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

Abstract

Glioblastoma multiforms (GBMs) are highly vascularized brain tumors containing a subpopulation of multipotent cancer stem cells. These cells closely interact with endothelial cells in neurovascular niches. In this study, we have uncovered a close link between the Notch1 pathway and the tumoral vascularization process of GBM stem cells. We observed that although the Notch1 receptor was activated, the typical target proteins (HES5, HEY1, and HEY2) were not or barely expressed in two explored GBM stem cell cultures. Notch1 signaling activation by expression of the intracellular form (NICD) in these cells was found to reduce their growth rate and migration, which was accompanied by the sharp reduction in neural stem cell transcription factor expression (ASCL1, OLIG2, and SOX2), while HEY1/2, KLF9, and SNAI2 transcription factors were upregulated. Expression of OLIG2 and growth were restored after termination of Notch1 stimulation. In xenotransplantation experiments, contrasting with the infiltrative and poorly vascularized tumors obtained with control GBM stem cells, Notch1 stimulation resulted in poorly disseminating but highly vascularized grafts containing large vessels with lumen. Notch1-stimulated GBM cells expressed pericyte cell markers and closely associated with endothelial cells. These results reveal an important role for the Notch1 pathway in regulating GBM stem cell plasticity and angiogenic properties. STEM CELLS 2015;33:21-34

Phosphoribosylpyrophosphate Synthetase 1 Knockdown Suppresses Tumor Formation of Glioma CD133+ Cells Through Upregulating Cell Apoptosis

“…A number of studies identified the genes and genetic pathways involved in the sustenance of GSCs, such as BMI1 and Notch (Baxter et al 2014;Guichet et al 2015;Schonberg et al 2014). However, as an important protein that participates in the synthesis of purines and pyrimidines, few studies have focused on the role of PRPS1 in tumorigenesis.…”

Pericytes of the neurovascular unit: key functions and signaling pathways

“…It remains unclear, however, whether MB cells have the potential to differentiate into pericytes, as shown for some other types of brain neoplastic cells that can generate pericytes to control blood vessel function during tumor growth 92,93 .…”

“…More recent studies revealed that self-renewing tumorigenic glioma stem cells (GSCs) give rise to pericytes to support vessel formation and tumor growth 92,93 . GSCs are recruited to endothelial cells by the stromal-derived factor-1 (SDF-1), an alpha-chemokine that binds to G-protein-coupled CXCR4, and are induced to become pericytes predominantly by TGF-β 93 .…”

Role of the anti-glioma drug AT13148 in the inhibition of Notch signaling pathway

“…The gene expression profiles of GSE44561 (Guichet et al, 2015), GSE48079 (Garner et al, 2013) and GSE22772 (Huber et al, 2013) were downloaded from National Center of Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (Barrett et al, 2005) (http://www.ncbi.nlm.gov/geo/). A total number of eight samples for GSE44561 with activated Notch signaling pathway by a forced expression of the Notch intracellular domain were available, including four embryonic human neural stem cells samples and four GBM samples, and the platform was GPL11532.…”