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

FASEB J. 2019 Nov;33(11):11973-11992. doi: 10.1096/fj.201802610RR. Epub 2019 Aug 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AC133 Antigen / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Chondroitin Sulfates / antagonists & inhibitors*
  • Chondroitin Sulfates / metabolism
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Glioma / metabolism
  • Glioma / pathology
  • Glycosaminoglycans / antagonists & inhibitors
  • Glycosaminoglycans / metabolism
  • Humans
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Rats
  • Signal Transduction / drug effects
  • Tumor Microenvironment / drug effects*
  • Urea / analogs & derivatives*
  • Urea / pharmacology


  • AC133 Antigen
  • Glycosaminoglycans
  • chondroitin sulfate glycosaminoglycan
  • aminoquinuride
  • A73025
  • Urea
  • Chondroitin Sulfates