The blood-tumor barrier (BTB) is a major obstacle for drug delivery to malignant brain tumors such as glioblastoma (GBM). 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 disrupted the BTB, but not the BBB, thereby increasing drug effusion into established tumors and enhancing the chemotherapeutic efficacy of drugs with poor BTB penetration. These findings highlight the clinical potential of targeting neoplastic pericytes to significantly improve treatment of brain tumors.

中文翻译：

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靶向神经胶质瘤干细胞衍生的周细胞破坏了血液肿瘤屏障并提高了化学疗法的功效。

血液肿瘤屏障（BTB）是药物向恶性脑肿瘤（例如成胶质细胞瘤（GBM））的主要递送障碍。因此，非常需要破坏BTB，但是由于需要维持正常的血脑屏障（BBB）而变得复杂。在这里，我们显示靶向神经胶质瘤干细胞（GSC）衍生的周细胞特异性破坏了BTB，并增强了向脑肿瘤中的药物渗出。我们发现，肿瘤血管的周细胞覆盖率与化疗后GBM患者的存活率呈负相关。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是维持GSC衍生的周细胞的必要因素。用依鲁替尼抑制BMX选择性靶向肿瘤性周细胞并破坏BTB，但不破坏BBB，从而增加了向既定肿瘤中的药物渗出，并增强了BTB渗透性差的药物的化学治疗功效。这些发现突出了靶向肿瘤性周细胞显着改善脑肿瘤治疗的临床潜力。