The PPAR? agonist Rosiglitazone induces paracrine signaling in melanoma cells that activate stromal cells and enhances tumor growth.

Besides improving insulin sensitivity in type 2 diabetes, the thiazolidinedione family of compounds and the pharmacologic activation of their best characterized target PPARg has been proposed as a therapeutic option for cancer treatment. In the present study, we reveal a new mechanism by which the thiazolidinedione rosiglitazone contributes to tumorigenesis, which limits its therapeutic potential in cancer. We provide evidence that rosiglitazone activates a tumorigenic paracrine communication program in a subset of human melanoma cells, that involves the secretion of cytokines, chemokines and angiogenic factors. This complex blend of paracrine signals activates non-malignant fibroblasts, endothelial cells and macrophages in a tumor-friendly way. In agreement with these data, we show that rosiglitazone promotes human melanoma development in xenografts, through enhanced angiogenesis and inflammation. Together, these findings establish an important tumorigenic action of rosiglitazone in melanoma cells. While studies conducted on cohorts of diabetic patients report overall benefits of TZDs in cancer prevention, we show that exposure of an established tumor to rosiglitazone may be deleterious. Overall design: A375 melanoma cells were treated for 24h with 5µM RGZ, 2µM T007 or a combination of both; three independent experiments were performed and in each of these 3 experiments, RNA samples from technical replicates of the same condition were pooled.