Astrocytes reverted to a neural progenitor-like state with transforming growth factor alpha are sensitized to cancerous transformation.
Gliomas, the most frequent primitive central nervous system tumors, have been suggested to originate from astrocytes or from neural progenitors/stem cells. However, the precise identity of the cells at the origin of gliomas remains a matter of debate because no pre-neoplastic state has been yet identified. Transforming growth factor (TGF)-alpha, an epidermal growth factor family member, is frequently overexpressed in the early stages of glioma progression. We previously demonstrated that prolonged exposure of astrocytes to TGF-alpha is sufficient to trigger their reversion to a neural progenitor-like state. To determine whether TGF-alpha dedifferentiating effects are associated with cancerous transforming effects, we grafted intracerebrally dedifferentiated astrocytes. We show that these cells had the same cytogenomic profile as astrocytes, survived in vivo, and did not give birth to tumors. When astrocytes dedifferentiated with TGF-alpha were submitted to oncogenic stress using gamma irradiation, they acquired cancerous properties: they were immortalized, showed cytogenomic abnormalities, and formed high-grade glioma-like tumors after brain grafting. In contrast, irradiation did not modify the lifespan of astrocytes cultivated in serum-free medium. Addition of TGF-alpha after irradiation did not promote their transformation but decreased their lifespan. These results demonstrate that reversion of mature astrocytes to an embryonic state without genomic manipulation is sufficient to sensitize them to oncogenic stress.
Dufour
Christelle
C
Inserm UMR894, Team Glial Plasticity, University Paris, Descartes, France.
Cadusseau
Josette
J
Varlet
Pascale
P
Surena
Anne-Laure
AL
de Faria
Giselle P
GP
Dias-Morais
Amelie
A
Auger
Nathalie
N
Léonard
Nadine
N
Daudigeos
Estelle
E
Dantas-Barbosa
Carmela
C
Grill
Jacques
J
Lazar
Vladimir
V
Dessen
Philippe
P
Vassal
Gilles
G
Prevot
Vincent
V
Sharif
Ariane
A
Chneiweiss
Herve
H
Junier
Marie-Pierre
MP
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D001932:Brain Neoplasms / Q000139:chemically induced* / Q000503:physiopathology; D054337:Cell Dedifferentiation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism / Q000528:radiation effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005720:Gamma Rays / Q000009:adverse effects; D005910:Glioma / Q000139:chemically induced* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D013312:Stress, Physiological / Q000502:physiology / Q000528:radiation effects; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology*
D016895:Culture Media, Serum-Free; D016211:Transforming Growth Factor alpha