Bacteria can trigger stomach cancer: CRC 1340 - Matrix in Vision - Charité

Helicobacter pylori infection stimulates stem cells in stomach glands

Longitudinal section of gastric glands following infection with H. pylori. Cell walls are depicted in green, nuclei in blue. Image: Max Planck Institute for Infection Biology, Berlin.

Working with colleagues from the Max Planck Institute for Infection Biology and the Stanford School of Medicine, researchers from Charité – Universitätsmedizin Berlin have shown how Helicobacter pylori (H. pylori) infection could cause stomach cancer. For the first time, this study was able to show a direct link between H. pylori and an increase in stem cell regeneration within stomach glands. By increasing the number of cells with stem cell potential, the presence of the bacterium also increases the risk of pathological changes. This study has been published in the current edition of Nature*.

H. pylori infection is common, and is considered the most significant risk factor for the development of stomach cancer. While infection is known to trigger an increase in cell division in affected tissues, the underlying mechanism had previously remained unknown. It has now been unraveled by a team of researchers led by Dr. Michael Sigal (Charité's Medical Department, Division of Hepatology and Gastroenterology, and BIH Charité Clinician Scientist) and Prof. Dr. Thomas F. Meyer (Director of the Max Planck Institute for Infection Biology, Berlin). Gastric glands have a high regenerative capacity and renew themselves every 7 to 14 days. How a bacterial infection might produce long-term changes under such conditions has puzzled the researchers.

“At the base of the glands, however, there are long-lived stem cells, which continuously generate new cells,” explains Dr. Sigal. He adds: “In addition to identifying these cells, we also wanted to discover the processes which control their regeneration.” Stem cell characterization revealed that there are two different types of stem cells in the stomach, both of which are positive for the protein AXIN2. “We found that the cells directly below the glands produce a specific molecule known as 'R-spondin'. This molecule has a major effect on stem cells. It drives cell division in one type of stem cell, thereby increasing the speed of gastric gland regeneration,” says the researcher. Infection with H. pylori results in an increased production of R-spondin and increased stem cell activity. It is likely that a sustained high rate of stem cell proliferation promotes cancer formation.

As part of their study, the researchers used an animal model to characterize the stem cells of the stomach. Using highly-sensitive new techniques, they were able to produce high-resolution images of molecules within the stomach tissue. In addition to visualizing the molecules responsible for controlling stem cells, the researchers were also able to show their proximity to the stem cell populations. The researchers also used a model of H. pylori infection which recreates the precursor stages of cancer in humans, and conducted experiments using 'organoids' – cell cultures derived from stem cells harvested directly from the stomach tissue of both animals and humans.

While it has long been recognized that certain viruses can cause cancer by introducing genes into the host cell, bacteria are also being studied as potential causative agents – although the underlying mechanisms are rather less clear. Working with colleagues, the research teams led by Dr. Sigal and Prof. Meyer have now been able to break down the established dogma, which holds that bacterial infections only affect cells at the surface. “Helicobacter pylori causes a life-long infection, and increases the number of long-lived cells with stem cell potential within the glands of the stomach. The rate of stem cell division is increased, which eventually leads to pathological changes in the epithelium,” explains Dr. Sigal. Prof. Meyer adds: “This study gives us a better insight into the mechanisms which cause stomach cancer. It also provides more general information regarding the manner in which chronic bacterial infections disrupt normal tissue function and increase the risk of cancer.” Prof. Meyer and his colleagues have been studying the disease-causing potential of H. pylori and its effect on the surface epithelium of the stomach for many years. In years to come, the study's findings may contribute to the development of better treatment options.

*Michael Sigal, Catriona Y. Logan, Marta Kapalczynska, Hans-Joachim Mollenkopf, Hilmar Berger, Bertram Wiedenmann, Roeland Nusse, Manuel R. Amieva & Thomas F. Meyer (2017) Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis, Nature. doi:10.1038/nature23642.