Gastric cancer ranks fifth among oncological diseases in terms of incidence and third in terms of cancer-related mortality worldwide. Every year, hundreds of thousands of people lose their lives due to this disease. Since gastric cancer is often diagnosed at advanced stages, treatment becomes difficult and the risk of death increases significantly.
Genetic predisposition, unhealthy dietary habits, Helicobacter pylori infection, smoking, alcohol consumption, and age are considered the main risk factors for the development of gastric cancer. However, among these factors, the most important and modifiable risk factor is Helicobacter pylori infection. H. pylori has been classified as a Group I carcinogen by the World Health Organization.
Helicobacter pylori is a gram-negative, spiral-shaped, microaerophilic bacterium that colonizes the gastric epithelium and is responsible for one of the most widespread bacterial infections worldwide. Although most individuals infected with H. pylori remain asymptomatic for a long time, gastritis eventually develops in almost all of them. When this chronic inflammatory process persists, it can lead to gastroduodenal ulcers, gastric carcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma.
H. pylori is mainly transmitted from person to person, and infection commonly occurs through the use of shared utensils and toothbrushes, as well as via the fecal–oral route. In addition, contaminated water and food products, as well as inadequately washed vegetables and fruits, may contribute to the spread of infection. Poor hygiene practices and inadequate sanitation are considered major risk factors for H. pylori transmission.
The exact mechanisms by which H. pylori causes gastric cancer are not fully understood, but it is believed that this bacterium damages the gastric mucosa, disrupts the regulation of gastric acid secretion, increases the production of inflammation-related cytokines, and induces genetic and epigenetic alterations. All these processes lead to cellular damage and abnormal cell growth, thereby increasing the risk of gastric cancer.
H. pylori infection activates a strong immune response in gastric epithelial cells and the mucosa. After epithelial cells recognize bacterial components, they secrete proinflammatory cytokines such as interleukin-8 (IL-8), IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α). These cytokines recruit neutrophils, macrophages, and lymphocytes to the site of infection. As a result, chronic active gastritis develops and a long-lasting inflammatory microenvironment is formed in the stomach.
Recruited immune cells produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) to eliminate the pathogen. However, these oxidizing agents damage not only the bacteria but also the DNA of gastric epithelial cells. ROS and RNS cause point mutations, DNA adduct formation, and single- or double-strand breaks, thereby increasing genetic instability. These processes play a crucial role in the initiation of carcinogenesis.
Virulence factors play a key role in the pathogenicity of H. pylori. The cytotoxin-associated gene A (CagA) protein enters epithelial cells and alters intracellular signaling pathways, increases cell proliferation, and disrupts intercellular junctions. Vacuolating cytotoxin A (VacA) causes cellular vacuolization, mitochondrial dysfunction, and functional impairment of T lymphocytes. These mechanisms promote uncontrolled cell division and weaken immune surveillance.
During chronic infection, H. pylori leads to destruction and atrophy of gastric glands. Intestinal metaplasia and dysplasia develop on the background of atrophic gastritis. This sequential pathological process is known as the Correa cascade and is considered the main pathway leading to gastric adenocarcinoma.
One of the intriguing questions is how Helicobacter pylori survives in the highly acidic environment of the stomach and how it evades the immune system to persist in the gastric mucosa for a long time. To survive in acidic conditions, the bacterium produces the enzyme urease. Urease breaks down urea in the stomach into ammonia, which neutralizes the surrounding environment and creates a protective microenvironment for the bacterium. This mechanism allows H. pylori to withstand the lethal effects of gastric acid.
H. pylori also possesses several mechanisms to evade the immune system. The bacterium produces antioxidant enzymes such as catalase, superoxide dismutase, and NapA to resist oxidative stress. The VacA toxin inhibits T-lymphocyte proliferation and function, thereby weakening the adaptive immune response. In addition, H. pylori induces antigenic variation and immunoregulatory cytokines, leading to a chronic but ineffective immune response, which enables the bacterium to persist in the gastric mucosa.
Long-term H. pylori infection results in chronic inflammation, oxidative stress, DNA damage, and disruption of intracellular signaling pathways, leading to genetic transformation of epithelial cells. Activation of oncogenes and inactivation of tumor suppressor genes result in malignant transformation of cells and the development of gastric cancer. Thus, H. pylori infection increases genetic instability in gastric epithelial cells through chronic inflammation and oxidative stress and promotes gastric adenocarcinoma development via virulence factors such as CagA and VacA that stimulate cell proliferation and immune evasion.
The significance of these mechanisms in humans has been confirmed by several studies. One such study was published in the New England Journal of Medicine on March 30, 2023. This Japanese study demonstrated that the combined effect of H. pylori infection and pathogenic mutations in DNA repair–related genes significantly increases the risk of gastric cancer.
Although Helicobacter pylori is often a silent bacterium, it can lead to serious and fatal consequences over time. Early detection and treatment of this bacterium play a crucial role in the prevention of gastric cancer. A healthy lifestyle and timely medical check-ups can save lives.
Referances:
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