Reactive Oxygen Species and H. pylori Infection: A Comprehensive Review of Their Roles in Gastric Cancer Development

Abstract

Gastric cancer (GC) is the fifth most common cancer worldwide and makes up a significant component of the global cancer burden. Helicobacter pylori (H. pylori) is the most influential risk factor for GC, with the International Agency for Research on Cancer classifying it as a Class I carcinogen for GC. H. pylori has been shown to persist in stomach acid for decades, causing damage to the stomach's mucosal lining, altering gastric hormone release patterns, and potentially altering gastric function. Epidemiological studies have shown that eliminating H. pylori reduces metachronous cancer. Evidence shows that various molecular alterations are present in gastric cancer and precancerous lesions associated with an H. pylori infection. However, although H. pylori can cause oxidative stress-induced gastric cancer, with antioxidants potentially being a treatment for GC, the exact mechanism underlying GC etiology is not fully understood. This review provides an overview of recent research exploring the pathophysiology of H. pylori-induced oxidative stress that can cause cancer and the antioxidant supplements that can reduce or even eliminate GC occurrence.

Keywords: Helicobacter pylori; antioxidants; gastric cancer; inflammation; oxidative stress.

Figure 1

The role of ROS generation in gastric carcinogenesis. The prolonged presence of H. pylori in gastric mucosal cells leads to oxidative stress, chronic inflammation, and DNA damage. In addition, H. pylori facilitates the production of ROS and RNS using the host inflammation cells in the gastric mucosa. This results in mucosal damage via the activation of neutrophils, which releases the oxidative stressors that facilitate the exposure of gastric epithelium to reactive oxygen species. Even though ROS can be generated by various cells, including macrophages and epithelial cells, neutrophils generate the bulk of ROS. Recent research has indicated that H. pylori-induced ROS production may influence gastric epithelial cell signal transduction, which contributes to GC [23]. (O₂^•−: superoxide anion, ^•OH: hydroxyl radicals, H₂O₂: hydrogen peroxide, NH₃: ammonia, NH₂Cl: monochloramine, OCl⁻: hypochlorite ion, HOCl: hypochlorous acid, Cl⁻: chloride, H⁺: hydrogen ion, SOD: superoxide dismutase, Cu⁺: cuprous ion, and Fe²⁺: ferrous ion).

Figure 2

The signaling pathways involved in H. pylori-mediated ROS production in gastric cancer. As a result of H. pylori’s virulence factors, gastric epithelial cells undergo oxidative stress, which activates the inflammatory signaling pathways NF-κB (involved in inflammation and angiogenesis), PI3K/Akt/mTOR (cell proliferation), AMPK (AMPactivated protein kinase) (cell survival), PTEN/MAPK (apoptosis and inflammation), ERK (gene expression and cell proliferation), JAK/STAT3 (cytoskeleton arrangement and cell migration), and NF-κB-mediated NLRP3 inflammasomes. Consequently, pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and COX-2) are secreted into the gastric cancer cells, which lead to inflammation, cell cycle arrest, invasion, and migration.

Figure 3

H. pylori’s virulence factor in ROS-mediated gastric cancer. The virulence factors of H. pylori (CagA, VacA, NAP, OMV, and urease) induce ROS production and inflammatory signaling in host cells and maintain an alkaline environment in which to protect itself against the acidic pH of the host environment. CagA involved in activation of inflammatory pathways, VacA involved in autophagic mechanism, LPS mediates upregulation of cell invasion and migration, NAP involved in neutrophil-mediated inflammation, OMV involved in triggering immune response, and urease/antioxidant enzymes regulating the gastric oxidative stress level.

Figure 4

Antioxidant supplementation for H. pylori-induced gastric cancer. Various antioxidant-based drugs inhibit signaling pathways that facilitate proliferation, differentiation, metastasis, invasion, and migration. In gastric cancer, these substances reduced oxidative stress, increased antioxidant enzymes, promoted apoptosis, and arrested the cell cycle.