Mechanisms of anti-angiogenic therapy

Angiogenesis inhibition is a promising approach to fight cancer. This strategy offers some advantages in comparison with conventional drugs, such as the inhibition of single vessels that can induce the death of many tumor cells. Moreover, this therapy can be used in the treatment of a wide range of solid tumors and may produce less resistance. Since angiogenesis is a complex process, it can be inhibited at different levels. The most established therapy is the inhibition of angiogenic signaling. Vascular endothelial growth factor (VEGF) pathway is the most important signaling pathway in the angiogenesis process, and for this reason, many inhibitors have been developed to block the action of VEGF or its receptors, VEGFRs. Another approach is the inhibition of endothelial progenitor cells (EPCs), mobilized from the bone marrow to the tumor site in hypoxia conditions, which contribute to the formation of new blood vessels and the pre-metastatic niche. The interaction between extracellular matrix and endothelial cells is very important during angiogenesis, so the inhibition of this interaction produces anti-angiogenic effects. An alternative strategy is based in the regression of preexisting tumor vasculature, which presents abnormalities in the structure and function in comparison with normal vessels. In this case, vascular-disrupting agents (VDAs) can cease the blood flow within minutes and lead to the formation of central necrosis. Finally, tumor vessel normalization produced after anti-angiogenic therapies may reduce the metastatic dissemination and improve delivery of drugs to the tumor.