TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma.
Glioma-initiating cells (GICs) are responsible for the initiation and recurrence of gliomas. Here, we identify a molecular mechanism that regulates the self-renewal capacity of patient-derived GICs. We show that TGF-beta and LIF induce the self-renewal capacity and prevent the differentiation of GICs. TGF-beta induces the self-renewal capacity of GICs, but not of normal human neuroprogenitors, through the Smad-dependent induction of LIF and the subsequent activation of the JAK-STAT pathway. The effect of TGF-beta and LIF on GICs promotes oncogenesis in vivo. Some human gliomas express high levels of LIF that correlate with high expression of TGF-beta2 and neuroprogenitor cell markers. Our results show that TGF-beta and LIF have an essential role in the regulation of GICs in human glioblastoma.
Medical Oncology Program, Vall d'Hebron University Hospital Research Institute, Barcelona, Spain.
Silvia
S
Peñuelas
Judit
J
Anido
Rosa M
RM
Prieto-Sánchez
Gerard
G
Folch
Ignasi
I
Barba
Isabel
I
Cuartas
David
D
García-Dorado
M Antonia
MA
Poca
Juan
J
Sahuquillo
Jose
J
Baselga
Joan
J
Seoane
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism
C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D050791:STAT Transcription Factors; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; C507904:JAK1 protein, human; D053613:Janus Kinase 1