Constitutive Notch2 signaling in neural stem cells promotes tumorigenic features and astroglial lineage entry.

Abstract:

: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.

journal_name

Cell Death Dis

journal_title

Cell death & disease

authors

Tchorz JS,Tome M,Cloëtta D,Sivasankaran B,Grzmil M,Huber RM,Rutz-Schatzmann F,Kirchhoff F,Schaeren-Wiemers N,Gassmann M,Hemmings BA,Merlo A,Bettler B

doi

10.1038/cddis.2012.65

subject

Has Abstract

pub_date

2012-06-21 00:00:00

pages

e325

issn

2041-4889

pii

cddis201265

journal_volume

3

pub_type

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