Seystahl Katharina, Tritschler Isabel, Szabo Emese, Tabatabai Ghazaleh, Weller Michael
Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
Neuro Oncol. 2015 Feb;17(2):254-65. doi: 10.1093/neuonc/nou218. Epub 2014 Aug 27.
The transforming growth factor (TGF)-β 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.
We characterized TGF-β pathway activity in 9 long-term glioma cell lines (LTCs) and 4 glioma-initiating cell lines (GICs) in relation to constitutive and exogenous TGF-β-induced VEGF release. Results were validated using The Cancer Genome Atlas transcriptomics data.
Glioma cells exhibit heterogeneous patterns of constitutive TGF-β pathway activation reflected by phosphorylation not only of SMAD2 and SMAD3 but also of SMAD1/5/8. Constitutive TGF-β pathway activity depends on the type I TGF-β receptor, ALK-5, 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-β 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-β compared with hypoxia. The role of SMAD5 signaling is highly context and cell-line dependent with a VEGF inhibitory effect at low TGF-β and pSMAD2 levels and a stimulatory effect when TGF-β is abundant.
TGF-β 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-β and VEGF pathways may open up new avenues of biomarker-driven exploratory clinical trials focusing on the microenvironment in glioblastoma.
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起主要作用,尤其是免疫抑制、迁移和血管生成,但它们之间的相互作用仍知之甚少。
我们对9种长期胶质瘤细胞系(LTCs)和4种胶质瘤起始细胞系(GICs)中的TGF-β通路活性进行了表征,这些细胞系与组成型和外源性TGF-β诱导的VEGF释放有关。结果使用癌症基因组图谱转录组学数据进行了验证。
胶质瘤细胞表现出组成型TGF-β通路激活的异质性模式,这不仅通过SMAD2和SMAD3的磷酸化反映,还通过SMAD1/5/8的磷酸化反映。组成型TGF-β通路活性取决于I型TGF-β受体ALK-5,并占组成型VEGF释放的69%,其在细胞系特异性方式中由SMAD2/3正向调节并由SMAD1/5/8信号负向调节。外源性TGF-β以SMAD和ALK-5依赖的方式在大多数细胞系中诱导VEGF释放。与缺氧相比,TGF-β诱导的VEGF分泌的诱导倍数之间没有相关性。SMAD5信号的作用高度依赖于背景和细胞系,在低TGF-β和pSMAD2水平时具有VEGF抑制作用,而在TGF-β丰富时具有刺激作用。
TGF-β以依赖ALK-5的方式调节胶质瘤细胞的VEGF释放,涉及SMAD2、SMAD3和SMAD1/5/8信号。TGF-β和VEGF通路之间的这种串扰可能为聚焦胶质母细胞瘤微环境的生物标志物驱动的探索性临床试验开辟新途径。