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Tumor and Stem Cell Biology

G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation

Saurabh Agarwal, Anna Lakoma, Zaowen Chen, John Hicks, Leonid S. Metelitsa, Eugene S. Kim and Jason M. Shohet
Saurabh Agarwal
1Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, Houston, Texas.
2Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
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Anna Lakoma
3Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
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Zaowen Chen
1Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, Houston, Texas.
2Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
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John Hicks
4Department of Pathology, Section of Pediatric Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
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Leonid S. Metelitsa
1Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, Houston, Texas.
2Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
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Eugene S. Kim
3Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
5Division of Pediatric Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, California.
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Jason M. Shohet
1Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, Houston, Texas.
2Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
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  • For correspondence: jmshohet@txch.org
DOI: 10.1158/0008-5472.CAN-14-2946 Published June 2015
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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. Cancer Res; 75(12); 2566–79. ©2015 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • E.S. Kim and J.M. Shohet share senior authorship of this article.

  • This work is dedicated to all the children and parents struggling with neuroblastoma who inspire us to search for a cure.

  • Received October 3, 2014.
  • Revision received April 7, 2015.
  • Accepted April 11, 2015.
  • ©2015 American Association for Cancer Research.
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Cancer Research: 75 (12)
June 2015
Volume 75, Issue 12
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G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation
Saurabh Agarwal, Anna Lakoma, Zaowen Chen, John Hicks, Leonid S. Metelitsa, Eugene S. Kim and Jason M. Shohet
Cancer Res June 15 2015 (75) (12) 2566-2579; DOI: 10.1158/0008-5472.CAN-14-2946

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G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation
Saurabh Agarwal, Anna Lakoma, Zaowen Chen, John Hicks, Leonid S. Metelitsa, Eugene S. Kim and Jason M. Shohet
Cancer Res June 15 2015 (75) (12) 2566-2579; DOI: 10.1158/0008-5472.CAN-14-2946
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