Abstract 5225: Endothelial-specific Jagged1 blockade prevents solid tumor growth in pre-clinical models

Angiogenesis is an essential process required for tumor growth and progression. The Notch signaling pathway has been identified as a key regulator of the neo-angiogenic process. Jagged-1 (Jag1) is a Notch ligand required for embryonic and retinal vascular development. Although its role as a pro-angiogenic ligand has been thoroughly studied in developmental contexts, the real contribution of this Notch ligand to tumor angiogenesis remains unknown. The current study addresses the role of endothelial Jagged1-mediated Notch signaling in the context of tumoral angiogenesis in two different mouse tumor models: subcutaneous Lewis Lung Carcinoma (LLC) tumor transplants and the autochthonous Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP). The role of endothelial Jagged1 in tumor growth and neo-angiogenesis was investigated with endothelial-specific Jag1 gain- and loss-of-function mouse mutants (eJag1OE and eJag1cKO). We show that the tumor vasculature of eJag1OE mutants presents increased vessel density, branching, and perivascular maturation, causing increased tumor perfusion. Ultimately, this leads to increased proliferation and survival of tumor cells, and increased epithelial-to-mesenchymal transition (EMT) resulting in increased LLC tumor growth as well as development and progression of prostate adenocarcinoma in mice. In contrast, in eJag1cKO mutants the vasculature is characterized by decreased vessel density, branching, and perivascular maturation, which restricts tumor vascular perfusion and increases vascular extravasation. This vascular phenotype leads to decreased proliferation and increased death of tumor cells, reduced EMT culminating in decreased LLC growth as well as inhibited development and progression of prostate adenocarcinoma in mice. Therefore, endothelial Jagged1 may constitute a novel promising target for solid cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Antonio Duarte, Ana-Rita Pedrosa, Alexandre Trindade, Catarina Carvalho, José Graça, Sandra Carvalho, Maria C. Peleteiro, Ralf H. Adams. Endothelial-specific Jagged1 blockade prevents solid tumor growth in pre-clinical models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5225. doi:10.1158/1538-7445.AM2015-5225