1441

CSF3R

CD114|GCSFR;colony stimulating factor 3 receptor (granulocyte);CSF3R;colony stimulating factor 3 receptor (granulocyte)

CD114 antigen|G-CSF receptor|G-CSF-R|granulocyte colony-stimulating factor receptor

1p35-p34.3

protein-coding

BACKGROUND: Recent advances in multidisciplinary treatment approaches have improved the overall prognosis of pediatric brain tumors, but some patients remain refractory to treatment and do poorly. Several molecularly targeted therapies are under development for the treatment of brain tumors, and high-grade gliomas in adults are a particular area of study. PROCEDURE: To better understand if these new therapies can be used in pediatric populations, we examined the expression of the following seven marker genes involved in signaling pathways targeted by new therapies: beta-catenin, suppressor of fused (SUFU), erythroblastic leukemia viral oncogene homolog (ERBB) 2, platelet-derived growthfactor receptoralpha (PDGFRalpha), proliferating cell nuclear antigen (PCNA), secreted protein acid and rich in cysteine (SPARC), and granulocyte colony-stimulating factor receptor (G-CSFR). Samples from 27 patients with the primitive neuroectodermal tumor (PNET)/medulloblastomas (MBs) (n = 8), ependymomas (n = 5), or gliomas (n = 14) were assessed by quantitative real-timePCR. [Correction made here after initial online publication]. We assigned an EXPscore to compare across samples and determined the levels of gene expression among tumor cell types. RESULTS: Gene expression varied among the different tumors, but, within a tumor type, clear expression patterns were seen. The expression of SUFU, ERBB2, and PCNA in metastatic MBs were greater than that seen in non-metastatic MBs. Most glioma cases highly expressed PDGFRalpha and G-CSFR.Additionally, the expression patterns of gliomas and ependymomas were similar (r= 0.77, P = 0.04), but PNET/MBs substantially differed from gliomas (r = -0.37, P = 0.41) or ependymomas (r = 0.23, P = 0.62). CONCLUSIONS: The development of newdrugs targeting up-regulated pathways may be useful for the treatment of pediatric brain tumors. As new drugs are developed, gliomas and ependymomas may be treated with similar compounds.#CI- Copyright (c) 2011 Wiley Periodicals, Inc.

Neuroblastoma is a neural crest-derived embryonal malignancy, which accounts for13% 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 theNGP 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 activationof 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. cancer Res; 73(13); 4134-46. (c)2013 AACR.