News Release

New insights into cause of stomach cancer

Peer-Reviewed Publication

University of Melbourne

Australian scientists have discovered a vital clue to the causes of stomach cancer and inflammatory bowel disease.

Stomach cancer is the fourth most common form of cancer death in Australia and the second most common in parts of South Asia including Japan and Korea. Until now, little was known about what caused this disease, which is difficult to treat and usually incurable.

The team's discovery, a collaborative effort largely between the University of Melbourne and the Ludwig Institute for Cancer Research in Melbourne, has identified the possible targets for the development of drugs to treat these diseases. The research will be published in the October edition of the journal, Nature Medicine.

Using mice, Dr Matthias Ernst at the Ludwig and Associate Professor Andy Giraud from the University of Melbourne (Western Hospital) found the clue when they made specific mutations to a molecule found on the surface of cells that is traditionally involved in helping regulate the body's immune system.

The receptor molecule called, gp130, acts as a molecular 'antenna', to transmit instructions to individual cells from soluble messenger molecules called cytokines found in the circulation and body fluids. This message service is what tells the cell how to respond to its environment.

Ernst and Giraud were surprised when the mice carrying mutations in gp130 developed cellular changes and other symptoms that mirrored those of gastric cancer and large bowel inflammation in humans.

Previous research in the USA and Japan has largely dismissed the regulatory role that gp130 plays in the protection of the digestive tract against stomach cancer and some forms of inflammatory bowel disease.

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

"Drug treatment is years away, but now that we have begun to unravel the molecular mechanisms underlying these diseases we can identify molecular targets to which pharmacological treatment can be directed in the future," he says.

It is known that a distinct family of cytokines bind to gp130 and activate at least two distinct intracellular signaling pathways that tell the cell exactly how to respond to the changing needs of the immune system and the repair and regeneration of tissues.

Ernst and Giraud were curious to find out what would happen when the two pathways were no longer activated simultaneously and in a coordinated fashion by mutating particular regions of the gp130 molecule.

Dr Ernst and his team at the Ludwig institute generated two sets of gp130 mutant mice. One set had a single amino acid change to the gp130 molecule. The other had a small chunk chopped off the end of the molecule. Each change altered the capacity of the gp130 receptor to activate one or the other intracellular signaling pathway.

Giraud and Ernst discovered that the single amino acid alteration induced cellular changes reminiscent of early gastric cancer in mice as young as 6-8 weeks.

The second set of mutant mice had reduced ability to repair damage in the colon and rectum making them highly susceptible to intestinal injury resulting in large bowel inflammation.

"The lining of the normal stomach has a natural capacity to undergo limited regeneration, but the gp130 mutation had obviously unlocked a cellular activity that is normally tightly regulated," says Ernst.

"The findings suggest that a fine balance exists between these two intracellular signaling pathways having evolved to fine tune, for instance, the cellular defense mechanism to deal with the harsh chemical and bacterial environment inside the gut," he says.

"What has been designed as a regenerative mechanism gets out of control in the stomach with one mutation while not being activated in the large bowel as a result of the other mutation.

"What we have yet to find is the cancer spreading to other organs. This metastatic process is what eventually kills patients. We are now trying to identify other gene mutations that enable metastatic progression of the disease in gp130 mice by breeding our mice with mice generated in other laboratories and carrying mutations in candidate genes.

"This work will enable us to piece together unambiguously the series of mutations that inevitably lead to metastatic gastric cancer."

Ernst and Giraud's colleagues from the Peter MacCallum Cancer Institute have already set up a study to find whether the mutations and genes involved in the gp130 mouse model are also affected in humans suffering from gastric cancer.

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