Abstract
Glioblastoma (GBM) is the most aggressive type of brain tumor. Microvascular proliferation and abnormal vasculature are the hallmarks of the GBM, aggravating disease progression and increasing patient morbidity. Here, we uncovered a key role of ETS1 on vascular abnormality in glioblastoma. ETS1 was upregulated in endothelial cells from human tumors compared to endothelial cells from paired control brain tissue. Knockdown of Ets1 in mouse brain endothelial cells inhibited cell migration and proliferation, and suppressed expression of genes associated with vascular abnormality in GBM. ETS1 upregulation in tumor ECs was dependent on TGFβ signaling, and targeting TGFβ signaling by inhibitor decreased tumor angiogenesis and vascular abnormality in CT-2A glioma model. Our results identified ETS1 as a key factor regulating tumor angiogenesis, and suggested that TGFβ inhibition may suppress the vascular abnormality driven by ETS1.
Highlights
Glioblastoma (GBM) is the most aggressive and common primary malignant brain tumor with a dismal prognosis [1]
The expression of ETS1 in distinct anatomical locations of 34 GBM samples was analyzed by using Ivy GAP database [38], which documented transcriptome from microdissected human GBM anatomic regions, including leading edge, infiltrating tumor region, cellular tumor core region, microvascular proliferation region and pseudopalisading necrosis region
These results indicate that ETS1 is upregulated in GBM Endothelial cells (ECs)
Summary
Glioblastoma (GBM) is the most aggressive and common primary malignant brain tumor with a dismal prognosis [1]. Microvascular proliferation and abnormal vasculature are the hallmarks of GBM [2,3]. Vascular abnormality aggravates GBM progression by promoting tumor cell invasiveness through inducing hypoxia [5,6]. Vasculature in GBM has been identified as an attractive therapeutic target for treatment [7]. Several signal pathways driving vascular abnormality in GBM have been uncovered, including hypoxia, transforming growth factor β (TGFβ), pleiotrophin (PTN) and vascular endothelial growth factor (VEGF) signaling pathways [9,10,11,12]. Further knowledges revealing molecular mechanisms of vascular abnormality in GBM may improve the efficiency of current vessel-targeting therapies and yield novel therapeutic strategies [14]
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