From inflammation to gastric cancer: Role of Helicobacter pylori

Abstract

Gastric cancer is a multifactorial disease and a leading cause of mortality and the risk factors for this include environmental factors and factors that influence host-pathogen interaction and complex interplay between these factors. Gastric adenocarcinomas are of two types, namely intestinal and diffuse type, and Helicobacter pylori (H. pylori) infection has been suspected of being causally linked to the initiation of chronic active gastritis, which leads to adenocarcinoma of the intestinal type. Even though most individuals with H. pylori infection do not show any clinical symptoms, long-term infection leads to inflammation of gastric epithelium and approximately 10% of infected patients develop peptic ulcers and 1-3% of patients develop gastric adenocarcinoma. Among the several mechanisms involved in tumorigenesis, CagA and peptidoglycan of H. pylori, which enter the infected gastric epithelial cells play an important role by triggering oncogenic pathways. Inflammation induced by H. pylori in gastric epithelium, which involves the cyclooxygenase-2/prostaglandin E2 pathway and IL-1β, is also an important factor that triggers chronic active gastritis and adenocarcinoma. H. pylori infection induced oxidative stress and dysregulated E-cadherin/β-catenin/p120 interactions and function also play a critical role in tumorigenesis. Environmental and dietary factors, in particular salt intake, are known to modify the pathogenesis induced by H. pylori. Gastric cancer induced by H. pylori appears to involve several mechanisms, making this mode of tumorigenesis a highly complicated process. Nevertheless, there are many events in this tumorigenesis that remain to be clarified and investigated.

Keywords: Helicobater pylori; gastric cancer; inflammation.

Figure 1.

Interaction between host responses, changes in gastric mucosa and environment during gastric carcinogenesis induced by Helicobacter pylori (H. pylori). A combination of several host responses, bacterial pathogen-mediated events, and environmental factors contribute to the precancerous cascade that culminates in gastric adenocarcinoma.

Figure 2.

Tumor inflammatory microenvironment: Interplay of factors derived from H. pylori and tumor cells. A crosstalk between tumor cell-derived inflammatory factors and macrophage-derived factors during infection of Helicobacter pylori (H. pylori) results in aggravation of the inflammatory microenvironment and the tumor cells acquiring stem cell property and progression of tumor in gastric epithelium. Signaling through the TLR/MyD88/NF-κB pathways to activate cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE-2), release of cytokines such as TNF-α and production of ROS, in macrophages and in tumor cells facilitate this tumor inflammatory environment.