Cholinergic switch associated with morphological differentiation in neuroblastoma.
The morphology of malignant cells distinguishes between undifferentiated, poorly differentiated and differentiating neuroblastomas and constitutes a strong prognostic factor. Spontaneous or treatment-induced maturation characterizes a subset of neuroblastomas. It constitutes the basis of retinoic acid treatment to improve survival in aggressive neuroblastomas. However, the molecular events that drive differentiation are poorly understood. In the present study we have investigated the relationships between gene expression profiles and differentiation criteria in stroma-poor neuroblastomas. This study included three undifferentiated (UN), 20 poorly differentiated (PDN) and 11 differentiating (DN) neuroblastomas. These groups could be clearly separated using unsupervised clustering methods, which further enabled a major classification impact of genes involved in neural development, differentiation and function to be identified. UNs are characterized by high ASCL1, high PHOX2B, low GATA2, low TH and low DBH expressions. Most PDNs harbour a clear adrenergic phenotype, even in the presence of missense PHOX2B mutations. Finally, all DN tumours demonstrate cholinergic features. Depending upon their association with adrenergic characteristics, this enables dual 'cholinergic/adrenergic' and 'fully cholinergic' neuroblastomas to be defined. This suggests that the cholinergic switch, a final specification process that occurs physiologically in a minority of sympathetic neurons, is a critical step of differentiation in some neuroblastic tumours. This switch is associated with a down regulation of DBH that is apparently not strictly dependent upon PHOX2B. Conversely, GATA2 and TFAP2B may play critical roles in maintaining adrenergic features in poorly differentiated tumours.
Bourdeaut
Franck
F
INSERM U830, Institut Curie, Génétique et biologie des Cancers, Paris, France.
Janoueix-Lerosey
Isabelle
I
Lucchesi
Carlo
C
Paris
Régine
R
Ribeiro
Agnès
A
de Pontual
Loïc
L
Amiel
Jeanne
J
Lyonnet
Stanislas
S
Pierron
Gaëlle
G
Michon
Jean
J
Peuchmaur
Michel
M
Delattre
Olivier
O
D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002799:Cholinergic Fibers / Q000473:pathology*; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D014157:Transcription Factors / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D004299:Dopamine beta-Hydroxylase; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; C065500:ASCL1 protein, human; C109220:NBPhox protein