Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.
Division of Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, Athens, Georgia, USA.
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.
胶质母细胞瘤（GBM）的侵袭性扩散与软骨素硫酸盐（CS）蛋白聚糖（CSPG）相关硫酸化糖胺聚糖（GAG）的变化有关，这些糖胺聚糖在肿瘤微环境（TME）中选择性地上调。我们假设在 TME 中抑制 CS-GAG 信号会阻止 GBM 的侵袭。在基于微流控的选择实验中，与单硫酸化（4-硫酸化）和未硫酸化透明质酸基质相比，大鼠 F98 GBM 细胞表现出增强的优先细胞侵袭到过硫酸化的 CS-A 和 CS-E [4-和 4,6-硫酸化 CS-GAG（COMP）]基质中，这可能受到不同 GAG 受体结合特异性的影响。F98 和人源性胶质瘤干细胞（GSCs）都表现出 GSC 标志物 CD133 和 CSPGs 的高度共定位。小分子硫酸化 GAG 拮抗剂双-2-甲基-4-氨基-喹啉-6-甲酰胺（surfen）降低了 F98 细胞在 COMP 基质中的侵袭和焦点粘附，并阻断了 F98 细胞和人 GSCs 中 CD133 和抗软骨素硫酸盐抗体（CS-56）对各自抗原的检测。Surfen 处理的 F98 细胞下调了 CSPG 结合受体的转录物和蛋白，以及总和激活的 ERK 和蛋白激酶 B。最后，用单次脑内注射 surfen 诱导的额叶肿瘤大鼠与未治疗对照组相比，肿瘤负荷和扩散减少。这些结果首次证明了 surfen 作为抑制 GBM 侵袭的硫酸化 GAG 信号抑制剂。-Logun, M. T., Wynens, K. E., Simchick, G., Zhao, W., Mao, L., Zhao, Q., Mukherjee, S., Brat, D. J., Karumbaiah, L. Surfen-mediated 阻断肿瘤外软骨素硫酸盐糖胺聚糖抑制胶质母细胞瘤侵袭。
