Helicobacter pylori and Gastric Cancer: Adaptive Cellular Mechanisms Involved in Disease Progression

Abstract

Helicobacter pylori (H. pylori) infection is the major risk factor associated with the development of gastric cancer. The transition from normal mucosa to non-atrophic gastritis, triggered primarily by H. pylori infection, initiates precancerous lesions which may then progress to atrophic gastritis and intestinal metaplasia. Further progression to dysplasia and gastric cancer is generally believed to be attributable to processes that no longer require the presence of H. pylori. The responses that develop upon H. pylori infection are directly mediated through the action of bacterial virulence factors, which drive the initial events associated with transformation of infected gastric cells. Besides genetic and to date poorly defined environmental factors, alterations in gastric cell stress-adaptive mechanisms due to H. pylori appear to be crucial during chronic infection and gastric disease progression. Firstly, H. pylori infection promotes gastric cell death and reduced epithelial cell turnover in the majority of infected cells, resulting in primary tissue lesions associated with an initial inflammatory response. However, in the remaining gastric cell population, adaptive responses are induced that increase cell survival and proliferation, resulting in the acquisition of potentially malignant characteristics that may lead to precancerous gastric lesions. Thus, deregulation of these intrinsic survival-related responses to H. pylori infection emerge as potential culprits in promoting disease progression. This review will highlight the most relevant cellular adaptive mechanisms triggered upon H. pylori infection, including endoplasmic reticulum stress and the unfolded protein response, autophagy, oxidative stress, and inflammation, together with a subsequent discussion on how these factors may participate in the progression of a precancerous lesion. Finally, this review will shed light on how these mechanisms may be exploited as pharmacological targets, in the perspective of opening up new therapeutic alternatives for non-invasive risk control in gastric cancer.

Keywords: Helicobacter pylori; autophagy; endoplasmic reticulum stress; gastric cancer; inflammation; oxidative stress; precancerous lesion.

Figure 1

Schematic illustration of our current understanding of adaptive cellular mechanisms triggered upon H. pylori infection, including ER stress and the UPR, autophagy, oxidative stress, and inflammation, indicating how they may participate in precancerous lesion progression. Responses in host gastric epithelial cells located in the gastric pits triggered upon H. pylori infection are attributable to the action of bacterial virulence factors. ER stress associated with H. pylori infection, leads to an increase in BiP, suggesting that H. pylori-induction of ER stress is relevant in early stages of GC precancerous lesions. The ER stress sensor PERK may also facilitate tumor development by increasing the migratory and invasive potential of gastric cells. Unresolved ER stress results in apoptosis. ER-stress induced apoptosis is mediated by the transcription of CHOP, leading to expression of the pro-apoptotic proteins Bim and Bax. Moreover, H. pylori benefits from NF-κB activation and negatively regulates apoptosis via A20 deubiquitinylase activity, thereby promoting persistence of the infection. Inhibition (or activation) of autophagy, resulting in accumulation of autophagosomes within the cell at the beginning of the precancerous cascade are depicted as increasing ROS production leading to persistent oxidative stress, which in turn promotes the acquisition of characteristics, favoring invasion and metastasis. Long-term inflammation of the gastric mucosa generates significant amounts of nitric oxide (NO), which alters the transcriptional regulation in gastric cells by increasing DNA methyl transferase activity. The resulting hypermethylation of gene promoter sequences leads to epigenetic changes in gene expression. Additionally, NF-κB target genes include those representing polymorphisms associated with an increased risk for GC in patients, such as TNFα, IL-1β, and IL-8. Gastric cells produce ROS in response to H. pylori infection by inducing pro-oxidant activities, such as the host spermine oxidase, NADPH oxidase or generating ROS from mitochondria following activation of TLR4 signaling.