Novel paracrine modulation of Notch-DLL4 signaling by fibulin-3 promotes angiogenesis in high-grade gliomas

摘要: High-grade gliomas are characterized by exuberant vascularization, diffuse invasion and significant chemoresistance, resulting in a recurrent phenotype that makes them impossible to eradicate the long-term. Targeting pro-tumoral signals glioma microenvironment could have impact against tumor cells supporting niche facilitates their growth. Fibulin-3 is protein secreted cells, but absent normal brain, promotes survival. We show here fibulin-3 paracrine activator of Notch signaling endothelial angiogenesis. overexpression increased VEGF levels, microvascular density, vessel permeability, while knockdown reduced density xenograft models glioma. localization human glioblastomas showed dense fiber-like condensations around blood vessels, which were suggesting remarkable association this with endothelium. At cellular level, enhanced cell motility sprouting, formation tubules, VEGF-independent Notch-dependent manner. ADAM10/17 activity inhibiting metalloprotease inhibitor TIMP3; resulted cleavage expression DLL4 independently signaling. Inhibition or pro-angiogenic effects culture. Taken together, these results reveal novel, role gliomas, highlighting relevance as an important molecular target microenvironment.