Constitutive Notch2 signaling in neural stem cells promotes tumorigenic features and astroglial lineage entry.
Recent studies identified a highly tumorigenic subpopulation of glioma stem cells (GSCs) within malignant gliomas. GSCs are proposed to originate from transformed neural stem cells (NSCs). Several pathways active in NSCs, including the Notch pathway, were shown to promote proliferation and tumorigenesis in GSCs. Notch2 is highly expressed in glioblastoma multiforme (GBM), a highly malignant astrocytoma. It is therefore conceivable that increased Notch2 signaling in NSCs contributes to the formation of GBM. Here, we demonstrate that mice constitutively expressing the activated intracellular domain of Notch2 in NSCs display a hyperplasia of the neurogenic niche and reduced neuronal lineage entry. Neurospheres derived from these mice show increased proliferation, survival and resistance to apoptosis. Moreover, they preferentially differentiate into astrocytes, which are the characteristic cellular population of astrocytoma. Likewise, we show that Notch2 signaling increases proliferation and resistance to apoptosis in human GBM cell lines. Gene expression profiling of GBM patient tumor samples reveals a positive correlation of Notch2 transcripts with gene transcripts controlling anti-apoptotic processes, stemness and astrocyte fate, and a negative correlation with gene transcripts controlling proapoptotic processes and oligodendrocyte fate. Our data show that Notch2 signaling in NSCs produces features of GSCs and induces astrocytic lineage entry, consistent with a possible role in astrocytoma formation.
Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, 4056 Basel, Switzerland.
J S
JS
Tchorz
M
M
Tome
D
D
Cloëtta
B
B
Sivasankaran
M
M
Grzmil
R M
RM
Huber
F
F
Rutz-Schatzmann
F
F
Kirchhoff
N
N
Schaeren-Wiemers
M
M
Gassmann
B A
BA
Hemmings
A
A
Merlo
B
B
Bettler
D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C497764:NOTCH2 protein, human; C497765:Notch2 protein, mouse; D051883:Receptor, Notch2