title: Spontaneous in vitro transformation of adult neural precursors into stem-like cancer cells.
abstract: Recent studies have found that cellular self-renewal capacity in brain cancer is heterogeneous, with only stem-like cells having this property. A link between adult stem cells and cancer stem cells remains, however, to be shown. Here, we describe the emergence of cancer stem-like cells from in vitro cultured brain stem cells. Adult rat subventricular zone (SVZ) stem cells transformed into tumorigenic cell lines after expansion in vitro. These cell lines maintained characteristic features of stem-like cells expressing Nestin, Musashi-1 and CD133, but continued to proliferate upon differentiation induction. Karyotyping detected multiple acquired chromosomal aberrations, and syngeneic transplantation into the brain of adult rats resulted in malignant tumor formation. Tumors revealed streak necrosis and displayed a neural as well as an undifferentiated phenotype. Deficient downregulation of platelet-derived growth factor (PDGF) receptor alpha was identified as candidate mechanism for tumor cell proliferation, and its knockdown by siRNA resulted in a reduction of cell growth. Our data point to adult brain precursor cells to be transformed in malignancies. Furthermore, in vitro expansion of adult neural stem cells, which will be mandatory for therapeutic strategies in neurological disorders, also harbors the risk for amplifying precursor cells with acquired genetic abnormalities and induction of malignant tumors after transplantation.
authors.affiliation: Department of Neuropathology. Franz-Penzoldt-Center, University of Erlangen-Nuremberg, Nuremberg, Germany. fas@ufl.edu
authors.forename: Florian A
authors.initials: FA
authors.lastname: Siebzehnrubl
authors.forename: Ina
authors.initials: I
authors.lastname: Jeske
authors.forename: Dorit
authors.initials: D
authors.lastname: Müller
authors.forename: Rolf
authors.initials: R
authors.lastname: Buslei
authors.forename: Roland
authors.initials: R
authors.lastname: Coras
authors.forename: Eric
authors.initials: E
authors.lastname: Hahnen
authors.forename: Hagen B
authors.initials: HB
authors.lastname: Huttner
authors.forename: Denis
authors.initials: D
authors.lastname: Corbeil
authors.forename: Johanna
authors.initials: J
authors.lastname: Kaesbauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Appl
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
authors.forename: Ingmar
authors.initials: I
authors.lastname: Blümcke
mesh_terms: D053687:Adult Stem Cells / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000166:cytology; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D016380:Brain Tissue Transplantation / Q000009:adverse effects; D002454:Cell Differentiation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D002869:Chromosome Aberrations; D007150:Immunohistochemistry; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D020796:Receptor, Platelet-Derived Growth Factor alpha