Uncovering the Role of H. pylori in Stomach Cancer

As the fifth most common cancer in the world, and with a ten year survival rate of around 15%, stomach cancer is responsible for a large proportion of global cancer deaths. An estimated 32% of cases in the UK are linked to infection with the bacteria Helicobacter pylori, but the underlying mechanisms behind this association are unknown.

Insights have recently been uncovered by an interdisciplinary team of researchers, who as part of recently published work, demonstrated the role that H. pylori plays in gastric stem cell renewal. We spoke to lead author, Professor Thomas Meyer from the Max Planck Institute for Infection Biology, to learn more about the study and its wider implications for the future diagnosis and treatment of stomach cancer. 

Anna MacDonald (AM): What led you to investigate the effects that H. pylori may have on gastric stem cells?

Thomas F. Meyer (TFM): We are interested in understanding the mechanisms by which H. pylori induces cancer. It is plausible that gastric cancer originates from adult cells in the stomach epithelium because of their renewal potential. However, other scenarios are also conceivable, e.g. involving more-differentiated cells. In order to distinguish between the various possibilities, it is necessary to know the principles of gland regeneration and homeostasis in greater detail. 

AM: Can you give us an overview of your findings?

TFM: We started from the idea that gastric gland regeneration is largely driven by Wnt signalling, which depends on the binding of two morphogenic proteins, Wnt and R-spondin. We analysed which cells in the gland respond to these factors and found – to our surprise – that it was not only the previously characterized Lgr5+ stems cells at the bottom of the gland, but also an even more distinct Lgr5- negative cell population slightly above. These Lgr5- cells reacted with a strong proliferative response to R-spondin and we could show that they are able to repopulate the whole gland and even reconstitute the bottom of the glands, if the Lgr5+ stems cells residing there are destroyed by a toxin. Thus, we identified two distinct stem cell types in the gastric glands, which can mutually replace each other, if the physiological conditions require. This mechanism of plasticity has implications on the preservation of mutations if a gland is affected by a pathogen such as H. pylori.

AM: What future work do you have planned?

TFM: We aim to get a better understanding of the equilibrium between different stem cell types in the glands. By disturbing the existing equilibrium, we will then be able to tell under which conditions mutations, like those predisposing to cancer, are preserved or cleared from the glands.

AM: What implications could your work have for the future of stomach cancer diagnosis and treatment?

TFM: In the future, genomics will play an important role in early diagnosis of disease. Once we know how mutations progress under pathological conditions in the stomach, we can get a better estimate of how seriously a patient is affected by a chronic H. pylori infection and initiate appropriate treatment. 

AM: Why has it been harder to prove the role that bacteria can play in causing cancer, compared to viruses?

TFM: Some viruses are well known for their transforming activity, even though the initial transformation event may have taken place years or decades before cancer emerged. Tumour viruses deposit part of their genome in infected host cells, and this virus DNA can be detected in the resulting tumour tissue, providing the link between the two events. This is not the case for carcinogenic bacteria, such as H. pylori. Instead, bacteria seem to transform host cells as a result of chronic colonisation - to draw firm causality, however, has been very difficult. Therefore, much more extensive and mechanistic studies – apart from supporting epidemiological evidence – are required to link any bacteria to carcinogenesis. 

AM: H. pylori is estimated to chronically infect half of all humans, but not all these people will go on to develop stomach cancer. What could be responsible for this?

TFM: Yes, not all people are chronically infected, and it is not entirely clear whether the non-infected half of the population just did not come into contact with H. pylori or whether at least some carry a natural resistance to infection. Similarly, only a minor fraction of infected people develop cancer and this may be due to both chance and genetic predisposition. In addition, the bacteria themselves may differ in their aggressiveness and their particular fit to their host. Many of these aspects of the relationship between pathogen and host may have an influence and we appear to be making progress in our understanding of this complex scenario, not only for H. pylori but also for other pathogenic bacteria that could be implicated in human cancer.

Thomas F. Meyer was speaking to Anna MacDonald, Editor for Technology Networks.