Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells.
Glioblastoma cells with stem-like properties control brain tumour growth and recurrence. Here, we show that endogenous neural precursor cells perform an anti-tumour response by specifically targeting stem-like brain tumour cells. In vitro, neural precursor cells predominantly express bone morphogenetic protein-7; bone morphogenetic protein-7 is constitutively released from neurospheres and induces canonical bone morphogenetic protein signalling in stem-like glioblastoma cells. Exposure of human and murine stem-like brain tumour cells to neurosphere-derived bone morphogenetic protein-7 induces tumour stem cell differentiation, attenuates stem-like marker expression and reduces self-renewal and the ability for tumour initiation. Neurosphere-derived or recombinant bone morphogenetic protein-7 reduces glioblastoma expansion from stem-like cells by down-regulating the transcription factor Olig2. In vivo, large numbers of bone morphogenetic protein-7-expressing neural precursors encircle brain tumours in young mice, induce canonical bone morphogenetic protein signalling in stem-like glioblastoma cells and can thereby attenuate tumour formation. This anti-tumour response is strongly reduced in older mice. Our results indicate that endogenous neural precursor cells protect the young brain from glioblastoma by releasing bone morphogenetic protein-7, which acts as a paracrine tumour suppressor that represses proliferation, self-renewal and tumour-initiation of stem-like glioblastoma cells.
Chirasani
Sridhar Reddy
SR
Cellular Neuroscience, Max Delbrück Center for Molecular Medicine, Robert Rössle Strasse 10, 13125 Berlin, Germany.
Sternjak
Alexander
A
Wend
Peter
P
Momma
Stefan
S
Campos
Benito
B
Herrmann
Ilaria M
IM
Graf
Daniel
D
Mitsiadis
Thimios
T
Herold-Mende
Christel
C
Besser
Daniel
D
Synowitz
Michael
M
Kettenmann
Helmut
H
Glass
Rainer
R
D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
D055419:Bone Morphogenetic Protein 7