Increasing evidence suggests that inflammatory cytokines play a critical role in tumor initiation and progression. We previously isolated a Cancer Stem Cell-like (CSC) subpopulation in neuroblastoma based on differential expression of the receptor for G-CSF (Granulocyte-Colony Stimulating Factor). Here we demonstrate that G-CSF selectively activates signal transducer and activator of transcription 3 (STAT3) within neuroblastoma CSC subpopulations, promoting their expansion in vitro and in vivo. Exogenous G-CSF enhances tumor growth and metastasis in human xenograft and murine neuroblastoma tumor models. In response to G-CSF, STAT3 transcriptionally activates the G-CSF receptor (encoded by CSF3R), creating a CSC sustaining positive-feedback loop. Blockade of G-CSF/STAT3 signaling loop with either anti-G-CSF antibody or STAT3 inhibitor depletes the CSC subpopulation within tumors, driving correlated tumor regression, blocking metastasis and increasing chemosensitivity. Taken together, these data define G-CSF as a tumorigenic growth factor for neuroblastoma and suggest a comprehensive re-evaluation of the clinical use of G-CSF in these patients. Our data also demonstrate that direct targeting of the G-CSF/STAT3 signaling represents a novel therapeutic approach for neuroblastoma.
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 CD114, which encodes the receptor for granulocyte colony-stimulating factor (G-CSF). 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, microRNA and gene expression. In addition, they reflect a primitive undifferentiated neuroectodermal/neural crest phenotype revealing a developmental hierarchy within neuroblastoma tumors. We detected this de-differentiated 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 this subpopulation may represent an additional target for novel therapeutic approaches to this aggressive pediatric malignancy.
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