Glioma stem-like cells (GSCs) contribute to tumor initiation, progression, and therapeutic resistance, but their cellular origin remains largely unknown. Here, using a stem/progenitor cell-fate tracking reporter system in which eGFP is expressed by promoter of OCT4 that is activated in stem/progenitor cells, we demonstrate that eGFP-negative glioma cells (GCs) became eGFP-positive-GCs in both in vitro cultures and in vivo xenografts. These eGFP-positive-GCs exhibited GSC features and primarily localized to the perivascular region in tumor xenografts, similar to the existence of OCT4-expressing GCs in the perivascular region of human glioblastoma specimens. Angiocrine factors, including nitric oxide (NO), converted eGFP-negative-GCs into eGFP-positive-GCs. Mechanistically, NO signaling conferred GSC features to GCs by increasing OCT4 and NOTCH signaling via ID4. NO signaling blockade and a suicide gene induction prevented tumorigenicity with a decrease in eGFP-positive-GCs in the perivascular region. Taken together, our results reveal the molecular mechanism underlying GSCs generation by cancer cell dedifferentiation.
|Number of pages||6|
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - 2018 Feb 19|
Bibliographical noteFunding Information:
This work was supported by grants from the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT and Future Planning ( 2011-0017544 and 2016R1D1A1B03931941 ), from Next-Generation Biogreen21 Program ( PJ01107701 ), and from General Program of the National Natural Science Foundation of China (nos. 81572891 ). We appreciate Ji-Hyun Kim for providing graphic abstract.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology