TY - JOUR
T1 - Surfen-mediated blockade of extratumoral chondroitin sulfate glycosaminoglycans inhibits glioblastoma invasion
AU - Logun, Meghan T.
AU - Wynens, Kallie E.
AU - Simchick, Gregory
AU - Zhao, Wujun
AU - Mao, Leidong
AU - Zhao, Qun
AU - Mukherjee, Subhas
AU - Brat, Daniel J.
AU - Karumbaiah, Lohitash
N1 - Funding Information:
The authors thank Dr. Jesse Schank and laboratory members [University of Georgia (UGA)] for providing access to the Applied Biosystems real‐time qPCR instrument. The authors also thank Dr. Tarun Saxena (Duke University, Durham, NC, USA) for technical inputs regarding the use of cell lines and conduct of surgical procedures. This work is supported by the U.S. National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (Grant 1R01NS099596‐01A1), and National Science Foundation (NSF) Engineering Research Center for Cell Manufacturing Technologies (CMaT) Grant EEC‐1648035 (to L.K.). M.T.L. acknowledges funding from the Achievement Rewards for College Scientists (ARCS) Foundation, Inc.. The authors also acknowledge support by the NIH Office of the Director (Grant 1S10OD021719‐01A1) for the purchase of the Imagestream × MK II for the UGA Center for Tropical and Emerging Global Diseases Cytometry Shared Resource Laboratory. The authors declare no conflicts of interest.
Funding Information:
The authors thank Dr. Jesse Schank and laboratory members [University of Georgia (UGA)] for providing access to the Applied Biosystems real-time qPCR instrument. The authors also thank Dr. Tarun Saxena (Duke University, Durham, NC, USA) for technical inputs regarding the use of cell lines and conduct of surgical procedures. This work is supported by the U.S. National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (Grant 1R01NS099596-01A1), and National Science Foundation (NSF) Engineering Research Center for Cell Manufacturing Technologies (CMaT) Grant EEC-1648035 (to L.K.). M.T.L. acknowledges funding from the Achievement Rewards for College Scientists (ARCS) Foundation, Inc. The authors also acknowledge support by the NIH Office of the Director (Grant 1S10OD021719-01A1) for the purchase of the Imagestream ? MK II for the UGA Center for Tropical and Emerging Global Diseases Cytometry Shared Resource Laboratory. The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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 CSA 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. FASEB J. 33, 11973-11992 (2019). www.fasebj.org.
AB - 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 CSA 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. FASEB J. 33, 11973-11992 (2019). www.fasebj.org.
KW - extracellular matrix
KW - glioma
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85074379525&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074379525&partnerID=8YFLogxK
U2 - 10.1096/fj.201802610RR
DO - 10.1096/fj.201802610RR
M3 - Article
C2 - 31398290
AN - SCOPUS:85074379525
SN - 0892-6638
VL - 33
SP - 11973
EP - 11992
JO - FASEB Journal
JF - FASEB Journal
IS - 11
ER -