March 29, 2010

Feedback loop explains cancer link

Signals released by immune cells during a bout of inflammatory bowel disease interfere with intestinal cells’ ability to regenerate. Yet people with inflammatory bowel diseases have a significantly higher risk of developing colon cancer: a hyper-activation of growth in those same intestinal cells.

Emory researchers have identified a feedback loop involving a growth-regulating circuit in intestinal cells, which helps explain these apparently contradictory observations. The findings also suggest that interfering with one component of the feedback loop may aid in controlling inflammatory bowel diseases.

The results were published in the March 26 issue of the journal Immunity.

Pathologist Asma Nusrat and her colleagues examined mice treated with a chemical, dextran sulfate, which gives them colitis. When they treated intestinal cells in dishes with inflammatory cytokines they identified in the living animals, the cells had a burst of growth but then started to die out after three days.

Nusrat’s team found that prolonged exposure to inflammatory cytokines induces intestinal cells to give off a protein called dickkopf, which eventually kills the cells.

Dickkopf inhibits a regulatory circuit, collectively known as the Wnt pathway, which controls the growth of intestinal epithelial cells. Most colon cancer cells have mutations in their DNA that push this circuit into overdrive. However, the circuit has to work at a moderate level or intestinal cells will not grow.

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