Targeting Glioma Stem Cell-Derived Pericytes Disrupts the Blood-Tumor Barrier and Improves Chemotherapeutic Efficacy.
Targeting Glioma Stem Cell-Derived Pericytes Disrupts the Blood-Tumor Barrier and Improves Chemotherapeutic Efficacy.
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靶向神经胶质瘤干细胞衍生的周细胞破坏血液肿瘤屏障并提高化疗效果
DOI：
10.1016/j.stem.2017.10.002
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发表时间：
2017-11-02
期刊：
影响因子：
23.9
通讯作者：
Bian XW
中科院分区：
文献类型：
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作者：
Zhou W;Chen C;Shi Y;Wu Q;Gimple RC;Fang X;Huang Z;Zhai K;Ke SQ;Ping YF;Feng H;Rich JN;Yu JS;Bao S;Bian XW
血肿瘤屏障（BTB）是恶性脑肿瘤（如胶质母细胞瘤）药物递送的主要障碍。因此，破坏BTB是高度期望的，但由于需要维持正常的血脑屏障（BBB）而变得复杂。在这里，我们表明，靶向胶质瘤干细胞（GSC）衍生的周细胞特异性地破坏BTB，并增强药物渗出到脑肿瘤。我们发现肿瘤血管的周细胞覆盖与化疗后GBM患者的生存率呈负相关。在异种移植模型中消除GSC衍生的周细胞破坏了BTB紧密连接并增加了血管通透性。我们确定BMX作为维持GSC衍生的周细胞的重要因素。用伊曲替尼抑制BMX选择性地靶向肿瘤周细胞并破坏BTB，但不破坏BBB，从而增加药物渗出到已建立的肿瘤中并增强BTB渗透性差的药物的化疗功效。这些发现突出了靶向肿瘤周细胞以显著增强脑肿瘤治疗的临床潜力。血脑屏障（BBB）阻止有害物质进入正常大脑，但血肿瘤屏障（BTB）阻止抗癌药物穿透GBM肿瘤。靶向GSC衍生的肿瘤周细胞选择性地破坏BTB而不是BBB，并有效地增强药物递送以有效地改善GBM治疗。
The blood-tumor barrier (BTB) is a major obstacle for drug delivery to malignant brain tumors such as glioblastoma. Disrupting the BTB is therefore highly desirable, but complicated by the need to maintain the normal blood-brain barrier (BBB). Here, we show that targeting glioma stem cell (GSC)-derived pericytes specifically disrupts the BTB and enhances drug effusion into brain tumors. We found that pericyte coverage of tumor vasculature is inversely correlated with GBM patient survival after chemotherapy. Eliminating GSC-derived pericytes in xenograft models disrupted BTB tight junctions and increased vascular permeability. We identified BMX as an essential factor for maintaining GSC-derived pericytes. Inhibiting BMX with ibrutinib selectively targeted neoplastic pericytes and disrupts the BTB, but not the BBB, thereby increasing drug effusion into established tumors and enhancing chemotherapeutic efficacy of drugs with poor BTB penetration. These findings highlight the clinical potential of targeting neoplastic pericytes to significantly enhance treatment of brain tumors. The blood-brain barrier (BBB) blocks entry of harmful materials into normal brains, but the blood-tumor barrier (BTB) prevents anti-cancer drugs from penetrating GBM tumors. Targeting GSC-derived neoplastic pericytes selectively disrupted the BTB but not BBB and potently enhanced drug delivery to effectively improve GBM treatment.
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影响因子：
10.3
作者：
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