Science Spotlight

H. pylori infection accelerates events that lead to gastric cancer development

From the Salama Lab, Human Biology Division

Chronic infection with Helicobacter pylori (H. pylori) is a significant risk factor for gastric cancer. The host's immune response (chronic inflammation) coupled with H. pylori's activity (release of toxic virulence factors) are some of the mechanisms that initially promote cancer. However, by the time gastric cancer develops, the bacterium is only detected in about half the patients. The absence of the bacterium at this stage has obscured H. pylori's role in cancer progression once the initial oncogenic events have taken place. New research from the Salama Lab in the Human Biology Division suggests that –contrary to the prevalent hypothesis– H. pylori infection can impact the molecular course of cancer progression beyond the initial chronic inflammation observed in infected patients that eventually develop cancer.  

The study, recently published in the journal Life Science Alliance, was led by postdoctoral fellow Dr. Valerie O'Brien, a Cancer Research Institute Irvington Fellow. "The common hypothesis for how H. pylori leads to cancer is that H. pylori-driven inflammation promotes the accumulation of oncogenic mutations and activation of oncogenic pathways, which can lead to cancer development even if H. pylori infection is cleared by the host. In other words, H. pylori is essential for initiating mutagenic gastric inflammation, but once oncogenic pathways become activated, H. pylori is dispensable", said Dr. O'Brien. In the study, O'Brien and colleagues tested this idea by evaluating the effects of sustained H. pylori infection on the morphology of the stomach's mucosa, the tissue immune response, and gene expression in a mouse model that recapitulates the events preceding gastric cancer in humans.

Dr. O'Brien explained, "In this model, expression of active KRAS in the stomach rapidly leads to inflammation, metaplasia, and mild dysplasia. If H. pylori is disfavored by these cancer-associated tissue changes, as per the prevailing model, one might expect H. pylori infection to now be irrelevant. On the contrary, we show that H. pylori can colonize the stomach throughout the onset of these changes, and moreover that the addition of H. pylori changes the molecular nature of both metaplasia and inflammation, causes epithelial hyperproliferation, and accelerates dysplasia." The investigators first compared the effects of H. pylori in KRAS-expressing mice after 2-, 6-, and 12-weeks following infection. Using histology, the investigators scored the tissues for immunopathology markers, including inflammation, loss of parietal cells, and enlargement of the surface epithelium. In general, compared to KRAS alone, the immunopathology markers were worse in mice with H. pylori infection, suggesting a role for the bacterium in accelerating gastric cancer development. Gene expression analyses revealed that infected mice had more significant numbers of immune cells, congruent with the higher degree of inflammation observed in these mice.

The vast majority of gastric cancers are attributed to infection with the bacterium Helicobacter pylori. Induction of an active KRAS allele in the stomach leads to tissue changes and inflammation that are hallmarks of gastric pre-cancer. We found that the combination of H. pylori infection and active KRAS induction led to altered tissue states, increased inflammation and cell proliferation, and more severe disease. However, eradication of H. pylori with antibiotics prevented these tissue changes. Created with BioRender.com.
The vast majority of gastric cancers are attributed to infection with the bacterium Helicobacter pylori. Induction of an active KRAS allele in the stomach leads to tissue changes and inflammation that are hallmarks of gastric pre-cancer. We found that the combination of H. pylori infection and active KRAS induction led to altered tissue states, increased inflammation and cell proliferation, and more severe disease. However, eradication of H. pylori with antibiotics prevented these tissue changes. Created with BioRender.com. Image provided by Dr. Valerie O'Brien.

Further examination of the gene expression signatures showed a unique inflammatory signature in infected mice compared to KRAS expression alone, suggesting that H. pylori infection alters the trajectory of cancer progression. These findings were confirmed by identifying differences in immune cell subsets in infected mice using multiplex fluorescent immunohistochemistry. These changes were mostly dependent on sustained H. pylori infection as antibiotic eradication of the bacterium reversed the altered disease trajectory. Finally, Dr. O'Brien shared some of the questions raised by their findings: "Even though the majority of gastric cancers are attributed to H. pylori infection, about half of patients apparently clear their infection at some point prior to cancer diagnosis. Our findings suggest that H. pylori-positive tumors may be distinct from H. pylori-negative tumors, with altered molecular markers and inflammatory signatures. Thus, H. pylori-positive tumors may have unique therapeutic vulnerabilities that could be exploited. In future work, we will test our biorepository of gastric cancer cases to determine the extent to which our findings in mice translate to humans"

O'Brien, VP, Koehne, AL, Dubrulle, J, Rodriguez, AE, Leverich, CK, Kong, VP, Campbell, JS, Pierce, RH, Goldenring, JR, Choi, E, & Salama, NR. 2020. Sustained Helicobacter pylori infection accelerates gastric dysplasia in a mouse model. Life science alliance4(2), e202000967. https://doi.org/10.26508/lsa.202000967

Fred Hutch/UW Cancer Consortium members Nina Salama and Robert H. Pierce contributed to this study.

This work was supported by the Innovation Grant from the Pathogen-Associated Malignancies Integrated Research Center at FHCRC, grants from the National Institutes of Health, fellowships from the Cancer Research Institute and Debbie's Dream Foundation, and the Jacques Chiller Award from the Department of Microbiology, University of Washington.

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