Possible routes of prostaglandin signaling in the induction of tumor angiogenesis. The experiments by Williams (1) suggest that COX-2 (and presumably prostaglandin synthesis) is required in the upstream stromal cells that provide VEGF to endothelial cells. Other investigators have found that COX-2 is required in the endothelial cells that will form the new blood vessels (downstream). Prostaglandins can exert their effects either through receptors on the cell surface, which are coupled to G proteins and various intracellular signaling pathways, or by the nuclear transcription factors (peroxisome proliferator–activated receptors). The routes through which prostaglandins act in this pathway are not known, but several possibilities are shown. In paracrine signaling, exogenous but locally produced prostaglandins (PG) act on the stromal cell to induce VEGF expression. Autocrine signaling differs in that the prostaglandins are produced in stromal cells and are secreted and act on receptors (blue) on the surface of these same cells. In intracrine signaling, prostaglandins also act on the producing cell, but they do so prior to being secreted. Similar events not shown here could occur in the downstream endothelial cell as well.