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The purpose of this study was to determine the role of Notch signaling in lymphatic endothelial cell (LEC) behavior and to determine the effects on tumor vasculature upon Notch inhibition. We hypothesized that disrupting Notch activity may interfere with tumor (lymph)angiogenesis by disrupting expression and activity of EC genes. To that end, we have created a treatment agent known as Notch1 decoy (hN1DFc). Activation or inactivation of Notch changes the gene profile of LEC and changes their in vitro behavior. An orthotopic model of human breast cancer was established. These tumors are rich in Notch-positive vasculature, and reliably metastasize to the lungs and/or lymph nodes, making this a good model for future studies of Notch inhibition on tumor vasculature.