INHIBITION OF TUMOR ANGIOGENESIS USING A SOLUBLE RECEPTOR ESTABLISHESA ROLE FOR TIE2 IN PATHOLOGICAL VASCULAR GROWTH

Tie2 is a novel receptor tyrosine kinase that is expressed almost excl usively by vascular endothelium. Disruption of Tie2 function in transg enic mice resulted in embryonic lethality secondary to characteristic vascular defects; similar defects occurred after disruption of the Tie 2 Ligand, These findings indicate that the Tie2/Tie2 ligand pathway pl ays important roles during development of the embryonic vasculature. T o determine whether the Tie2 pathway was involved in pathologic angiog enesis in adult tissues, a soluble form of the extracellular domain of murine Tie2 (ExTek.6His) was developed and used as a Tie2 inhibitor, After a single application of the ExTek.6His protein into a rat cutane ous window chamber, growth of a mammary tumor inside the chamber was r educed by > 75% (P < 0.005), and tumor vascular length density was red uced by 40% when compared with control-treated tumors (P < 0.01), In t he rat cornea, ExTek.6His blocked angiogenesis stimulated by tumor cel l conditioned media, ExTek.6His protein did not affect the viability o f cultured tumor cells, indicating that the antitumor effect of ExTek. 6His was due to the inhibition of tumor angiogenesis. These data demon strate a role far the Tie2 pathway in pathologic angiogenesis, suggest ing that targeting this pathway may yield effective antiangiogenic age nts for treatment of cancer and other angiogenic diseases.