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Cracking Gut Bugs' Cancer-Causing Strategy

13 December 2001 (All day)
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Haywire. By commandeering a signaling pathway, H. pylori causes cells to malform.

Most disease-causing bacteria were tracked down long ago, but for decades one microbe got away with murder. Discovered in 1982, Helicobacter pylori triggers ulcers and cancer that kill 7 million people each year, and scientists have learned much about the bug's ulcer-causing abilities. Now a new study clarifies H. pylori's more deadly talent, showing exactly how it forces stomach cells to deform and migrate--an early step in turning cancerous.

People infected with H. pylori are two to six times as likely as uninfected people to develop either stomach cancer or lymphoma. When H. pylori infects the stomach lining, stomach cells may elongate until they resemble hummingbird beaks. The microbe is known to inject a protein called CagA into the stomach cells, where it is tagged with phosphate groups. Because adding or removing phosphate from proteins can scramble cell signals and help induce cancer, scientists wondered if this was H. pylori's strategy.

To find out, molecular oncologist Masanori Hatakeyama of Hokkaido University in Sapporo, Japan, and his colleagues first made an educated guess about which human protein CagA interacts with inside stomach cells. They picked hepatocyte growth factor (HGF), because stomach cells treated with it look exactly like CagA-treated cells. The HGF receptor alters a signaling protein called SHP-2, and the group wondered whether CagA does too.

The scientists found that antibodies to CagA fish out SHP-2 from stomach cell extracts, and vice versa, indicating that the two proteins team up. What's more, cells infected with a mutated version of CagA that didn't bind SHP-2 helped CagA elongate the cells. They proved the point by showing that SHP-2 clips phosphates from additional signaling proteins, but only when it's bound to CagA. Together, these results mean that CagA plugs into the normal cellular signaling system, Hatakeyama says, leading the cell astray and putting it at risk of becoming cancerous.

Cellular microbiologist Brett Finlay calls the work "a major step forward" in explaining how H. pylori tweaks normal cell signaling pathways, nudging stomach cells one step closer to malignancy. Other experts emphasize that many of the molecular links between H. pylori and cancer remain to be discovered--but H. pylori investigators are closing in on their quarry.

Related sites

Facts on H. pylori infection from the CDC
More background on H. pylori, sponsored by the drug company AstraZenica
Information on H. pylori and ulcers from the National Institutes of Health
The benefits of H. pylori

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