Abstract 3476: Blockade of endothelial Notch diminishes tumor growth and perfusion

Abstract

Abstract Canonical Notch signaling comprises a family of receptors and ligands that modulate cell fate and differentiation. Upon ligand binding, Notch receptors undergo a series of cleavages that culminate in the translocation of the intracellular domain to the nucleus, resulting in transcriptional activation through the derepression and activation at CSL-bound promoters. Notch activity is essential for embryonic vascular development and was recently also shown to be important for adult neovascularization. Notably, blocking Notch signaling by inhibition of the ligand Dll4 increased endothelial proliferation and sprouting, but resulted in non-perfused vasculature and tumor growth inhibition. Moreover, Dll4 inhibition was shown to diminish vascular mural cells, such as pericytes, in tumors. Whether these effects of Dll4 blockade on tumor vasculature resulted specifically from Notch inhibition in endothelial cells remains to be fully elucidated. We investigated this question using a tetracycline-inducible binary transgenic system, in which Notch is blocked by the expression of a dominant-negative form of mastermind-like 1 (dnMAML-GFP) under the control of the VE-cadherin promoter. Lewis lung carcinoma (LLC) cells overexpressing VEGFA (LLC-VEGFA) were implanted subcutaneously in the dorsa of double transgenic (Tg) or control mice. Tumors in the double Tg mice were significantly smaller than in control single Tg mice. Moreover, blood vessel perfusion from LLC-VEGFA tumors was significantly reduced in the double Tg mice compared to the control Tg mice. However, neither the abundance nor the branching architecture of LLC-VEGFA tumor blood vessels appeared to be different in the double Tg mice. Pericyte abundance, maturation and distribution relative to blood vessels did not change in the double Tg mice. Flow cytometry of tumor-derived cells and fluorescence microscopy analysis of tumor cryosections confirmed that dnMAML-GFP is expressed specifically in endothelial cells. Our data suggest that specific blockade of Notch in endothelial cells, induced by dnMAML-GFP, affects tumor growth through a mechanism different from previously-reported Dll4 inhibition studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3476. doi:10.1158/1538-7445.AM2011-3476