title: Primary glioblastoma cultures: can profiling of stem cell markers predict radiotherapy sensitivity?
abstract: Human glioblastomas may be hierarchically organized. Within this hierarchy, glioblastoma-initiating cells have been proposed to be more resistant to radiochemotherapy and responsible for recurrence. Here, established stem cell markers and stem cell attributed characteristics such as self-renewal capacity and tumorigenicity have been profiled in primary glioblastoma cultures to predict radiosensitivity. Furthermore, the sensitivity to radiotherapy of different subpopulations within a single primary glioblastoma culture was analyzed by a flow cytometric approach using Nestin, SRY (sex-determining region Y)-box 2 (SOX2) and glial fibrillary acidic protein. The protein expression of Nestin and SOX2 as well as the mRNA levels of Musashi1, L1 cell adhesion molecule, CD133, Nestin, and pleiomorphic adenoma gene-like 2 inversely correlated with radioresistance in regard to the clonogenic potential. Only CD44 protein expression correlated positively with radioresistance. In terms of proliferation, Nestin protein expression and Musashi1, pleiomorphic adenoma gene-like 2, and CD133 mRNA levels are inversely correlated with radioresistance. Higher expression of stem cell markers does not correlate with resistance to radiochemotherapy in the cancer genome atlas glioblastoma collective. SOX2 expressing subpopulations exist within single primary glioblastoma cultures. These subpopulations predominantly form the proliferative pool of the primary cultures and are sensitive to irradiation. Thus, profiling of established stem cell markers revealed a surprising result. Except CD44, the tested stem cell markers showed an inverse correlation between expression and radioresistance. Markers used to define glioma-initiating cells (GIC) are generally not defining a more resistant, but rather a more sensitive group of glioma cells. An exemption is CD44 expression. Also proliferation of the GIC culture itself was not systematically associated with radiosensitivity or - resistance, but a SOX-2 positive, proliferative subgroup within a GIC culture is showing the highest radiosensitivity.
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors: Dieter
authors: D
authors: Lemke
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors: Markus
authors: M
authors: Weiler
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Jonas
authors: J
authors: Blaes
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors: Benedikt
authors: B
authors: Wiestler
authors: Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany.
authors: Leonie
authors: L
authors: Jestaedt
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Ann-Catherine
authors: AC
authors: Klein
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors: Sarah
authors: S
authors: Löw
authors: Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors: Günter
authors: G
authors: Eisele
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Bernhard
authors: B
authors: Radlwimmer
authors: Institute of Neuropathology, University Clinic Heidelberg, Heidelberg, Germany.
authors: David
authors: D
authors: Capper
authors: Department for Neurosurgery, Universitätsmedizin of Mannheim, Mannheim, Germany.
authors: Kirsten
authors: K
authors: Schmieder
authors: Institute for Brain Research, University of Tübingen, Tübingen, Germany.|Institute of Neurology (Edinger Institute), Goethe University, Frankfurt/Main, Germany.
authors: Michel
authors: M
authors: Mittelbronn
authors: Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany.
authors: Stephanie E
authors: SE
authors: Combs
authors: Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany.
authors: Martin
authors: M
authors: Bendszus
authors: Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors: Michael
authors: M
authors: Weller
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKFZ Heidelberg, Heidelberg, Germany.
authors: Michael
authors: M
authors: Platten
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors: Wolfgang
authors: W
authors: Wick
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000528:radiation effects*; D005260:Female; D005544:Forecasting; D005909:Glioblastoma / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000528:radiation effects*; D011878:Radiotherapy / Q000379:methods; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D014408:Biomarkers, Tumor
keywords: CD133; Glioma-initiating cells; SOX2; profiling; radiotherapy sensitivity; stem cell markers