Ccl5 establishes an autocrine high-grade glioma growth regulatory circuit critical for mesenchymal glioblastoma survival.
Ccl5 establishes an autocrine high-grade glioma growth regulatory circuit critical for mesenchymal glioblastoma survival.
复制标题
DOI：
10.18632/oncotarget.16516
复制
发表时间：
2017-05-16
期刊：
影响因子：
--
通讯作者：
Gutmann DH
中科院分区：
文献类型：
--
作者：
Pan Y;Smithson LJ;Ma Y;Hambardzumyan D;Gutmann DH
胶质母细胞瘤（GBM）是成人中最常见的恶性脑肿瘤，中位生存期为15个月。这些不良的临床结果促进了阻断肿瘤癌细胞生长的药物的开发;然而，肿瘤微环境中的非肿瘤细胞来源的信号（趋化因子和细胞因子）也可能代表可行的治疗靶点。一种这样的趋化因子Ccl 5由低级别肿瘤相关的小胶质细胞产生，负责维持神经纤维瘤病1型（NF 1）小鼠视神经胶质瘤在体内的生长。由于恶性胶质瘤可以实现部分独立于肿瘤微环境中的非肿瘤细胞产生的生长调节因子，通过产生与低级别对应物中基质细胞分泌的相同细胞因子，我们测试了胶质母细胞瘤中的CCL 5/CCL 5受体信号传导产生对高级别胶质瘤生长重要的自分泌回路的假设。在此，我们证明了CCL 5表达的增加仅限于人和小鼠间充质GBM（M-GBM），这是一种以NF 1丢失为特征的分子亚型。我们进一步表明，NF 1蛋白，神经纤维蛋白，通过抑制AKT/mTOR信号负调控Ccl 5的表达。与其作为胶质母细胞瘤生长调节剂的作用一致，M-GBM细胞中的Ccl 5敲低降低了体外M-GBM细胞存活，并增加了体内小鼠胶质母细胞瘤存活。最后，我们证明了CCL 5通过非常规的CCL 5受体CD 44来抑制M-GBM凋亡。总的来说，这些研究结果揭示了一个NF 1依赖性CCL 5介导的途径，调节M-GBM细胞的生存，并支持的概念，即旁分泌因子的重要性低级别胶质瘤生长可以篡夺高级别肿瘤，以创建自分泌调节电路，维持恶性胶质瘤的生存。
Glioblastoma (GBM) is the most common malignant brain tumor in adults, with a median survival of 15 months. These poor clinical outcomes have prompted the development of drugs that block neoplastic cancer cell growth; however, non-neoplastic cell-derived signals (chemokines and cytokines) in the tumor microenvironment may also represent viable treatment targets. One such chemokine, Ccl5, produced by low-grade tumor-associated microglia, is responsible for maintaining neurofibromatosis type 1 (NF1) mouse optic glioma growth in vivo. Since malignant gliomas may achieve partial independence from growth regulatory factors produced by non-neoplastic cells in the tumor microenvironment by producing the same cytokines secreted by the stromal cells in their low-grade counterparts, we tested the hypothesis that CCL5/CCL5-receptor signaling in glioblastoma creates an autocrine circuit important for high-grade glioma growth. Herein, we demonstrate that increased CCL5 expression was restricted to both human and mouse mesenchymal GBM (M-GBM), a molecular subtype characterized by NF1 loss. We further show that the NF1 protein, neurofibromin, negatively regulates Ccl5 expression through suppression of AKT/mTOR signaling. Consistent with its role as a glioblastoma growth regulator, Ccl5 knockdown in M-GBM cells reduces M-GBM cell survival in vitro, and increases mouse glioblastoma survival in vivo. Finally, we demonstrate that Ccl5 operates through an unconventional CCL5 receptor, CD44, to inhibit M-GBM apoptosis. Collectively, these findings reveal an NF1-dependent CCL5-mediated pathway that regulates M-GBM cell survival, and support the concept that paracrine factors important for low-grade glioma growth can be usurped by high-grade tumors to create autocrine regulatory circuits that maintain malignant glioma survival.