Abstract
Glioblastoma recurrence after treatment with the anti–vascular endothelial growth factor (VEGF) agent bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. Our group has previously reported that Tie2-expressing monocytes (TEMs) are aberrantly present at the tumor/normal brain interface after anti-VEGF therapies and their significant role in the invasive outgrowth of these tumors. Here, we aimed to further understand the mechanisms leading to this pro-invasive tumor microenvironment. Examination of a U87MG xenogeneic glioma model and a GL261 murine syngeneic model showed increased tumor expression of angiopoietin 2 (Ang2), a natural ligand of Tie2, after anti-angiogenesis therapies targeting VEGF or VEGF receptor (VEGFR), as assessed by immunohistochemical analysis, immunofluorescence analysis, and enzyme-linked immunosorbent assays of tumor lysates. Migration and gelatinolytic assays showed that Ang2 acts as both a chemoattractant of TEMs and an enhancing signal for their tumor-remodeling properties. Accordingly, in vivo transduction of Ang2 into intracranial gliomas increased recruitment of TEMs into the tumor. To reduce invasive tumor outgrowth after anti-angiogenesis therapy, we targeted the Ang-Tie2 axis using a Tie2 decoy receptor. Using syngeneic models, we observed that overexpression of soluble Tie2 within the tumor prevented the recruitment of TEMs to the tumor and the development of invasion after anti-angiogenesis treatment. Taken together, these data indicate an active role for the Ang2-Tie2 pathway in invasive glioma recurrence after anti-angiogenesis treatment and provide a rationale for testing the combined targeting of VEGF and Ang-Tie2 pathways in patients with glioblastoma.
Highlights
Glioblastoma is the most common and aggressive type of primary brain tumor
Our group previously reported the acquisition of an invasive phenotype and the overrepresentation of Tie2-expressing monocytes (TEMs) at areas of invasion in gliomas following anti-VEGF therapy [12, 15]
Using brain tissue sections from U87MG glioma–bearing athymic mice treated with the anti-VEGF agent aflibercept or control, we performed immunostaining for Ang1 and angiopoietin 2 (Ang2)
Summary
Glioblastoma is the most common and aggressive type of primary brain tumor. Despite therapeutic advances over the past decade, the diagnosis of glioblastoma is associated with a median overall survival time of 15–18 months and a 5-year survival rate of less than 5% [1]. Recurrence of glioblastoma after therapy is inevitable. Bevacizumab, an anti–vascular endothelial growth factor (VEGF) antibody, was approved in 2009 to treat glioblastoma recurrence on the basis of encouraging preclinical and clinical results [2, 3]. There www.impactjournals.com/oncotarget is evidence that bevacizumab reduces tumor edema, angiogenesis, and disease burden, the use of this agent as well as other VEGFA/VEGFR2-targeting drugs has been followed by adaptive tumor responses in preclinical models and clinical settings [4,5,6,7,8]. Several anti-VEGF escape mechanisms are being explored including the induction of a heightened invasive phenotype [7, 9,10,11,12]
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