WNT and cyclooxygenase-2 cross-talk accelerates adenoma growth.

Both Wnt and cyclooxygenase (COX-2) pathways are activated in most sporadic and familial colorectal cancers, especially in those with chromosomal instability. We have recently shown that a common target of both signaling pathways, the peroxisome proliferator-activated receptor (PPAR)-delta, is involved in intestinal adenoma growth. Activation of this receptor by synthetic agonist (GW501516) or COX-2-derived prostaglandin E2 (PGE2) accelerates intestinal adenoma growth in Apc(Min) mice. Moreover, these effects are lost in Apc(Min) mice lacking PPARdelta. These findings implicate PPARdelta as a focal point of cross-talk between the Wnt and prostaglandin signaling pathways. Based on this work it looks as if PPARdelta agonists currently in development for treatment of dyslipidemias and obesity may increase the risk of tumor formation in humans. By contrast, antagonists of PPARdelta may provide a novel approach for prevention and treatment of colorectal cancer.