Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.
Cell Stem Cell. 2017 Nov 2;21(5):591-603.e4. doi: 10.1016/j.stem.2017.10.002.
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.
血脑屏障（BTB）是药物递送至恶性脑肿瘤（如胶质母细胞瘤[GBM]）的主要障碍。因此，破坏 BTB 是非常可取的，但由于需要维持正常的血脑屏障（BBB），这变得非常复杂。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破坏 BTB 并增强药物渗透到脑肿瘤中。我们发现，周细胞对肿瘤血管的覆盖与 GBM 患者化疗后的生存呈负相关。在异种移植模型中消除 GSC 衍生的周细胞会破坏 BTB 紧密连接并增加血管通透性。我们发现 BMX 是维持 GSC 衍生的周细胞所必需的重要因素。用伊布替尼抑制 BMX 选择性地靶向肿瘤性周细胞并破坏 BTB，但不破坏 BBB，从而增加了已建立的肿瘤内药物渗透并增强了 BTB 穿透性差的药物的化疗疗效。这些发现强调了靶向肿瘤性周细胞以显著改善脑肿瘤治疗的临床潜力。
