Pathways of Gastric Carcinogenesis, Helicobacter pylori Virulence and Interactions with Antioxidant Systems, Vitamin C and Phytochemicals

Abstract

Helicobacter pylori is a class one carcinogen which causes chronic atrophic gastritis, gastric intestinal metaplasia, dysplasia and adenocarcinoma. The mechanisms by which H. pylori interacts with other risk and protective factors, particularly vitamin C in gastric carcinogenesis are complex. Gastric carcinogenesis includes metabolic, environmental, epigenetic, genomic, infective, inflammatory and oncogenic pathways. The molecular classification of gastric cancer subtypes has revolutionized the understanding of gastric carcinogenesis. This includes the tumour microenvironment, germline mutations, and the role of Helicobacter pylori bacteria, Epstein Barr virus and epigenetics in somatic mutations. There is evidence that ascorbic acid, phytochemicals and endogenous antioxidant systems can modify the risk of gastric cancer. Gastric juice ascorbate levels depend on dietary intake of ascorbic acid but can also be decreased by H. pylori infection, H. pylori CagA secretion, tobacco smoking, achlorhydria and chronic atrophic gastritis. Ascorbic acid may be protective against gastric cancer by its antioxidant effect in gastric cytoprotection, regenerating active vitamin E and glutathione, inhibiting endogenous N-nitrosation, reducing toxic effects of ingested nitrosodimethylamines and heterocyclic amines, and preventing H. pylori infection. The effectiveness of such cytoprotection is related to H. pylori strain virulence, particularly CagA expression. The role of vitamin C in epigenetic reprogramming in gastric cancer is still evolving. Other factors in conjunction with vitamin C also play a role in gastric carcinogenesis. Eradication of H. pylori may lead to recovery of vitamin C secretion by gastric epithelium and enable regression of premalignant gastric lesions, thereby interrupting the Correa cascade of gastric carcinogenesis.

Keywords: CagA; Correa pathway; Helicobacter pylori; ascorbic acid; chronic atrophic gastritis; dietary salt; gastric cancer; glutathione; nitrosamines; oxidative stress; phytochemicals; vitamin C.

Figure 1

Pathways of H. pylori survival, chemotaxis, adhesion, colonization, virulence, inflammation, host immunotolerance, atrophic gastritis, oxidative stress, DNA methylation, cellular proliferation, EMT and oncogenesis in the gastric epithelium. H. pylori CagA injection causes disruption of E-cadherin and intercellular adhesion, loss of cell polarity, enhanced cell motility and development of the ‘hummingbird’ phenotype.

Figure 2

Age-standardized region-specific incidence (GLOBOCAN data) for gastric cancer in 2018. Adapted from Bray et al. (2018) with permission [1].

Figure 3

Contribution of environmental and intracellular (IC) sources of reactive oxygen species (ROS) with resulting oxidative stress and activation of oncogenes and inflammation. This can be modified by endogenous antioxidant systems, metal ion chelators and ingested phytochemicals including vitamin C (ascorbate) [30].

Figure 4

The redox potential of ascorbate. At the normal acidic gastric pH, secreted gastric ascorbic acid dissociates into ascorbate. Ascorbate can act as an antioxidant by reversible oxidation to DHA, and then be regenerated by glutathione-dependent DHA reductase back to ascorbate. DHA can be irreversibly oxidized to 2,3 di-keto-L-gulonic acid and thence excreted in the urine as oxalate.

Figure 5

Modern Correa pathway of intestinal-type gastric carcinogenesis, with risk factors and host mechanisms in green, molecular genetics in blue, and preventive factors in yellow. As histological changes progress, antioxidant systems and DNA repair mechanisms become less effective and the epigenetic effects of Helicobacter pylori infection and environmental carcinogens more difficult to reverse. AA: ascorbic acid; BMD: bone marrow derived; cdx: caudal type homeobox gene; c-erbB: human epidermal growth factor oncogene; CDH1: E-cadherin gene; GSH: glutathione; HPE: Helicobacter pylori eradication, LOH: loss of heterozygosity; SPEM: spasmolytic polypeptide-expressing metaplasia; TET1: ten eleven translocation methylcytosine dioxygenase 1 [6,19,26].

Figure 6

The three sources of DNA damaging hydroxyl radicals; from nitric oxide (NO) reacting with superoxide radicals to form peroxynitrite, from Fenton reactions with hydrogen peroxide (H₂O₂) and ferrous iron, or from superoxide reacting with hypochlorous acid (HOCl) from neutrophils. Nitric oxide synthase (NOS), Superoxide dismutase (SOD), NADPH oxidase (NOX), hydroxyl radical (OH·). Adapted from Knaapen et al. with permission [76].

Figure 7

Inhibition of H. pylori urease by vitamin C [137].

Figure 8

Odds ratios for risk factors and protective factors in gastric carcinogenesis (associations with 95% confidence intervals). Protective factors are shown in green (dark green, significant; light green, non-significant (NS)) and risk factors are shown in red (red, significant; orange, non significant). BMI: body mass index, EtOH: alcohol. Adapted from Poorolajal et al. [164].