title: G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation.
abstract: Increasing evidence suggests that inflammatory cytokines play a critical role in tumor initiation and progression. A cancer stem cell (CSC)-like subpopulation in neuroblastoma is known to be marked by expression of the G-CSF receptor (G-CSFR). Here, we report on the mechanistic contributions of the G-CSFR in neuroblastoma CSCs. Specifically, we demonstrate that the receptor ligand G-CSF selectively activates 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 acts in a feed-forward loop to transcriptionally activate the G-CSFR and sustain neuroblastoma CSCs. Blockade of this G-CSF-STAT3 signaling loop with either anti-G-CSF antibody or STAT3 inhibitor depleted the CSC subpopulation within tumors, driving correlated tumor growth inhibition, decreased metastasis, and increased chemosensitivity. Taken together, our results define G-CSF as a CSC-activating factor in neuroblastoma, suggest a comprehensive reevaluation of the clinical use of G-CSF in these patients to support white blood cell counts, and suggest that direct targeting of the G-CSF-STAT3 signaling represents a novel therapeutic approach for neuroblastoma.
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, Houston, Texas. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: Anna
authors.initials: A
authors.lastname: Lakoma
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, Houston, Texas. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Zaowen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology, Section of Pediatric Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
authors.forename: John
authors.initials: J
authors.lastname: Hicks
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, Houston, Texas. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Leonid S
authors.initials: LS
authors.lastname: Metelitsa
authors.affiliation: Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas. Division of Pediatric Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, California.
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, Houston, Texas. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas. jmshohet@txch.org.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Shohet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D050796:STAT3 Transcription Factor; D016179:Granulocyte Colony-Stimulating Factor