The dynamic roles of angiopoietins in tumor angiogenesis

Angiopoietin (Ang)-1 and -2, and mouse Ang-3/human Ang-4 are ligands of the receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Tie)-2. It is well established that the Ang-Tie-2 pathway is involved in tumor angiogenesis. However, the exact effects of angiopoietins on tumor angiogenesis are under debate. Experimental and clinical studies have demonstrated that increased expression of Ang-1 and -2 promotes or inhibits tumor angiogenesis, and correlates with a reduced or extended survival time of patients, and with a declined or improved clinical outcome. In general, these studies suggest that Ang-1 is a proangiogenic factor that promotes endothelial cell survival and tumor angiogenesis, especially in the presence of vascular endothelial growth factor; whereas Ang-2 destabilizes vasculature that leads to the initiation of angiogenesis or apoptosis of endothelial cells/vessel regression in the presence or absence of vascular endothelial growth factor, respectively, and that the cell-surface tethered Ang-3 displays antiangiogenic activity. Together, these results suggest that the Ang-Tie-2 functional axis is an attractive target for antiangiogenesis-based cancer therapy.