Conversion of glioma cells to glioma stem-like cells by angiocrine factors

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>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 <I>OCT4</I> that is activated in stem/progenitor cells, we demonstrate that eGFP-negative glioma cells (GCs) became eGFP-positive-GCs in both <I>in vitro</I> cultures and <I>in vivo</I> 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.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Glioma cells are converted to glioma stem-like cells in <I>in vivo</I> xenografts. </LI> <LI> Angiocrine factors convert glioma cells to glioma stem-like cells. </LI> <LI> Nitric oxide regulates ID4 and OCT4 expression in glioma stem-like cells. </LI> <LI> Blockade of nitric oxide signaling prevents tumor progression. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>