Award Number : W 81 XWH - 07 - 1 - 0362 TITLE : Notch as a Diagnostic Marker and Therapeutic Target in Human Breast Cancer

نویسنده

  • Jan K. Kitajewski
چکیده

Notch signaling is required for vascular development andtumor angiogenesis. Although inhibition of the Notch ligandDelta-like 4 can restrict tumor growth and disrupt neo-vasculature, the effect of inhibiting Notch receptor function onangiogenesis has yet to be defined. In this study, we generateda soluble form of the Notch1 receptor (Notch1 decoy) andassessed its effect on angiogenesis in vitro and in vivo . Notch1decoy expression reduced signaling stimulated by the bindingof three distinct Notch ligands to Notch1 and inhibitedmorphogenesis of endothelial cells overexpressing Notch4.Thus, Notch1 decoy functioned as an antagonist of ligand-dependent Notch signaling. In mice, Notch1 decoy alsoinhibited vascular endothelial growth factor–induced angio-genesis in skin, establishing a role for Notch receptor functionin this process. We tested the effects of Notch1 decoy on tumorangiogenesis using two models: mouse mammary Mm5MTcells overexpressing fibroblast growth factor 4 (Mm5MT-FGF4) and NGP human neuroblastoma cells. Exogenouslyexpressed FGF4 induced Notch ligand expression in Mm5MTcells and xenografts. Notch1 decoy expression did not affecttumorigenicity of Mm5MT-FGF4 cells in vitro but restrictedMm5MT-FGF4 xenograft growth in mice while markedlyimpairing neoangiogenesis. Similarly, Notch1 decoy expres-sion did not affect NGP cells in vitro but disrupted vessels anddecreased tumor viability in vivo . These results stronglysuggest that Notch receptor signaling is required for tumorneoangiogenesis and provides a new target for tumor therapy.[Cancer Res 2008;68(12):4727–35]

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تاریخ انتشار 2010