Targeting Hyaluronan Interactions for Glioblastoma Stem Cell Therapy
Targeting Hyaluronan Interactions for Glioblastoma Stem Cell Therapy
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DOI：
10.1007/s12307-019-00224-2
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发表时间：
2019-04-01
影响因子：
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通讯作者：
Kim, Yonghyun
中科院分区：
文献类型：
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作者：
Hartheimer, Joline S.;Park, Seungjo;Kim, Yonghyun
即使经过严格的治疗，多形性胶质母细胞瘤（GBM）的中位存活率也很低，这很大程度上是由于胶质母细胞瘤干细胞（GSC）群体具有耐药性。已知GSC可以重塑其微环境，但细胞外基质成分透明质酸（HA）和透明质酸酶（HAases）在GSC群体中的确切作用仍然很大程度上未知。我们的目的是确定HAase如何通过破坏HA-CD44信号通路使GSCs对化疗药物敏感。在gsc富集培养基中培养GBM细胞系U87-MG和患者源性D456细胞，分别用HA或HAase处理。通过流式细胞术、共聚焦显微镜和qRT-PCR检测GSC标志物、ha相关基因和耐药基因的表达。采用WST-8检测HAase联合替莫唑胺（temozolomide， TMZ）处理后细胞增殖情况。HA可促进无血清培养基培养的GBM细胞中GSC标记物和CD44的表达。相反，添加HAase抑制GSC基因表达，同时促进CD44的表达。最后，HAase使GBM细胞对TMZ敏感。我们建议通过破坏促进干细胞的HA靶向GSCs，将HAase和化疗药物联合治疗。这种联合疗法即使在替莫唑胺单独治疗引起耐药性的情况下也显示出希望。
Even with rigorous treatments, glioblastoma multiforme (GBM) has an abysmal median survival rate, greatly due to the drug-resistant glioblastoma stem cell (GSC) population. GSCs are known to remodel their microenvironment, but the precise role of extracellular matrix components hyaluronic acid (HA) and hyaluronidases (HAases) on the GSC population is still largely unknown. Our objective was to determine how HAase can sensitize GSCs to chemotherapy drugs by disrupting the HA-CD44 signaling. GBM cell line U87-MG and patient-derived D456 cells were grown in GSC-enriching media and treated with HA or HAase. Expressions of GSC markers, HA-related genes, and drug resistance genes were measured via flow cytometry, confocal microscopy, and qRT-PCR. Proliferation after combined HAase and temozolomide (TMZ) treatment was measured via WST-8. HA supplementation promoted the expression of GSC markers and CD44 in GBM cells cultured in serum-free media. Conversely, HAase addition inhibited GSC gene expression while promoting CD44 expression. Finally, HAase sensitized GBM cells to TMZ. We propose a combined treatment of HAase and chemotherapy drugs by disrupting the stemness-promoting HA to target GSCs. This combination therapy shows promise even when temozolomide treatment alone causes resistance.