Crosstalk between glioma-initiating cells and endothelial cells drives tumor progression.
Crosstalk between glioma-initiating cells and endothelial cells drives tumor progression.
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DOI：
10.1158/0008-5472.can-13-1597
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发表时间：
2014-08-15
期刊：
影响因子：
11.2
通讯作者：
Kim H
中科院分区：
文献类型：
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作者：
Jeon HM;Kim SH;Jin X;Park JB;Kim SH;Joshi K;Nakano I;Kim H
胶质瘤起始细胞（GIC）位于血管周围微环境中以维持自我更新能力，负责胶质母细胞瘤的起始、进展和复发。然而，控制GIC和内皮细胞之间串扰的分子机制知之甚少。在这里，我们报告说，在GIC和内皮细胞，血小板衍生生长因子（PDGF）驱动的一氧化氮（NO）合酶的激活增加NO依赖性分化抑制剂4（ID 4）的表达，这反过来又促进JAGGED 1-NOTCH活性通过抑制miR 129，特异性抑制JAGGED 1抑制。该信号传导轴促进肿瘤进展沿着增加的GIC自我更新和异种移植肿瘤中肿瘤脉管系统的生长，其被NOTCH抑制剂显著抑制。在原发性GIC中，ID 4水平与NOS 2（NO合成酶-2）、HES 1和HEY 1正相关，与miR 129负相关。因此，靶向血管周围微环境中的PDGF-NOS-ID 4-miR 129轴和NOTCH活性可能作为胶质母细胞瘤的有效治疗方式。
Glioma-initiating cells (GIC), which reside within the perivascular microenvironment to maintain self-renewal capacity, are responsible for glioblastoma initiation, progression, and recurrence. However, the molecular mechanisms controlling crosstalk between GICs and endothelial cells are poorly understood. Here, we report that, in both GICs and endothelial cells, platelet-derived growth factor (PDGF)–driven activation of nitric oxide (NO) synthase increases NO-dependent inhibitor of differentiation 4 (ID4) expression, which in turn promotes JAGGED1–NOTCH activity through suppression of miR129 that specifically represses JAGGED1 suppression. This signaling axis promotes tumor progression along with increased GIC self-renewal and growth of tumor vasculature in the xenograft tumors, which is dramatically suppressed by NOTCH inhibitor. ID4 levels correlate positively with NOS2 (NO synthase-2), HES1, and HEY1 and negatively with miR129 in primary GICs. Thus, targeting the PDGF–NOS–ID4–miR129 axis and NOTCH activity in the perivascular microenvironment might serve as an efficacious therapeutic modality for glioblastoma.