Abstract
One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs.
Highlights
Glioblastoma (GBM) is the most common and lethal primary adult brain tumor
These results demonstrate that Glioma-associated macrophages (GAM) induce Endothelial cells (EC) activation
In this study, we report a new mechanism of endothelial cell activation in GBM, which is mediated by TNFα secreting GAMs
Summary
Chemotherapy, and radiation, the prognosis for GBM patients remains very poor with a median survival time of only 12–15 months [34]. These highly invasive and vascularized tumors inevitably escape treatment. Given that GBMs are a highly vascular tumor, antiangiogenic therapies (AATx) have held considerable promise. Inhibitors targeting the key angiogenic regulator, vascular endothelial growth factor (VEGF), have shown a lack of efficacy in the clinic. Two phase III clinical trials targeting VEGF showed that Bevacizumab failed to improve overall survival (OS) in GBM patients, diminishing the enthusiasm for AATx in these tumors [10, 15]. A greater understanding of the underlying molecular mechanisms that promote
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