How Helicobacter pylori causes gastric cancer

The international team of scientists headed by Dr. Nicole Tegtmeyer of the Chair of Microbiology at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) investigated how bacteria destroy the stomach's protective layer. This protective layer is composed of densely packed epithelial cells that protect the stomach against the effects of gastric acid. The researchers have now discovered that H. pylori secretes an enzyme, a protease called HtrA, which it uses much like a weapon to penetrate this protective layer. HtrA cleaves the three proteins occludin, claudin-8 and E-cadherin, rupturing the layer of epithelial cells. As a result, the H. pylori bacteria can access deeper, normally pathogen-free tissue layers, and inflict further damage. This is the first step towards gastric cancer starting to develop.

This first phase, however, is followed by one that is even more dangerous, as the team discovered. Needle-like protrusions, termed type IV secretion systems, are activated and function as 'molecular syringes'. Using a receptor-dependent mechanism, these inject a bacterial toxin, the CagA protein, through the basolateral membrane of the host cells. The injected CagA subsequently reprograms host cells, making them potentially cancerous. Another effect of this protein is that it prevents the human immune system from recognising and eliminating the bacteria -- a crucial mechanism for the long-term survival of H. pylori in the human stomach.

A new approach to treating gastric cancer

Dr. Tegtmeyer expects these findings will make it possible to develop important new antibacterial therapeutic approaches, as HtrA and CagA are ideal novel drug targets. The team has already started to test specific HtrA inhibitors. "We hope that suitable active agents can either completely prevent infection or inhibit the injection of CagA," explains Tegtmeyer.