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Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth
Erik H. Knelson, … , Stephen G. Marcus, Gerard C. Blobe
Erik H. Knelson, … , Stephen G. Marcus, Gerard C. Blobe
Published June 17, 2014
Citation Information: J Clin Invest. 2014;124(7):3016-3031. https://doi.org/10.1172/JCI74270.
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Research Article Oncology Article has an altmetric score of 70

Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth

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Abstract

Neuroblastoma prognosis is dependent on both the differentiation state and stromal content of the tumor. Neuroblastoma tumor stroma is thought to suppress neuroblast growth via release of soluble differentiating factors. Here, we identified critical growth-limiting components of the differentiating stroma secretome and designed a potential therapeutic strategy based on their central mechanism of action. We demonstrated that expression of heparan sulfate proteoglycans (HSPGs), including TβRIII, GPC1, GPC3, SDC3, and SDC4, is low in neuroblasts and high in the Schwannian stroma. Evaluation of neuroblastoma patient microarray data revealed an association between TGFBR3, GPC1, and SDC3 expression and improved prognosis. Treatment of neuroblastoma cell lines with soluble HSPGs promoted neuroblast differentiation via FGFR1 and ERK phosphorylation, leading to upregulation of the transcription factor inhibitor of DNA binding 1 (ID1). HSPGs also enhanced FGF2-dependent differentiation, and the anticoagulant heparin had a similar effect, leading to decreased neuroblast proliferation. Dissection of individual sulfation sites identified 2-O, 3-O-desulfated heparin (ODSH) as a differentiating agent, and treatment of orthotopic xenograft models with ODSH suppressed tumor growth and metastasis without anticoagulation. These studies support heparan sulfate signaling intermediates as prognostic and therapeutic neuroblastoma biomarkers and demonstrate that tumor stroma biology can inform the design of targeted molecular therapeutics.

Authors

Erik H. Knelson, Angela L. Gaviglio, Jasmine C. Nee, Mark D. Starr, Andrew B. Nixon, Stephen G. Marcus, Gerard C. Blobe

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Figure 4

sHSPGs enhance FGF2 signaling in neuroblastoma cells to promote differentiation via ERK and ID1.

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sHSPGs enhance FGF2 signaling in neuroblastoma cells to promote differen...
(A) Western blots for differentiation markers in 5Y treated for 96 hours with 1 ng/ml FGF2, sTβRIII (10 ng/ml), sSDC3, sSDC4, or sHSPG (+100 ng/ml or ++1 μg/ml). Densitometry for NF160 normalized to β-actin is shown as the percentage of control. (B) Western blots for phosphorylated and total ERK as well as ID1 in 5Y treated for 96 hours with sTβRIII (10 ng/ml), sSDC3, or sHSPG (1 μg/ml). Densitometry for p-ERK and ID1 normalized to β-actin is shown as the percentage of control. (C) Linear regression and multivariate regression analyses using the microarray meta-dataset. (D) Western blots for differentiation markers and TβRIII in cells transfected for 96 hours with wild-type sTβRIII or sTβRIII with a single amino acid substitution to prevent heparan sulfate modification (TβRIII S534A). Densitometry for NF160 normalized to β-actin is shown as the percentage of control. (E) Western blots for differentiation markers in 5Y treated for 96 hours with sTβRIII (10 ng/ml), sSDC3 (1 μg/ml), PD173074, UO126, CI1040 (1 μM), or SU5402 (10 μM). Transient transfection with dominant negative FGFR1 (dnFGFR1) or IRES-GFP control. GFP fluorescence was used to confirm construct expression. Densitometry for NF160 normalized to β-actin is shown as the percentage of control.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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