Crosstalk between peroxisome proliferator-activated receptor δ and VEGF stimulates cancer progression

Peroxisome proliferator-activated receptor (PPAR) delta is a member of the nuclear hormone receptor superfamily. PPAR delta may ameliorate metabolic diseases such as obesity and diabetes. However, PPAR delta's role in colorectal carcinogenesis remains controversial. Here, we present genetic and pharmacologic evidence demonstrating that deletion of PPAR delta decreases intestinal adenoma growth in Apc(Min/+) mice and inhibits tumor-promoting effects of a PPAR delta agonist GW501516. More importantly, we found that activation of PPAR delta up-regulated VEGF in colon carcinoma cells. VEGF directly promotes colon tumor epithelial cell survival through activation of PI3K-Akt signaling. These results not only highlight concerns about the use of PPAR delta agonists for treatment of metabolic disorders in patients who are at high risk for colorectal cancer, but also support the rationale for developing PPAR delta antagonists for prevention and/or treatment of cancer.