Targeting vessel maturation: an anti-angiogenesis based cancer therapy

UnrestrictedAngiogenesis is an extremely complex process regulated by several different signaling pathways. The identification of novel molecular targets and understanding of their interaction with angiogenesis pathways are required to design rational anti-angiogenesis therapies. Notch-Dll4 and EphB4-EphrinB2 receptor-ligand pairs are key players in these pathways. The following studies provide evidence for two potential anti-angiogenesis therapies, soluble Dll4 (sDll4) and soluble EphB4 (sEphB4). First, the role of Dll4 in vascular remodeling at sites of angiogenesis, including tumor vasculature was investigated. Results showed that loss of Dll4 function promotes endothelial cell migration, excessive vascular network formation, and reduction in pericyte recruitment, both in embryos and adult mice. Soluble forms of Dll4 interrupted Dll4-Notch signaling and recapitulated the vascular alterations seen in the gene knock-out mice, including increased vascular network formation, decreased or absent vascular lumen, and reduced recruitment of pericytes resulting in tissue hypoxia and decreased tumor growth. Second, a comprehensive analysis of the Eph receptor tyrosine kinases was conducted to determine which members are expressed and contribute to Kaposi Sarcoma (KS) pathogenesis. In addition, the biological effects of blocking EphrinB2 in vitro and in vivo using a soluble form of EphB4 (sEphB4) was studied. sEphB4 blocks EphB4-EphrinB2 interaction, and inhibits KS tumor growth with marked reduction in vessel density, vessel maturity and vessel perfusion. Its anti-tumor activity was comparable or better than VEGF moAb in KS treatment. Combination of soluble EphB4 and VEGF moAb resulted in additive anti-tumor effect. Thus, more effective anti-angiogenic therapeutics may arise from a better understanding of the molecular and cellular mechanisms involved in tumor angiogenesis and the response to anti-angiogenic therapies in a wide range of cancers