Researchers: Professor Susan Watson, Professor John Atherton, Professor Christopher Hawkey, Professor John Scholefield, and Professor Richard Logan, University of Nottingham

Programme Grant

Grant Total: £350,000

The purpose of the grant was to help fund the establishment of an Institute to pioneer the development and use of ways that will quickly identify patients with conditions likely to lead to cancer of the oesophagus (gullet), the stomach, and the large bowel or colon, and to develop means of stopping these dangerous cancers occurring.

The collaborative research team confirmed that the hormone gastrin (a circulating "chemical messenger") can increase the growth of stomach and bowel cancer cells growing in the test tube. Gastrin levels are increased in patients whose stomachs are infected with a bacterium called “Helicobacter pylori”. Infection of the stomach with certain types of H. pylori has been shown to cause stomach cancer. The researchers developed a "vaccine" that blocks the action of gastrin. It now plans to test the vaccine in patients with pre-cancerous conditions to see if it can reduce the risk of these patients developing cancer.

Core’s funding for this project ended in 2006. Here is and extract from Professor Watson’s final report.

Research Aims

• To identify patients at risk of developing gastric or colorectal cancer.
• To investigate a role for the hormone (chemical messenger in the body) gastrin, in gastric and colorectal cancer development.
• To investigate the role of aspirin in combination with anti-gastrin therapies as a potential treatment for patients with gastric or colorectal cancer.
• To investigate the role of Helicobacter pylori (H. pylori) in gastric cancer
• To develop screening tests for potential stomach cancer-causing strains of H. pylori.
• To see whether gastrin encourages H. pylori growth and expression of disease-causing factors.

Results of Research

• After trying several approaches, we eventually developed an accurate blood test for showing whether people are infected with H. pylori expressing the dangerous (m1) or less toxic (m2) forms of the VacA toxin. An interesting and unexpected finding was that many people appeared to be infected with both m1 and m2 strains. We studied this further and showed that in some cases strains were evolving in people’s stomachs to become more or less toxic. We think this is very important for trying to work out who will get either ulcers or cancer from H. pylori infection and in developing the best way of treating people to prevent disease.     

• Although cancer-associated strains are usually of the VacA m1 type, in China they are of the m2 type. Our preliminary work suggested that this was a different type of m2 VacA which was more toxic and we did experiments in which we identified the changes in the toxin gene responsible for this and proved that these changes make some more able to cause cancer. We called these types i1. Next we developed a molecular test one can do on the bacterium to show whether it is this toxic i1 type. Finally, we showed that this test was useful for looking at strains, that it correctly predicted which strains were toxic, and that as we had expected, m2 strains from parts of China where stomach cancer is common were all of this toxic i1 type.

• We repeated a previous published study showing that the human hormone gastrin encouraged growth of H. pylori and showed that it was inconsistent and that in fact, in the strains we looked at, there was no effect on growth or toxin production. However, at this time several reports showed that the human stress hormones adrenaline (A) and noradrenaline (NA) were growth factors for several bacteria, and given the well-recognised association between stress and peptic ulceration we explored this in H. pylori. We showed that A/NA did promote growth and toxin production in H. pylori – a fascinating finding of potential importance both for how ulcers form and how H. pylori survives for a long time in the human stomach to cause cancer. This work is continuing and we are currently examining the underlying mechanisms. We are hoping to use the data we generate in further grant applications.

• We have derived panels of mutants from three wild-type H. pylori strains reported by other groups to colonise Mongolian gerbils. These are the NCTC 11637, SS1 and B128 7.13 strains. The mutants are deficient for the major virulence-associated genes vacA, cagA and cagE. Since the wild-type strains are reported to differ in their capacity to elicit gastric pathology, we have conducted pilot experiments in gerbils to determine the strain which colonised most consistently and elicited the strongest inflammatory response and highest serum gastrin concentration. Our pilot experiments also enabled us to optimise our methodology and investigate the effects of gerbil gender (reported by others to influence the response to infection) and the optimal time post-infection for detecting hypergastrinaemia and various stages of inflammatory and pre-cancerous pathology in the stomach.

• Using pre-cancerous human patient samples from the bowel and stomach a number of proteins including gastrin, COX-2 and the gastrin/CCK-2 receptor, which are expressed at higher levels in pre-malignant colorectal lesions have been identified and shown to be over-expressed compared to normal cells from the same sites. Expression of these potential early cancer markers will now be investigated in the context of early gastric cancer lesions including atrophic gastritis and intestinal metaplasia. In vivo models of intestinal metaplasia have shown that anti-gastrin therapy can decrease intestinal cell proliferation rates and significantly increase survival times, particularly in combination with a COX-2 inhibitor.  Additionally, measurements in the laboratory have shown that anti-gastrin agents can increase the efficacy of aspirin as an anti- cancer drug. A number of larger studies based on these findings are currently being evaluated or awaiting completion.

Implications for future prevention, treatment or cure

• From these findings we can suggest that aspirin or COX-2 inhibitors, in combination with anti-gastrin therapies represent a potential new treatment of gastric and colorectal pre-cancerous changes. Putative cancer markers have also been identified in pre-malignant bowel and stomach lesions.

• We can screen for the most toxic strains of H. pylori which are known to be most likely to cause cancer, using a simple blood test. This paves the way for large studies to examine exactly how important the most toxic strains are in causing cancer. However it probably could not be used as a useful test in individual patients as so many have both toxic and non-toxic strains, and so we will further examine this co-infection scenario.

• Strains can evolve within peoples’ stomachs to become more or less toxic. We need to understand this better and see how common it is, but it may mean that all strains can potentially cause disease as all could evolve to become more toxic, and thus when we are thinking of community treatment or vaccination programmes we should consider all strains, not just the toxic ones.

• We have also identified a new feature of the toxin gene in H. pylori which is responsible for differences in toxicity. We can now test strains to see whether they have this feature and this may help in developing community management strategies for H. pylori.

• Adrenaline and noradrenaline are released during stress and smoking and the finding that these cause H. pylori to grow and produce disease-causing factors potentially provides the missing link between stress and peptic ulceration. It also may contribute to ulcers in intensive care where patients are sometimes given adrenaline and noradrenaline intravenously. More research is needed to see whether this is the case. This may eventually have implications for managing H. pylori infection in smokers, stressful situations and on intensive care units. Perhaps most importantly it may provide a model by which stress influences other diseases in which bacteria play a role such as inflammatory bowel disease and irritable bowel syndrome.