Inflammatory mediators and nuclear receptor signaling in colorectal cancer.

Long-term use of cyclooxygenase (COX) inhibitors (NSAIDs) in humans leads to a 50% reduction in risk for colorectal cancer. However, prolonged use of COX-2 selective inhibitors (coxibs) increases cardiovascular toxicity in some individuals, which highlights the importance of identifying all of the molecular targets that drive progression of colorectal cancer. Colorectal cancer offers a unique model to study the synergistic induction of intestinal neoplasia via dysregulation of multiple signaling pathways. Emerging evidence demonstrates that the peroxisome proliferator-activated receptor delta (PPARdelta) is a focal point of crosstalk between the signaling cascades involved in the progression of colorectal cancer. More importantly, activation of PPARdelta can promote tumor growth by inhibiting epithelial tumor cell apoptosis via a VEGF autocrine signaling loop. These findings may provide a rationale for the development of PPARdelta antagonists for cancer prevention and/or treatment.