Abstract
Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti-angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin-2 (Ang-2) as a potential target in both naive and bevacizumab-treated glioblastoma. Ang-2 expression was absent in normal human brain endothelium, while the highest Ang-2 levels were observed in bevacizumab-treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang-2, whereas the combined inhibition of VEGF and Ang-2 leads to extended survival, decreased vascular permeability, depletion of tumor-associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206(+) (M2-like) macrophages were identified as potential novel targets following anti-angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang-2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang-2 may potentially overcome resistance to bevacizumab therapy.
Highlights
Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor in adults (Ohgaki & Kleihues, 2005)
We provide evidence that the combined inhibition of angiopoietin and VEGF signaling may obliterate resistance to VEGF monotherapy caused by upregulation of Ang-2 in endothelial cells, accompanied by the presence of alternatively polarized perivascular macrophages
In GBM biopsies derived from patients that received bevacizumab therapy following standard radiochemotherapy, vessel density decreased compared to the pre-treatment biopsy, whereas Ang-2 expression was increased in the remaining tumor vessels
Summary
Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor in adults (Ohgaki & Kleihues, 2005). Bevacizumab is widely used for the treatment of recurrent GBM (Cohen et al, 2009). Two phase III clinical trials reported prolonged progression-free survival in primary GBM, beneficial results appear to be transient as tumors eventually progress and the majority of patients does not benefit from an increased overall survival (Chinot et al, 2014; Gilbert et al, 2014). Of note, based on expression profiling, GBMs have been subdivided in different genetic subtypes (Phillips et al, 2006; Verhaak et al, 2010), and a recent study suggests that only glioblastomas that display the proneural subtype are susceptible to bevacizumab therapy (Sandmann et al, 2015). Additional radiological, tissue- or bloodbased biomarkers that predict responses to bevacizumab therapy are largely missing (Brauer et al, 2013)
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