBVaGC: Epstein-Barr virus-associated gastric cancer; Helicobacter pylori: H. pylori; EBER: EBV-encoded RNA.