PMID- 24835569 OWN - NLM STAT- MEDLINE DCOM- 20150518 LR - 20160518 IS - 1875-9777 (Electronic) IS - 1875-9777 (Linking) VI - 15 IP - 2 DP - 2014 Aug 7 TI - Targeting self-renewal in high-grade brain tumors leads to loss of brain tumor stem cells and prolonged survival. PG - 185-98 LID - S1934-5909(14)00144-1 [pii] LID - 10.1016/j.stem.2014.04.007 [doi] AB - 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. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Zhu, Zhe AU - Zhu Z AD - Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. FAU - Khan, Muhammad Amir AU - Khan MA AD - Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. FAU - Weiler, Markus AU - Weiler M AD - Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Neurooncology, University Clinic Heidelberg and German Cancer Consortium (DKTK), Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. FAU - Blaes, Jonas AU - Blaes J AD - Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. FAU - Jestaedt, Leonie AU - Jestaedt L AD - Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. FAU - Geibert, Madeleine AU - Geibert M AD - Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. FAU - Zou, Peng AU - Zou P AD - Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. FAU - Gronych, Jan AU - Gronych J AD - Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. FAU - Bernhardt, Olga AU - Bernhardt O AD - Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. FAU - Korshunov, Andrey AU - Korshunov A AD - Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany. FAU - Bugner, Verena AU - Bugner V AD - Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. FAU - Lichter, Peter AU - Lichter P AD - Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. FAU - Radlwimmer, Bernhard AU - Radlwimmer B AD - Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. FAU - Heiland, Sabine AU - Heiland S AD - Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. FAU - Bendszus, Martin AU - Bendszus M AD - Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. FAU - Wick, Wolfgang AU - Wick W AD - Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Neurooncology, University Clinic Heidelberg and German Cancer Consortium (DKTK), Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. FAU - Liu, Hai-Kun AU - Liu HK AD - Helmholtz Young Investigator Group, Normal and Neoplastic CNS Stem Cells, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: l.haikun@dkfz-heidelberg.de. LA - eng SI - GEO/GSE46125 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140515 PL - United States TA - Cell Stem Cell JT - Cell stem cell JID - 101311472 RN - 0 (Nes protein, mouse) RN - 0 (Nestin) RN - 147336-22-9 (Green Fluorescent Proteins) SB - IM CIN - Nat Rev Cancer. 2014 Jul;14(7):452-3. PMID: 24898059 CIN - Cell Stem Cell. 2014 Aug 7;15(2):114-6. PMID: 25105574 MH - Animals MH - Apoptosis MH - Brain/pathology MH - Brain Neoplasms/*pathology MH - Cell Cycle MH - Cell Differentiation MH - Cell Lineage MH - Cell Proliferation MH - Cell Survival MH - Glioma/metabolism/*pathology MH - Green Fluorescent Proteins/metabolism MH - Humans MH - Mice MH - Neoplasm Transplantation MH - Neoplastic Stem Cells/*pathology MH - Nestin/metabolism MH - Neurons/cytology MH - Signal Transduction MH - Xenograft Model Antitumor Assays EDAT- 2014/05/20 06:00 MHDA- 2015/05/20 06:00 CRDT- 2014/05/20 06:00 PHST- 2012/12/15 00:00 [received] PHST- 2013/12/03 00:00 [revised] PHST- 2014/04/10 00:00 [accepted] PHST- 2014/05/20 06:00 [entrez] PHST- 2014/05/20 06:00 [pubmed] PHST- 2015/05/20 06:00 [medline] AID - S1934-5909(14)00144-1 [pii] AID - 10.1016/j.stem.2014.04.007 [doi] PST - ppublish SO - Cell Stem Cell. 2014 Aug 7;15(2):185-98. doi: 10.1016/j.stem.2014.04.007. Epub 2014 May 15.