Abstract
Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.
Highlights
Agents targeting the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-2 axis in glioblastoma have widely been tested [1]
Subgroup analysis of 40 specimens allowing a distinct differentiation between tumor core (n = 34) and infiltration zone (n = 6) disclosed that VEGFR-2-positive glioblastoma cells were more frequently found in the infiltration zone
Lu et al recently described a molecular mechanism by which VEGF blockade in glioblastoma cells causes enhanced tumor cell invasion through activation of the hepatocyte growth factor (HGF) receptor MET in a hypoxia-independent manner inducing a program reminiscent of epithelial-to-mesenchymal transition [6]
Summary
Agents targeting the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-2 axis in glioblastoma have widely been tested [1]. Recent phase III trials in newly diagnosed glioblastoma demonstrated a failure of the monoclonal anti-VEGFdirected antibody bevacizumab (BEV) to extend overall survival (OS) when combined with chemoradiation, despite benefits in progression-free survival (PFS) and quality of life [2, 3]. Upon progression on BEV, glioblastoma can display a more infiltrative pattern of recurrence [7]. A recent study from our own group argued that the promotion of distant tumor growth or a gliomatosis-like growth phenotype at recurrence is relevant at best in a minority of patients [8]. An analysis from the AVAglio trial argues against a specific propensity of BEV to induce diffuse or infiltrative growth, but identified a subgroup of patients showing this tumor growth behavior [9]. Molecular profiling allowing an identification of subgroups of tumors that are at increased risk to develop early resistance towards antiangiogenic treatments remains an unmet need
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