neuroblastic differentiation

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.

Gene expression profiling (19768740)

and differentiation criteria in stroma-poor neuroblastomas. This study included three

 undifferentiated neuroblastomas (UN)

• UNs are characterized by high ASCL1, high PHOX2B, low GATA2, low TH and low DBH expressions.

 poorly differentiated neuroblastomas (PDN)

• Most PDNs harbour a clear adrenergic phenotype, even in the presence of missense PHOX2B mutations.

 differentiating neuroblastomas (DN)

• 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.

References

 Cholinergic switch associated with morphological differentiation in neuroblastoma. Bourdeaut F, Janoueix-Lerosey I, Lucchesi C, Paris R, Ribeiro A, de Pontual L, Amiel J, Lyonnet S, Pierron G, Michon J, Peuchmaur M, Delattre O. J Pathol. 2009 Dec;219(4):463-72. PMID: 19768740