Notch1 Stimulation Induces a Vascularization Switch With Pericyte-Like Cell Differentiation of Glioblastoma Stem Cells

摘要: Glioblastoma multiforms (GBMs) are highly vascularized brain tumors containing a subpopulation of multipotent cancer stem cells. These cells closely interact with endothelial in neurovascular niches. In this study, we have uncovered close link between the Notch1 pathway and tumoral vascularization process GBM We observed that although receptor was activated, typical target proteins (HES5, HEY1, HEY2) were not or barely expressed two explored cell cultures. signaling activation by expression intracellular form (NICD) these found to reduce their growth rate migration, which accompanied sharp reduction neural transcription factor (ASCL1, OLIG2, SOX2), while HEY1/2, KLF9, SNAI2 factors upregulated. Expression OLIG2 restored after termination stimulation. Remarkably, NICD induced pericyte markers (NG2, PDGFRβ, α-smooth muscle actin [αSMA]) This paralleled induction several angiogenesis-related most notably cytokines (heparin binding epidermal [HB-EGF], IL8, PLGF), matrix metalloproteinases (MMP9), adhesion (vascular molecule 1 [VCAM1], intercellular [ICAM1], integrin alpha 9 [ITGA9]). xenotransplantation experiments, contrasting infiltrative poorly obtained control cells, stimulation resulted disseminating but grafts large vessels lumen. Notch1-stimulated associated results reveal an important role for regulating plasticity angiogenic properties.