Neuroblastoma is a neural crest-derived embryonal
malignancy, which accounts for 13% of all pediatric
cancer mortality, primarily due to
tumor recurrence.
Therapy-resistant cancer stem cells are implicated in
tumor relapse, but definitive phenotypic evidence of the existence of these cells has been lacking. In this study, we define a highly tumorigenic subpopulation in
neuroblastoma with stem cell characteristics, based on the expression of CSF3R, which encodes the receptor for
granulocyte colony-stimulating factor (
G-CSF).
G-CSF receptor positive (aka G-CSFr(+) or CD114(+)) cells isolated from a primary
tumor and the NGP cell line by flow cytometry were highly tumorigenic and capable of both self-renewal and differentiation to progeny cells. CD114(+) cells closely resembled embryonic and induced pluripotent stem cells with respect to their profiles of cell cycle,
miRNA, and gene expression. In addition, they reflect a primitive undifferentiated neuroectodermal/neural crest phenotype revealing a developmental hierarchy within
neuroblastoma tumors. We detected this dedifferentiated neural crest subpopulation in all established
neuroblastoma cell lines, xenograft
tumors, and primary
tumor specimens analyzed.
Ligand activation of CD114 by the addition of exogenous
G-CSF to CD114(+) cells confirmed intact STAT3 upregulation, characteristic of
G-CSF receptor signaling. Together, our data describe a novel distinct subpopulation within
neuroblastoma with enhanced tumorigenicity and a stem cell-like phenotype, further elucidating the complex heterogeneity of solid
tumors such as
neuroblastoma. We propose that this subpopulation may represent an additional target for novel therapeutic approaches to this aggressive pediatric
malignancy.