Mangani Davide, Weller Michael, Seyed Sadr Emad, Willscher Edith, Seystahl Katharina, Reifenberger Guido, Tabatabai Ghazaleh, Binder Hans, Schneider Hannah
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland (D.M., M.W., E.S.S., K.S., G.T., H.S.); Center for Neuroscience, University of Zurich, Zurich, Switzerland (M.W., G.T.); Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany (E.W., H.B.); Institute of Neuropathology, Heinrich Heine University, Düsseldorf, Germany (G.R.); German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, partner site, Essen/Düsseldorf, Germany (G.R.).
Neuro Oncol. 2016 Dec;18(12):1610-1621. doi: 10.1093/neuonc/now112. Epub 2016 Jun 10.
The vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β pathways regulate key biological features of glioblastoma. Here we explore whether the TGF-β pathway, which promotes angiogenesis, invasiveness, and immunosuppression, acts as an escape pathway from VEGF inhibition.
The role of the TGF-β pathway in escape from VEGF inhibition was assessed in vitro and in vivo and by gene expression profiling in syngeneic mouse glioma models.
We found that TGF-β is an upstream regulator of VEGF, whereas VEGF pathway activity does not alter the TGF-β pathway in vitro. In vivo, single-agent activity was observed for the VEGF antibody B20-4.1.1 in 3 and for the TGF-β receptor 1 antagonist LY2157299 in 2 of 4 models. Reduction of tumor volume and blood vessel density, but not induction of hypoxia, correlated with benefit from B20-4.1.1. Reduction of phosphorylated (p)SMAD2 by LY2157299 was seen in all models but did not predict survival. Resistance to B20 was associated with anti-angiogenesis escape pathway gene expression, whereas resistance to LY2157299 was associated with different immune response gene signatures in SMA-497 and GL-261 on transcriptomic profiling. The combination of B20 with LY2157299 was ineffective in SMA-497 but provided prolongation of survival in GL-261, associated with early suppression of pSMAD2 in tumor and host immune cells, prolonged suppression of angiogenesis, and delayed accumulation of tumor infiltrating microglia/macrophages.
Our study highlights the biological heterogeneity of murine glioma models and illustrates that cotargeting of the VEGF and TGF-β pathways might lead to improved tumor control only in subsets of glioblastoma.
血管内皮生长因子（VEGF）和转化生长因子（TGF）-β信号通路调节胶质母细胞瘤的关键生物学特性。在此，我们探讨促进血管生成、侵袭和免疫抑制的TGF-β信号通路是否作为VEGF抑制的逃逸途径。
在同基因小鼠胶质瘤模型中，通过体外和体内实验以及基因表达谱分析评估TGF-β信号通路在逃避VEGF抑制中的作用。
我们发现TGF-β是VEGF的上游调节因子，而在体外VEGF信号通路活性不会改变TGF-β信号通路。在体内，VEGF抗体B20-4.1.1在4个模型中的3个显示出单药活性，TGF-β受体1拮抗剂LY2157299在4个模型中的2个显示出单药活性。肿瘤体积和血管密度的降低，但不是缺氧的诱导，与B20-4.1.1的疗效相关。LY2157299在所有模型中均可见磷酸化（p）SMAD2的降低，但不能预测生存。对B20的耐药与抗血管生成逃逸途径基因表达相关，而对LY2157299的耐药在转录组分析中与SMA-497和GL-261中不同的免疫反应基因特征相关。B20与LY2157299联合在SMA-497中无效，但在GL-261中可延长生存期，这与肿瘤和宿主免疫细胞中pSMAD2的早期抑制、血管生成的长期抑制以及肿瘤浸润小胶质细胞/巨噬细胞的延迟积累有关。
我们的研究突出了小鼠胶质瘤模型的生物学异质性，并表明同时靶向VEGF和TGF-β信号通路可能仅在部分胶质母细胞瘤中改善肿瘤控制。
