P04.70 Anti-Notch1 treatment suppressed the invasion, self-renewal and tumor growth of glioma initiating cells mediated by chemokine system CXCL12/CXCR4. (19th September 2018)

• Record Type: Journal Article
• Authors: Yi, L; Yang, X
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 3
• Page Start: iii296
• Page End: iii296
• Publication Date: 2018-09-19
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy139.304
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: Glioma initiating cells (GICs), also known as glioma stem cells (GSCs), play an important role in the progression and recurrence of glioblastoma multiforme (GBM) due to their potential for self-renewal, multiple differentiation and tumor initiation. In the recent years, Notch1 has been found to be overexpressed in GICs. However, the regulatory mechanism of Notch1 in the self-renewal and invasion ability of GICs remains unclear. This study aims to explore the effect of Notch pathway on self-renewal and invasion of GICs and the underlying mechanisms. Material and Methods: Bioinformatic analysis and immunohistochemistry (IHC) were performed to evaluate the expression of Notch1 and Hes1 in glioma samples and its correlation with patient prognosis. Immunofluorescent (IF) staining was performed to observe the distribution of Notch1 and CXCR4 in GBM and GICs. Both pharmacological intervention and RNA interference were employed to investigate the role of Notch1 in GICs self-renewal, invasion and tumor growth in vitro or in vivo. The crosstalk effect of Notch1 and CXCL12/CXCR4 system on GIC self-renewal and invasion was explored by sphere formation assay, limiting dilution assay and Transwell assay. Western blots were used to verify the activation of Notch1/CXCR4/AKT pathway in self-renewal, invasion and tumor growth of GICs. The orthotopic GICs implantations were established to analyze the role and the mechanism of Notch1 in glioma progression in vivo. Results: High Notch1 signaling activity was correlated with poor patient prognosis. Notch1 and CXCR4 were both upregulated in GICs, compared to Notch1 positive glioma cells comprised a large proportion in the CD133+ glioma cell spheres, CXCR4 positive glioma cells which usually expressed Notch1 both and dispersed in the periphery of the sphere, only represent a small subset of CD133+ glioma cell spheres. Notch1 contributes to the invasion, migration and self-renewal of GICs by CXCL12/CXCR4 system. Furthermore, downregulation of the Notch1 pathway by shRNA and Gamma secretase inhibitor (GSI) MK0752 significantly inhibited the PI3K/AKT/mTOR signaling pathway via the decreased expression of CXCR4 in GICs, and weakened the self-renewal and invasion ability of GICs. In vivo experiments showed that knockdown expression of Notch1 significantly prolonged the survival length of glioma-bearing mice and inhibited GICs growth and invasiveness. Conclusion: Anti-Notch1 treatment suppressed the invasion, self-renewal and tumor growth of glioma initiating cells mediated by chemokine system CXCL12/CXCR4. Targeting Notch1 mediated GICs self-renewal and invasiveness with CXCR4 inhibitors might be a promising strategy for the treatment of GBMs.