Angiopoietin 2 as a therapeutic target in hepatocellular carcinoma treatment: current perspectives

Hepatocellular carcinoma (HCC) is a hypervascular malignancy and is the third leading cause of death worldwide. The disease has multiple predisposing risk factors and limited treatment options. Although the precise mechanism(s) underlying HCC is unknown, several pathways have been implicated in its development. HCC is a vascular tumor and angiogenesis is believed to play an important role in its progression. Hypoxia is believed to increase the expression of vascular endothelial growth factor (VEGF) through the expression of the hypoxia-inducible factor-1α. VEGF and angiopoietin 2 (Ang2) are expressed on cancer cells, whereas angiopoietin 1 (Ang1) occurs predominantly in support cells of large blood cells as well as stromal, endothelial, and tumor cells. Ang2 is concomitantly an agonist and antagonist of angiopoietin 1 and is expressed during vascular remodeling. This prevents vascular stability and allows VEGF to stimulate endothelial cells. Ang2 is expressed along with growing blood vessels, destabilizing the vascular integrity. Inhibiting Ang2 can, on the other hand, promote vesicular stability and decrease angiogenesis. We discuss in this review angiopoietin as a therapeutic target alone or in combination with other therapies.