[HTML][HTML] Targeting self-renewal in high-grade brain tumors leads to loss of brain tumor stem cells and prolonged survival

Z Zhu, MA Khan, M Weiler, J Blaes, L Jestaedt… - Cell stem cell, 2014 - cell.com
Z Zhu, MA Khan, M Weiler, J Blaes, L Jestaedt, M Geibert, P Zou, J Gronych, O Bernhardt…
Cell stem cell, 2014cell.com
Cancer stem cells (CSCs) have been suggested as potential therapeutic targets for treating
malignant tumors, but the in vivo supporting evidence is still missing. Using a GFP reporter
driven by the promoter of the nuclear receptor tailless (Tlx), we demonstrate that Tlx+ cells in
primary brain tumors are mostly quiescent. Lineage tracing demonstrates that single Tlx+
cells can self-renew and generate Tlx− tumor cells in primary tumors, suggesting that they
are brain tumor stem cells (BTSCs). After introducing a BTSC-specific knock-out of the Tlx …
Summary
Cancer stem cells (CSCs) have been suggested as potential therapeutic targets for treating malignant tumors, but the in vivo supporting evidence is still missing. Using a GFP reporter driven by the promoter of the nuclear receptor tailless (Tlx), we demonstrate that Tlx+ cells in primary brain tumors are mostly quiescent. Lineage tracing demonstrates that single Tlx+ cells can self-renew and generate Tlx tumor cells in primary tumors, suggesting that they are brain tumor stem cells (BTSCs). After introducing a BTSC-specific knock-out of the Tlx gene in primary mouse tumors, we observed a loss of self-renewal of BTSCs and prolongation of animal survival, accompanied by induction of essential signaling pathways mediating cell-cycle arrest, cell death, and neural differentiation. Our study demonstrates the feasibility of targeting glioblastomas and indicates the suitability of BTSCs as therapeutic targets, thereby supporting the CSC hypothesis.
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