The role of inflammatory responses in mouse gastric tumorigenesis

Abstract

It has been established that chronic inflammation plays an important role in cancer development. The expression of cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin biosynthesis, is induced in most cancer tissues and plays a key role in tumorigenesis. Helicobacter pylori infection causes atrophic gastritis, which is associated with the induction of COX-2 expression and its downstream product, prostaglandin E2 (PGE2), biosynthesis. Transgenic mice expressing COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in the gastric mucosa show the generation of an inflammatory microenvironment via the activation of the COX-2/PGE2 pathway. Notably, simultaneous activation of canonical Wnt signaling and the COX-2/PGE2 pathway causes intestinal-type gastric tumor development, although Wnt activation alone is not sufficient for tumor formation. These results suggest that H. pylori infection-associated chronic inflammation contributes to gastric tumorigenesis through activation of the COX-2/PGE2 pathway. Using a gastric tumor mouse model (Gan mice), we found that the inflammatory microenvironment induces the activation of epidermal growth factor receptor (EGFR) signaling and promotes canonical Wnt signaling. Moreover, infiltrated macrophages express tumor necrosis factor-α (TNF-α) in gastric tumors, which plays an important role in tumor promotion through the induction of NADPH oxidase organizer 1 (NOXO1) expression. NOXO1 contributes to the production of reactive oxygen species (ROS) by the NOX1 complex, which is thought to be important for the maintenance of stem cell properties. These studies indicate that chronic inflammation promotes gastric tumorigenesis through a variety of mechanisms. Accordingly, targeting an inflammatory microenvironment should be an effective therapeutic or preventive strategy for gastric cancer.