NOTCH Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts
By Xing Fan, L. Khaki, Thant S. Zhu, Mary Soules, Caroline E Talsma, N. Gul, Cheryl M. Koh, Jiangyang Zhang, Yue-Ming Li, J. Maciaczyk and 5 more. Stem Cells, 2009
669 citations recorded by the source corpus.
Cancer stem cells (CSCs) are thought to be critical for the engraftment and long‐term growth of many tumors, including glioblastoma (GBM). The cells are at least partially spared by traditional chemotherapies and radiation therapies, and finding new treatments that can target CSCs may be critical for improving patient survival. It has been shown that the NOTCH signaling pathway regulates normal stem cells in the brain, and that GBMs contain stem‐like cells with higher NOTCH activity. We therefore used low‐passage and established GBM‐derived neurosphere cultures to examine the overall requirement for NOTCH activity, and also examined the effects on tumor cells expressing stem cell markers. NOTCH blockade by γ‐secretase inhibitors (GSIs) reduced neurosphere growth and clonogenicity in vitro, whereas expression of an active form of NOTCH2 increased tumor growth. The putative CSC markers CD133, NESTIN, BMI1, and OLIG2 were reduced following NOTCH blockade. When equal numbers of viable cells pretreated with either vehicle (dimethyl sulfoxide) or GSI were injected subcutaneously into nude mice, the former always formed tumors, whereas the latter did not. In vivo delivery of GSI by implantation of drug‐impregnated polymer beads also effectively blocked tumor growth, and significantly prolonged survival, albeit in a relatively small cohort of animals. We found that NOTCH pathway inhibition appears to deplete stem‐like cancer cells through reduced proliferation and increased apoptosis associated with decreased AKT and STAT3 phosphorylation. In summary, we demonstrate that NOTCH pathway blockade depletes stem‐like cells in GBMs, suggesting that GSIs may be useful as chemotherapeutic reagents to target CSCs in malignant gliomas. STEM CELLS 2010;28:5–16
Subfields: Cancer Research, Genetics, Oncology
View Paper: https://www.semanticscholar.org/paper/01e70fa864be5e7d04784176723f84d5607e0153
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Citations in the corpus
- Oxygen in stem cell biology: a critical component of the stem cell niche. (2010, background): “For example, blockade of Notch signaling with gamma-secretase inhibitors depletes cancer stem-like cells in gliomas and inhibits growth of xenografts (Fan et al., 2010).”
- Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells (2013, background): “Our finding adds EZH2 to a growing list of upstream pathways leading to the STAT3 activation in GSCs, including IL-6, Notch, PI3K, LIF, BMX, and various receptor tyrosine kinases (epidermal growth factor receptor, platelet-derived growth factor, and MET) (Bromberg et al., 1999; Fan et al., 2010; Gur”
- Notch signalling in solid tumours: a little bit of everything but not all the time (2011, background): “This study also suggested that blocking Notch activity results in the decreased phosphorylation of AKT and STAT3, leading to decreased CSC proliferation and increased apoptosi”
- Cancer stem cells in glioblastoma (2015, background): “The dependence of glioma CSCs on Notch signaling is further supported by experiments demonstrating depletion of CSCs by treatment with γ-secretase inhibitors (Fan et al. 2006, 2010).”
- iNOS promotes CD24+CD133+ liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway (2018, background): “The Notch signaling pathway promotes the self-renewal, differentiation, proliferation, survival, and migration of CSCs in several malignancies (20, 21).”