Spontaneous in vitro transformation of adult neural precursors into stem-like cancer cells.
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.
Siebzehnrubl
Florian A
FA
Department of Neuropathology. Franz-Penzoldt-Center, University of Erlangen-Nuremberg, Nuremberg, Germany. fas@ufl.edu
Jeske
Ina
I
Müller
Dorit
D
Buslei
Rolf
R
Coras
Roland
R
Hahnen
Eric
E
Huttner
Hagen B
HB
Corbeil
Denis
D
Kaesbauer
Johanna
J
Appl
Thomas
T
von Hörsten
Stephan
S
Blümcke
Ingmar
I
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
D034741:RNA, Small Interfering; D020796:Receptor, Platelet-Derived Growth Factor alpha