▎ WuXi AppTec content team editor
Previous studies have shown that about 75% to 90% of gastric adenocarcinomas are associated with Helicobacter pylori (Hp) infection. In addition, about 5% to 10% of gastric adenocarcinomas are associated with Epstein-Barr virus infection. Although nearly 50% of the world's population is infected with Hp, only 1% to 3% of the population eventually progresses to gastric adenocarcinoma under the combined effects of Hp strains, host susceptibility, and chronic inflammatory responses.
Recently, Nature Reviews Gastroenterology & Hepatology published a blockbuster review detailing the important role of Hp in the formation of gastric adenocarcinoma. The paper emphasizes that early detection and eradication of Hp infection is crucial in preventing chronic gastritis from developing into gastric adenocarcinoma.
In addition, given that immunosuppressive features may already exist at the site of the host lesion several years before the formation of gastric adenocarcinoma, effectively identifying relevant marker changes in the process of gastric atrophy into gastric epithelial metaplasia may help us improve the level of prevention and treatment of gastric adenocarcinoma!
Screenshot source: Nature Reviews Gastroenterology & Hepatology
The main risk factor for gastric adenocarcinoma
Nearly 60% of the world's stomach cancer patients are in East Asia, and nearly half of them are in China. Recent studies have confirmed that hp infection is a strong associative factor in both non-cardia gastric cancer (including gastric adenocarcinoma) and cardia gastric cancer. In addition, other environmental risk factors for gastric adenocarcinoma include a high-salt diet and nitrate exposure. Genetic studies have shown that about 50% of gastric adenocarcinomas are chromosomally unstable gastric adenocarcinomas, and 21% are highly microsatellite unstable (MSI-H) gastric adenocarcinomas.
The vast majority of people with Hp infection have no obvious symptoms, and at least 20% of infected people have difficulty eradicating Hp infection with antibiotic treatment due to bacterial resistance and lack of treatment adherence. The paper highlights that nearly 20% of people infected with Hp may experience serious complications (including gastric atrophy, gastric metaplasia, and gastric adenocarcinoma) under the combined effect of multiple risk factors.
Specifically, these factors include:
Environmental factors: such as smoking or tobacco exposure;
Dietary factors: such as more intake of smoked foods, more intake of high-nitrate foods, high-salt diet;
Host susceptibility: such as genetic variation (including gene polymorphisms of cytokines such as IL-1β, TNF-α), iron deficiency, and blood type O.
How does Hp drive the development of gastric adenocarcinoma?
About 75% to 90% of patients with gastric adenocarcinoma show positive serum Hp. Previous studies have shown that Hp infection is associated with persistent immune infiltration (chronic gastritis), and changes in the immune microenvironment caused by Hp infection (changing the host's innate immunity, adaptive immunity to build an immunosuppressive environment) play an important role in the development of chronic gastritis into gastric adenocarcinoma.
In addition, Hp can also induce the occurrence of related pathological events by regulating vacuolar toxin-related factor A (VacA) and cytotoxin-related factor A (CagA).
Similar to many other solid tumors that originate in epithelial cells, different types of cells in the support structure around gastric tumors can play a variety of roles in their growth as initiators, promoters, and promoters, including stromal cells, neuronal cells, endothelial cells, and a large number of immune cells.
The paper emphasizes that it is not clear which immune cells in Hp-related gastric cancer are involved in the transformation of normal gastric epithelial cells into metaplasia and dysplasia.
▲The type of immune cells that Hp infection recruits at the site of the stomach lesion (Image source: Reference[1])
The presence of Hp can be found at different stages of disease progression in patients with gastric adenocarcinoma. In addition to Hp, studies have shown that the presence of Prevo bacteria, streptococcus, Pseudomonas, Sphingosine monocytogenes, Bacillus, and Acinetobacter can also be found in normal mucous membranes adjacent to gastric tumors.
In addition, animal studies have shown that Acinetobacter spp. can induce gastritis and elicit a TH1 immune response, while there is also an increase in the level of Bacteroides and Haemophilus related markers in the blood circulation of patients with gastric adenocarcinoma.
Therefore, although Hp may have mediated the initial process of gastric adenocarcinoma, after the atrophy of the gastric mucosa, what role Hp, other bacteria and immune cells play in the development of gastric metaplasia and gastric adenocarcinoma remains to be further explored.
What is the significance of Hp early detection and eradication?
The persistence of chronic gastritis can promote apoptosis of gastric parietal cells and cause chronic atrophic gastritis. The human body can go from Hp infection to serious complications such as gastric atrophy, gastric metaplasia and even gastric adenocarcinoma, which can take months or years. During this period, the gradual reduction of acid-secreting gastric wall cells reduces the level of gastric acid and affects the composition of the gastric microorganisms.
Although only a small percentage of people with Hp infection develop clinically significant complications. However, hp-based infection plays a key role in driving the development of gastric adenocarcinoma, so early detection, eradication, and even prevention of hp infection are important.
A key node in the development of gastric adenocarcinoma
Because the expression of neoplastic antigens in EBV-positive gastric adenocarcinoma and MSI-H gastric adenocarcinoma makes it more likely to produce a higher degree of inflammatory response (i.e., "hot tumor"), it is more likely to produce an effect under chemotherapy combined with immunotherapy regimens.
In contrast, most of the gastric adenocarcinoma subtypes, such as diffuse gastric adenocarcinoma with genetic variations, and intestinal gastric adenocarcinoma driven by Hp infection, are "cold tumors" from an immunological point of view. Hp may contain immunomodulatory sequences that promote immunosuppression by inducing Treg cells. In addition, there may be an immune evasion mechanism in Gastric adenocarcinoma associated with Hp infection, so anti-tumor immunotherapy is clearly ineffective.
The paper points out that gastric epithelial cell metaplasia (including degree and type) is a key node in the development of gastric adenocarcinoma.
Since the immunosuppressive environment of the stomach may already exist years before the diagnosis of gastric adenocarcinoma, a more in-depth study of the inhibitory factors of the immune response during Hp infection, exploring the molecular changes that occur during the transformation of gastric atrophy into a key node between the metaplasia of the gastric mucosa, may help us develop biomarkers to detect epithelial changes early and improve the level of treatment of gastric adenocarcinoma.
In addition, on this basis, to identify the possible risk factors of the host, we are expected to predict which part of the individual has a higher risk of complications in the future, and effectively prevent gastritis from developing into gastric adenocarcinoma.