A Notch1 Ectodomain Construct Inhibits Endothelial Notch Signaling, Tumor Growth, and Angiogenesis

Abstract

Notch signaling is required for vascular development and tumor angiogenesis.

Impaired angiogenesis and altered Notch signaling in mice overexpressing endothelial Egfl7

“…13 As a control, the Notch4 adenovirus was replaced with a LacZ adenovirus. Two days later, each lentiviral-infected HUVEC line (1.5 ϫ 10 5 cells; EGFL7-overexpressing, EGFL7 knockdown, and control lines) was seeded on fibrin gels in a 24-well plate.…”

“…We have previously shown that overexpressing NOTCH4 in HUVECs promotes formation of cellular processes. 13 Here, NOTCH4/GFP-overexpressing HUVECs were added to a HUVEC monolayer infected with pCCLEGFL7, pLKO61, or an empty vector control. In the absence of ectopic NOTCH4, the morphology of the control GFP-expressing cells remained unchanged, independent of the level of EGFL7 expression in the monolayer (data not shown).…”

Tips, Stalks, Tubes: Notch-Mediated Cell Fate Determination and Mechanisms of Tubulogenesis during Angiogenesis

“…The protein consists of the 36 EGF-like repeats of the Notch1 extracellular domain, fused to a human Fc domain. Initial work indicates that this protein construct is capable of acting as a competitive inhibitor of Notch signaling (Funahashi et al 2008). Because different Notch ligands bind differently to their receptor, it is possible that further modification of this basic inhibitor design may generate competitive inhibitors of specific avenues of Notch signaling, allowing wellcontrolled analysis of the ligands' roles in tumor angiogenesis and providing a potentially useful mechanism of targeted pharmacological inhibition.…”

Asymmetric Division in the Immuno-Hematopoietic System

“…Notch signaling in endothelial cells has been inhibited using a decoy of Notch1, successfully reducing tumor growth. Other decoys of Dll1, Dll4 and Jagged1 have been successfully developed (Funahashi Y., et al 2008, Varnum-Finney B., et al 2000and Small D., et al 2001). However, decoys show an important disadvantage.…”