Abstract 3297: Endothelial cells function as a niche to cancer stem-like cells by providing notch ligands in glioblastoma

Abstract

Abstract Recent data show 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 molecular mechanism by which endothelial cells function as a stem cell niche is largely unknown. We had demonstrated recently that activation of NOTCH signaling is required for GBM CSLC propagation both in vitro and in vivo. To investigate if the acquisition of NOTCH activation in GBM CSLCs results from adjacent endothelial cells, we first examined the expression of NOTCH ligands JAG/DLL in primary GBM frozen samples. We found that JAG1, JAG2 and DLL4 are expressed mostly in endothelial cells adjacent to NESTIN- and NOTCH receptor-positive cancer cells. Some tumor cells also express JAG1, JAG2, and DLL1, but not DLL4, adjacent to NESTIN- and NOTCH-receptor positive cells in primary GBMs. Furthermore, we found that forced differentiated GBM cells from GBM neurospheres express a higher level of NOTCH ligands and a lower level of stem cell marker CD133, have reduced NOTCH activity, and are less tumorigenic in mice compared to GBM neurospheres. In addition, when we co-cultured GBM neurospheres with human brain microvascular endothelial cells (hBMECs) which express NOTCH ligands JAG/DLL, we found that hBMECs promote GBM neurosphere growth, increase the CD133-positive CSLC population and clonogenicity in vitro, whereas knocking down JAG1 or DLL4 in hBMECs abrogates hBMEC-induced GBM growth both in vitro and in vivo. Finally, we found that knockdown of JAG1 or DLL4 in hBMECs decreases growth of GBM intracranial xenograft in mice through reducing the CD133-positive population. In summary, we have demonstrated that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and surrounding endothelial cells, suggesting that targeting both CSLCs and their niche may provide an effective strategy to deplete GBM CSLCs. 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 3297. doi:10.1158/1538-7445.AM2011-3297