Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
Clin Cancer Res. 2019 Mar 15;25(6):1851-1866. doi: 10.1158/1078-0432.CCR-18-1965. Epub 2018 Dec 7.
Pilocytic astrocytoma is the most common childhood brain tumor, characterized by constitutive MAPK activation. MAPK signaling induces oncogene-induced senescence (OIS), which may cause unpredictable growth behavior of pilocytic astrocytomas. The senescence-associated secretory phenotype (SASP) has been shown to regulate OIS, but its role in pilocytic astrocytoma remains unknown. The patient-derived pilocytic astrocytoma cell culture model, DKFZ-BT66, was used to demonstrate presence of the SASP and analyze its impact on OIS in pilocytic astrocytoma. The model allows for doxycycline-inducible switching between proliferation and OIS. Both states were studied using gene expression profiling (GEP), Western blot, ELISA, and cell viability testing. Primary pilocytic astrocytoma tumors were analyzed by GEP and multiplex assay.
SASP factors were upregulated in primary human and murine pilocytic astrocytoma and during OIS in DKFZ-BT66 cells. Conditioned medium induced growth arrest of proliferating pilocytic astrocytoma cells. The SASP factors IL1B and IL6 were upregulated in primary pilocytic astrocytoma, and both pathways were regulated during OIS in DKFZ-BT66. Stimulation with rIL1B but not rIL6 reduced growth of DKFZ-BT66 cells and induced the SASP. Anti-inflammatory treatment with dexamethasone induced regrowth of senescent cells and inhibited the SASP. Senescent DKFZ-BT66 cells responded to senolytic BCL2 inhibitors. High and SASP expression in pilocytic astrocytoma tumors was associated with favorable progression-free survival.
We provide evidence for the SASP regulating OIS in pediatric pilocytic astrocytoma, with IL1B as a relevant mediator. SASP expression could enable prediction of progression in patients with pilocytic astrocytoma. Further investigation of the SASP driving the unpredictable growth of pilocytic astrocytomas, and its possible therapeutic application, is warranted.
毛细胞型星形细胞瘤是最常见的儿童脑肿瘤，其特征是组成性 MAPK 激活。MAPK 信号诱导致癌基因诱导的衰老（OIS），这可能导致毛细胞型星形细胞瘤不可预测的生长行为。衰老相关分泌表型（SASP）已被证明可调节 OIS，但它在毛细胞型星形细胞瘤中的作用尚不清楚。使用患者来源的毛细胞型星形细胞瘤细胞培养模型 DKFZ-BT66 来证明 SASP 的存在，并分析其对毛细胞型星形细胞瘤中 OIS 的影响。该模型允许在增殖和 OIS 之间进行四环素诱导的切换。两种状态均使用基因表达谱（GEP）、Western blot、ELISA 和细胞活力测试进行研究。通过 GEP 和多重分析对原发性毛细胞型星形细胞瘤肿瘤进行分析。
在原发性人类和鼠毛细胞型星形细胞瘤以及 DKFZ-BT66 细胞中的 OIS 过程中，SASP 因子上调。条件培养基诱导增殖的毛细胞型星形细胞瘤细胞生长停滞。在原发性毛细胞型星形细胞瘤中，IL1B 和 IL6 等 SASP 因子上调，并且在 DKFZ-BT66 中的 OIS 过程中，这两条通路均受到调节。用 rIL1B 而非 rIL6 刺激可降低 DKFZ-BT66 细胞的生长并诱导 SASP。用地塞米松进行抗炎治疗可诱导衰老细胞重新生长并抑制 SASP。衰老的 DKFZ-BT66 细胞对 SASP 抑制剂 BCL2 有反应。毛细胞型星形细胞瘤肿瘤中高表达 和 SASP 与无进展生存期有利相关。
我们提供了证据表明 SASP 调节儿科毛细胞型星形细胞瘤中的 OIS，其中 IL1B 是一种相关介质。SASP 表达可用于预测毛细胞型星形细胞瘤患者的进展。进一步研究 SASP 驱动毛细胞型星形细胞瘤不可预测生长的可能性及其可能的治疗应用是值得的。
