Two-for-one gastric research result - plus a bonus

Take one gene, introduce two different mutations, and reproduce the symptoms of two major diseases of the digestive tract: gastric cancer and inflammatory bowel disease.

And in addition to that two-for-one result, Assoc Prof Andy Giraud of Melbourne University (Western Hospital) and Dr Matthias Ernst of the Ludwig Institute for Cancer Research have convicted a suspect gene that their US and Japanese peers had previously exonerated.

The gene, called gp130, specifies a receptor - a molecular switch - on the surface of cells that line the stomach bowel.

The receptor receives instructions from the immune system, borne by circulating cytokines - messenger molecules from the immune system that regulate two distinct genetic pathways involved in repair and regeneration of the stomach and bowel lining.

By creating two different strains of transgenic mice, Giraud and Ernst were able to explore the specific effects of mutations that disrupt these separate pathways.

The two pathways are involved in repairing and regenerating tissues - they are simultaneously active and work in harmony in normal cells to ensure tissues damaged by harsh substances in the diet are repaired. Cells must be able to grow and proliferate to replace damaged cells, but controlled proliferation can lead to cancer.

Giraud and Ernst created two different transgenic mouse strns to explore the consequences of disrupting the coordinated activity of the two genetic pathways controlled by the gp130 receptor. They showed that a point mutation - a single-letter change in the DNA code -that substitutes a 'wrong' amino acid in one section of the protein, processed tissue abnormalities resembling those observed in the early stages of human gastric cancer.

Common killer

Gastric cancer is the fourth leading cause of cancer deaths in Australia, and the second most common cause in south-east Asia. It is commonly lethal, because most patents are not diagnosed until after the cancer has spread elsewhere in the body.

Transgenic mice with only one copy of the gene are normal, but 100 per cent of mice inheriting the mutant gene from both parents developed early symptoms of gastric cancer by the age of six to eight weeks.

"Nobody suspected that interference with the messenger service engaged by gp130 could be linked with a 100 per cent prevalence of early stages of gastric cancer in mice," Dr Giraud said.

The cells of the stomach lining normally have only a limited capacity for repair and regeneration, suggesting that gp130 keeps the repair process under tight control - by disrupting the control, the point mutation allows cells to proliferate rapidly, which can lead to gastric cancer.

The other mouse strain has a deletion mutation that lops off the end of the gene, producing a truncated receptor molecule that replicates the symptoms of human inflammatory bowel disease (IBD), better known as Crohn's disease. Crohn's disease results in chronic, debilitating inflammation of the bowel lining, and increases a patient's lifetime risk of bowel cancer by around 10 per cent.

These mice had a reduced ability to repair tissue damage to the lining of the colon and rectum, resulting in chronic inflammation.

Giraud and Ernst will publish their findings next month in the international journal Nature Genetics. Their research overturns earlier US and Japanese studies that concluded gp130 was not a key player in either gastric cancer or inflammatory bowel disease.

Ernst said that while the gp130 gene is present in species as distantly related as man, mice and the fruit fly Drosophila - "In fact, it's the only cytokine-type receptor in the fruit fly, Drosophila, which lacks an immune system," Ernst said.

The fact that the gene differs only slightly in these distantly related species points to a crucial role in regulating cell growth and replication - and Ernst said that meant it was likely to be a player in human gastric cancer and IBD.

Ernst said that while the discovery may eventually led to therapies to prevent gastric cancer and IBD, its immediate importance was that it gave researchers an entry point to explore the genetic mechanisms involved in these diseases.

He said other receptors were known to regulate the same genetic pathways as gp130, so mutations involving the genes for these receptors, or genes within the pathways they control, may also be involved in human gastric cancer and IBD.

Crohn's a risk factor

Ernst said there was now "very good evidence" that Crohn's disease was itself a risk factor for bowel cancer.

He said further research would investigate whether the mice with the mutation that produced gastric cancer symptoms were more susceptible than normal mice to infection by Helicobacter pylori, the bacterium that causes most stomach ulcers.

Persistent Helicobacter infections in mammals damage and inflame the lining of the stomach, leading to chronic stomach ulcers - and human patients with chronic stomach ulcers have an increased risk of developing gastric cancer.