| Angiogenesis is induced by an increase in pro-angiogenic factors in tissue microenvironments, which stimulates transduction of signals that promote endothelial cell proliferation, chemotaxis, and survival. Endothelial cells regulate neovascularization through activation of the Raf-MEK-ERK and PI3K-AKT pathways. During tumor angiogenesis, it is unknown what mechanisms regulate neovascularization and endothelial cell survival. Addressing these issues, murine organs and tumors were investigated for activation of ERK and AKT in their vasculatures. Tumors expressed activated ERK in more vessels than normal murine organs. In contrast, AKT was activated in both tumor and normal endothelium. To examine the effects of inhibition of ERK activation, tumors were treated with sorafenib, a Raf kinase inhibitor. Following treatment, there was decreased ERK activation. On the other hand, AKT activation remained unchanged in tumor vasculature of three tumor models after sorafenib administration. Changes in endothelial cell signaling were accompanied by decreased tumor growth and inhibition of angiogenesis. These suggest that sorafenib controls tumor growth through decreased angiogenesis, which is regulated by ERK inhibition in tumor endothelia. Due to the restricted expression of activated ERK in tumor endothelium, and its decreased expression in tumor endothelium following sorafenib treatment and angiogenic inhibition, ERK activation may be a good biomarker for responses to sorafenib therapy. These studies highlight the importance of understanding endothelial cell signaling in the vasculature of both normal and tumor tissues in vivo. In gaining a better knowledge of activated pathways in endothelia, we can identify potential targets to inhibit pathological angiogenesis and ways to monitor angiogenic and antiangiogenic events. |
