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FASEB J. 2019 Aug 9:fj201802610RR. doi: 10.1096/fj.201802610RR. [Epub ahead of print]

Surfen-mediated blockade of extratumoral chondroitin sulfate glycosaminoglycans inhibits glioblastoma invasion.

Author information

1
Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.
2
Division of Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, Athens, Georgia, USA.
3
Edgar L. Rhodes Center for Animal and Dairy Science, College of Agriculture and Environmental Sciences, University of Georgia, Athens, Georgia, USA.
4
Department of Physics and Astronomy, University of Georgia, Athens, Georgia, USA.
5
Department of Chemistry, University of Georgia, Athens, Georgia, USA.
6
School of Electrical and Computer Engineering, College of Engineering, University of Georgia, Athens, Georgia, USA.
7
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Abstract

Invasive spread of glioblastoma (GBM) is linked to changes in chondroitin sulfate (CS) proteoglycan (CSPG)-associated sulfated glycosaminoglycans (GAGs) that are selectively up-regulated in the tumor microenvironment (TME). We hypothesized that inhibiting CS-GAG signaling in the TME would stem GBM invasion. Rat F98 GBM cells demonstrated enhanced preferential cell invasion into oversulfated 3-dimensional composite of CS-A and CS-E [4- and 4,6-sulfated CS-GAG (COMP)] matrices compared with monosulfated (4-sulfated) and unsulfated hyaluronic acid matrices in microfluidics-based choice assays, which is likely influenced by differential GAG receptor binding specificities. Both F98 and human patient-derived glioma stem cells (GSCs) demonstrated a high degree of colocalization of the GSC marker CD133 and CSPGs. The small molecule sulfated GAG antagonist bis-2-methyl-4-amino-quinolyl-6-carbamide (surfen) reduced invasion and focal adhesions in F98 cells encapsulated in COMP matrices and blocked CD133 and antichondroitin sulfate antibody (CS-56) detection of respective antigens in F98 cells and human GSCs. Surfen-treated F98 cells down-regulated CSPG-binding receptor transcripts and protein, as well as total and activated ERK and protein kinase B. Lastly, rats induced with frontal lobe tumors and treated with a single intratumoral dose of surfen demonstrated reduced tumor burden and spread compared with untreated controls. These results present a first demonstration of surfen as an inhibitor of sulfated GAG signaling to stem GBM invasion.-Logun, M. T., Wynens, K. E., Simchick, G., Zhao, W., Mao, L., Zhao, Q., Mukherjee, S., Brat, D. J., Karumbaiah, L. Surfen-mediated blockade of extratumoral chondroitin sulfate glycosaminoglycans inhibits glioblastoma invasion.

KEYWORDS:

extracellular matrix; glioma; tumor microenvironment

PMID:
31398290
DOI:
10.1096/fj.201802610RR

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