Streptococcal infection led to gastritis and stomach cancer in mice

Experiments in mice showed that Streptococcus anginosus caused acute gastritis, which rapidly progressed to chronic form and induced atrophy metaplasia and dysplasia of the gastric mucosa. In addition, the infection accelerated the progression of induced gastric cancer through cell proliferation and inhibition of apoptosis. According to a paper published in the journal Cell, these effects were mediated by the interaction between the bacterial surface protein TmpC and the annexin A2 receptor on gastric epithelial cells, which induced the activation of mitogen-activated protein kinase.

Gastric cancer is considered the fifth most common cancer and the leading cause of cancer-related mortality worldwide. The main risk factor for gastric cancer is Helicobacter pylori infection, which contributes to the development of gastritis, atrophy and intestinal metaplasia. However, among infected patients, only one to three percent eventually develop gastric cancer, due to which other risk factors are suspected to be involved.

Previously, scientists found that patients with gastric cancer had five pathogens present in their mouths that were associated with the tumor. Among these pathogens was the bacterium Streptococcus anginosus, which mainly inhabits the oral cavity, nasopharynx, gastrointestinal tract and vagina and can cause invasive purulent infections such as abscesses. Notably, S. anginosus is resistant to low pH conditions (3-5), which allows it to survive in the gastric mucosa. However, the role of the bacterium in gastric carcinogenesis and its pathogenic molecular mechanisms are largely unexplored.

Now, the same group of researchers led by Jun Yu (Jun Yu) from the Chinese University of Hong Kong has studied how S. anginosus affects the pathomorphology of the gastric mucosa of mice, including gnotobiotic mice. To do this, the scientists injected the bacterium into normal mice once every three days for two weeks, after which they showed persistent colonization in the basal region of the gastric mucosa. At the same time, 26 percent of the mice showed acute inflammation of the gastric mucosa, which was confirmed by infiltration with neutrophils in the submucosa. As a positive control, H. pylori caused mild to moderate inflammation in 44.5 percent of mice. PCR assays showed active induction of proinflammatory chemokines in streptococcus-infected mice. Remarkably, even with chronic infection, only gastric tissue was affected in the mice; it had no effect on body weight, appetite liver and kidney function and did not cause inflammation in the colon. Streptococcal and Helicobacter infection had synergistic pathologic effects on the gastric mucosa, including in the development of atrophic gastritis.

Gastric tumorigenesis follows the pattern of precancerous lesions in the sequence atrophy-metaplasia-dysplasia-dysplasia. Given that S. anginosus causes chronic gastritis, the researchers found that after nine months, infection resulted in mild atrophy of parietal cells, which progressed to moderate to severe atrophy after 12 months (p = 0.01). Mucinous metaplasia and mild dysplasia of the gastric mucosa and elevated pH were also observed in the mice after 12 months.

All these indicated that S. anginosus infection was capable of inducing a number of precancerous changes in the gastric mucosa with enhanced cell proliferation. Similar experiments with gnobiotic mice confirmed the direct pathogenic effect of the bacterium on the development of gastric tumors. Moreover, experiments with induced gastric cancer showed that the tumor weight (p = 0.03) and tumor-to-gastric weight ratio (p = 0.003) were much larger in mice with S. anginosus infection than in control mice.

Immunohistochemical studies demonstrated that S. anginosus alters the condition of gastric mucosal cells and affects the tumor microenvironment, promoting oncogenesis. To explain the underlying mechanism by which S. anginosus directly attaches to gastric epithelial cells and penetrates them, leading to tumor formation, the scientists attempted to identify bacterial adhesins that are able to bind to cell receptors. Mass spectrometry identified the surface lipoprotein TmpC, which functions as a purine nucleotide transporter. Genetic and biophysical studies showed that the complementary receptor to TmpC is the annexin A2 receptor: its depletion resulted in the absence of tumor cell changes. RNA analysis of gastric tissues of normal mice infected with S. anginosus showed that excessive activation of annexin A2 receptor leads to subsequent activation of MAP-kinases that increase the expression of p-ERK1/2, p-JNK and p-AKT - one of the main molecular mediators of carcinogenesis.

This is the first study to examine in detail the cellular and molecular mechanisms of carcinogenesis in the stomach during Streptococcus anginosus infection. Its results will help to develop the most effective and safe therapeutic approaches that can reduce the risk of gastric cancer in this infection.

However, earlier scientists found that the prevalence of Helicobacter infection has decreased worldwide, which may also lead to a decrease in the prevalence of gastric cancer.