Differential regulation of TGF-β-induced, ALK-5-mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma
Differential regulation of TGF-β-induced, ALK-5-mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma
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DOI：
10.1093/neuonc/nou218
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发表时间：
2015-02-01
期刊：
影响因子：
15.9
通讯作者：
Weller, Michael
中科院分区：
文献类型：
--
作者：
Seystahl, Katharina;Tritschler, Isabel;Weller, Michael
背景转化生长因子（TGF）-β和血管内皮生长因子（VEGF）通路在胶质母细胞瘤的发病机制中具有重要作用，特别是免疫抑制、迁移和血管生成，但它们之间的相互作用仍不清楚。我们在9个长期胶质瘤细胞系（LTC）和4个胶质瘤起始细胞系（GIC）中表征了TGF-β通路活性与组成性和外源性TGF-β诱导的VEGF释放的关系。使用癌症基因组图谱转录组学数据验证结果。胶质瘤细胞表现出组成性TGF-β途径激活的异质性模式，这不仅反映在SMAD 2和SMAD 3的磷酸化上，还反映在SMAD 1/5/8的磷酸化上。组成型TGF-β途径活性取决于I型TGF-β受体ALK 5，并占组成型VEGF释放的高达69%，其以细胞系特异性方式由SMAD 2/3正调控并由SMAD 1/5/8信号传导负调控。在大多数细胞系中，外源性TGF-β以SMAD和ALK-5依赖性方式诱导VEGF释放。与缺氧相比，TGF-β诱导的VEGF分泌的倍数诱导之间没有相关性。SMAD 5信号传导的作用是高度环境和细胞系依赖性的，在低TGF-β和pSMAD 2水平下具有VEGF抑制作用，并且在TGF-β丰富时具有刺激作用。TGF-β以ALK-5依赖性方式调节胶质瘤细胞的VEGF释放，涉及SMAD 2、SMAD 3和SMAD 1/5/8信号传导。TGF-β和VEGF通路之间的这种串扰可能会开辟生物标志物驱动的探索性临床试验的新途径，重点关注胶质母细胞瘤的微环境。
Background. The transforming growth factor (TGF)-beta and vascular endothelial growth factor (VEGF) pathways have a major role in the pathogenesis of glioblastoma, notably immunosuppression, migration, and angiogenesis, but their interactions have remained poorly understood.Methods. We characterized TGF-beta pathway activity in 9 long-term glioma cell lines (LTCs) and 4 glioma-initiating cell lines (GICs) in relation to constitutive and exogenous TGF-beta-induced VEGF release. Results were validated using The Cancer Genome Atlas transcriptomics data.Results. Glioma cells exhibit heterogeneous patterns of constitutive TGF-beta pathway activation reflected by phosphorylation not only of SMAD2 and SMAD3 but also of SMAD1/5/8. Constitutive TGF-beta pathway activity depends on the type I TGF-beta receptor, ALK5, and accounts for up to 69% of constitutive VEGF release, which is positively regulated by SMAD2/3 and negatively regulated by SMAD1/5/8 signaling in a cell line-specific manner. Exogenous TGF-beta induces VEGF release in most cell lines in a SMAD-and ALK-5-dependent manner. There is no correlation between the fold induction of VEGF secretion induced by TGF-beta compared with hypoxia. The role of SMAD5 signaling is highly context and cell-line dependent with a VEGF inhibitory effect at low TGF-beta and pSMAD2 levels and a stimulatory effect when TGF-beta is abundant.Conclusions. TGF-beta regulates VEGF release by glioma cells in an ALK-5-dependent manner involving SMAD2, SMAD3, and SMAD1/5/8 signaling. This crosstalk between the TGF-beta and VEGF pathways may open up new avenues of biomarker-driven exploratory clinical trials focusing on the microenvironment in glioblastoma.