At the Bench: Helicobacter pylori, dysregulated host responses, DNA damage, and gastric cancer

Abstract

Helicobacter pylori infection is the strongest known risk factor for the development of gastric cancer. Given that ∼50% of the global population is infected with this pathogen, there is great impetus to elucidate underlying causes that mediate progression from infection to cancer. Recent evidence suggests that H. pylori-induced chronic inflammation and oxidative stress create an environment conducive to DNA damage and tissue injury. DNA damage leads to genetic instability and eventually, neoplastic transformation. Pathogen-encoded virulence factors induce a robust but futile immune response and alter host pathways that lower the threshold for carcinogenesis, including DNA damage repair, polyamine synthesis and catabolism, antioxidant responses, and cytokine production. Collectively, such dysregulation creates a protumorigenic microenvironment within the stomach. This review seeks to address each of these aspects of H. pylori infection and to call attention to areas of particular interest within this field of research. This review also seeks to prioritize areas of translational research related to H. pylori-induced gastric cancer based on insights garnered from basic research in this field. See related review by Dalal and Moss, At the Bedside: H. pylori, dysregulated host responses, DNA damage, and gastric cancer.

Keywords: DFMO; carcinogenesis; oxidative stress.

Figure 1.. Schematic summary of the interactions between H. pylori and innate and adaptive immune cells in the stomach.

H. pylori infection leads to IL-8 production, which may be dependent on CagA translocation. IL-8 is a chemoattractant that recruits neutrophils. H. pylori NapA and urease cause neutrophils to undergo an oxidative burst, exuding substantial amounts of ROS into the infected microenvironment. Moreover, NapA leads to increased survival in neutrophils, compounding their effects on oxidative stress. Macrophage iNOS is induced by urease during infection, leading to the production of NO, a RNS. As yet, undetermined H. pylori (HP) factors induce Arg2 activation in macrophages, resulting in apoptosis. ODC is also induced in macrophages during infection. This leads to downstream H₂O₂ production by SMOX and apoptosis. Moreover, H. pylori infection alters the cytokine milieu produced by DCs in favor of an increased T_reg response and a decreased Th1/Th17 response. Such alterations promote immune tolerance and persistence of the pathogen.

Figure 2.. Schematic summary of the pathways altered in gastric epithelial cells during H. pylori infection that lead to ROS production and DNA damage.

H. pylori CagA induces SMOX expression, leading to H₂O₂ production, which causes ROS accumulation and apoptosis. MDL 72527 inhibits SMOX and attenuates the deleterious effects of its activation. DFMO is a specific inhibitor of ODC, which also serves to decrease SMOX-mediated DNA damage and oxidative stress. DFMO exerts an inhibitory effect on H. pylori. ROS lead to various forms of DNA damage, including transversions, oxidative DNA damage (8-OHdG and 8-oxoG), and double-strand breaks (γH2AX). This, combined with H. pylori-mediated inhibition of DNA damage repair, leads to genomic instability within gastric epithelial cells. Subsequently, molecular alterations and neoplastic transformations occur, lowering the threshold for gastric carcinogenesis.