Ablation of neuropilin-1 improves the therapeutic response in conventional drug-resistant glioblastoma multiforme
Ablation of neuropilin-1 improves the therapeutic response in conventional drug-resistant glioblastoma multiforme
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DOI：
10.1038/s41388-020-01462-1
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发表时间：
2020-10-01
期刊：
影响因子：
8
通讯作者：
Mukhopadhyay, Debabrata
中科院分区：
文献类型：
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作者：
Angom, Ramcharan Singh;Mondal, Sujan Kumar;Mukhopadhyay, Debabrata
多形性胶质母细胞瘤（GBM）是一种高增生性、局部侵袭性肿瘤，预后差，复发率高。尽管抗vegf（血管内皮生长因子）治疗为GBM患者提供了短期益处，但随着肿瘤发展成更具侵袭性和耐药表型并最终复发，这种方法会失败。最近，胶质瘤干细胞（GSCs）和脑肿瘤起始细胞（BTICs）都被认为与GBM复发及其对治疗的抵抗有关。我们观察到，表达VEGF或neuropilin-1 (NRP-1) shrna的患者源性GBM细胞减弱了癌症干细胞标记物，抑制了肿瘤启动细胞的神经球形成能力和迁移。此外，在斑马鱼和小鼠模型中，VEGF和NRP-1敲低均抑制患者来源的GBM异种移植物的生长。有趣的是，与VEGF缺失相比，nrp -1缺失的患者来源的GBM异种移植物显著延长了小鼠的存活时间。我们的研究结果还表明，NRP-1消融患者来源的GBM细胞可以提高TMZ的敏感性，并提高相应荷瘤小鼠的总体存活率。这一改善的结果可能为化疗和放疗之外靶向NRP-1抑制GBM进展和有效的治疗策略提供见解。
Glioblastoma multiforme (GBM) is a highly proliferative and locally invasive cancer with poor prognosis and a high recurrence rate. Although anti-VEGF (vascular endothelial growth factor) therapy offers short-term benefit to GBM patients, this approach fails as the tumor develops into a more invasive and drug-resistant phenotype and ultimately recurs. Recently, both glioma stemlike cells (GSCs) and brain tumor-initiating cells (BTICs) have been implicated in GBM recurrence and its resistance to therapy. We observed that patient-derived GBM cells expressing shRNAs of VEGF or neuropilin-1 (NRP-1) attenuate cancer stem cell markers, inhibit the tumor-initiating cell's neurosphere-forming capacity, and migration. Furthermore, both VEGF and NRP-1 knockdown inhibit the growth of patient-derived GBM xenografts in both zebrafish and mouse models. Interestingly, NRP-1-depleted patient-derived GBM xenografts substantially prolonged survival in mice compared to that of VEGF depletion. Our results also demonstrate that NRP-1 ablation of patient-derived GBM cells improves the sensitivity of TMZ and enhances the overall survival of the respective tumor-bearing mice. This improved outcome may provide insight into the inhibition of GBM progression and effective treatment strategies by targeting NRP-1 in addition to chemotherapy and radiotherapy.