New pathogen on the block: S. anginosus may promote gastric cancer

Streptococcus anginosus induces gastric inflammation, atrophy, and tumorigenesis in mice, researchers from the Chinese University of Hong Kong (CUHK) have reported.

“Although Helicobacter pylori infection is a known risk factor for gastric cancer, only 1─3 percent of infected individuals eventually develop gastric cancer, inferring the involvement of other contributing factors,” wrote the researchers. [Cell 2024;187:882-896.e17]

S. anginosus, a gram-positive bacterium that primarily resides in the oral cavity, nasopharynx, gastrointestinal tract and vaginal tract, can be found in the gastric mucosa of 50─70 percent of Chinese individuals, while the prevalence of H. pylori infection among the Chinese population is approximately 40 percent. Previous research revealed that S. anginosus is enriched in the gastric mucosa of patients with gastric cancer. [Gut 2018;67:1024-1032]

Expanding on their prior work, the researchers conducted metagenomic profiling of gastric mucosal samples from S. anginosus–infected mice across different stages of gastric tumorigenesis (ie, from superficial gastritis, atrophic gastritis, and intestinal metaplasia to gastric cancer).

Results showed that S. anginosus induced acute gastritis in mice after 2 weeks of infection, even at 1 year after H. pylori eradication. “S. anginosus is markedly resilient to low pH conditions [pH 3─5], which facilitates its survival in the gastric mucosa, and it can cause invasive pyogenic infections,” wrote the researchers.

Following 3 months of S. anginosus infection, the researchers noted chronic gastritis in mice, which persisted at 6 months, 9 months and 12 months. S. anginosus infection elicited levels of inflammation equivalent to that caused by H. pylori infection, especially at later time points, suggesting that long-term S. anginosus infection caused intensive chronic gastritis comparable with that after H. pylori infection.

Notably, S. anginosus provoked precancerous atrophy-metaplasia-dysplasia sequence and accelerated gastric tumorigenesis in mouse models. “The surface protein of S. anginosus [ie, TMPC] binds with Annexin A2 receptor [ANXA2] on gastric epithelial cells to elicit bacteria attachment, colonization, invasion, and downstream activation of oncogenic MAPK signalling,” explained Dr Kaili Fu of the Institute of Digestive Disease, CUHK. “Moreover, we found that S. anginosus impaired gastric barrier function, induced cell proliferation, and reshaped gastric tumour microenvironment to promote tumorigenesis.”

“Notably, coinfection of H. pylori and S. anginosus leads to an even higher risk of precancerous atrophy, metaplasia, or gastric cancer, indicating that the two pathogens may act collaboratively to promote gastric inflammation [and tumorigenesis],” highlighted co-corresponding author, Professor Joesph Sung of the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.

“H. pylori infection and family history are long recognized as the two main risk factors for gastric cancer,” commented Sung. “The discovery of enrichment of S. anginosus in the gastric mucosa across different stages of gastric cancer opens up a whole new direction in understanding the pathogenesis of gastric cancer.”

“The study has taken 5 years to complete, and its results have been published in Cell. This is the first CUHK-led study to be published in the journal,” pointed out co-corresponding author, Professor Jun Yu, Director of Institute of Digestive Disease, CUHK. Moving forward, the researchers will explore the therapeutic potential of targeting S. anginosus to reduce gastric inflammation and cancer risk.