Abstract 4235: Notch ligand-dependent cancer stem cell niche in glioblastoma

Abstract

Abstract Recent data shows that endothelial cells function as a stem cell niche to promote CD133-positive cancer stem-like cells (CSLCs) self-renewal in glioblastoma (GBM). However, the mechanism by which endothelial cells function as a stem cell niche is largely unknown. To test if endothelial cells and differentiated tumor cells could function as a niche by providing Notch ligands to CSLCs, first we co-cultured GBM neurospheres with primary human endothelial cells (PHECs) which express Notch ligand Jagged/Delta. We found that PHECs promote GBM neurosphere growth, CD133 expression and clonogenicity in vitro, whereas knocking down Notch ligand expression in PHECs abrogates PHEC-induced GBM growth. We also found that the CD133-negative GBM cells express a higher level of Jagged/Delta and glial differentiation marker GFAP compared with CD133-positive population. When GBM neurospheres were forced to differentiate and grow as mono-layer attached cells, CD133-positive population was reduced, whereas expression of GFAP (glial marker), GalC (oligodendrocyte marker), Tuj1 (neuronal marker) and Notch ligands were induced. Furthermore, treatment of GBM neurospheres with a Jagged peptide increases GBM growth in a dosage dependent fashion. In addition, Notch ligands are highly expressed in the blood vessels of GBM primary tumors and intracranial xenografts in mouse, and CSLCs accumulate around the blood vessels within the tumors. Finally, we found that knocking down Notch ligands in PHECs inhibits GBM xenograft propagation in mice through reducing CD133-positive population. In summary, we show that Notch activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells replicating the classical process of lateral inhibition and by stromal niche signals, suggesting that targeting both CSLCs and their niche may provide a profound strategy to deplete GBM CSLCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4235.