期刊
MOLECULAR IMAGING
卷 18, 期 -, 页码 -出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/1536012119870899
关键词
glioma stem cells (GSCs); CD133; dual optical imaging system; temozolomide resistance; Btk inhibitor
资金
- [TCRD-TPE-107-43]
- [TCRD-TPE-108-46]
- [103TMU-TMUH-06]
- [108-wf-phd-03]
- [MOST 104-0210-01-09-02]
- [MOST 105-0210-01-13-01]
Glioblastoma multiforme represents one of the deadliest brain tumor types, manifested by a high rate of recurrence and poor prognosis. The presence of glioma stem cells (GSCs) can repopulate the tumor posttreatment and resist therapeutics. A better understanding of GSC biology is essential for developing more effective interventions. We established a CD133 promoter-driven dual reporter, expressing green fluorescent protein (GFP) and firefly luciferase (CD133-LG), capable for in vitro and in vivo imaging of CD133+ GSCs. We first demonstrated the reporter enabled in vitro analyses of GSCs. DBTRG-05MG (Denver Brain Tumor Research Group 05) carrying CD133-LG (DBTRG-05MG-CD133-LG) system reported increased GFP/luciferase activities in neurospheres. Additionally, we identified and isolated CD133+/GFP+ cells with increased tumorigenic properties, stemness markers, Notch1, beta-catenin, and Bruton's tyrosine kinase (Btk). Furthermore, prolonged temozolomide (TMZ) treatment enriched GSCs (reflected by increased percentage of CD133+ cells). Subsequently, Btk inhibitor, ibrutinib, suppressed GSC generation and stemness markers. Finally, we demonstrated real-time evaluation of anti-GSC function of ibrutinib in vivo with TMZ-enriched GSCs. Tumorigenesis was noninvasively monitored by bioluminescence imaging and mice that received ibrutinib showed a significantly lower tumor burden, indicating ibrutinib as a potential GSC inhibitor. In conclusion, we established a dual optical imaging system which enables the identification of CD133+ GSCs and screening for anti-GSC drugs.
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