Bevacizumab is routinely used in combination with chemotherapy for the treatment of recurrent glioblastoma. Unfortunately, several recent clinical reports suggest that antiVEGF treatment may in fact promote a promigratory cellular tumor phenotype in patients with recurrent glioblastoma. Importantly, these clinical observations are supported by several preclinical studies that in principle show that antiVEGF treatment in mice or rats promotes a proinvasive phenotype and may even increase tumor metastasis. A possible explanation for this phenomenon, which represents a major challenge and clinical drawback, might be the induction of hypoxia and upregulation of hypoxiainducible genes via the HIF alpha pathway. Indeed, it has been suggested that hypoxiamediated migration of tumor cells is responsible for the development of pseudopalisading glioma cells surrounding necroses, a histological hallmark of glioblastoma. As such, these cells may represent glioma cells that are hypoxic and try to escape from a low oxygen microenvironment. The molecular mechanisms underlying this event are only partly understood.The protooncogene cmet, for example, has been shown to be upregulated by hypoxia and to trigger invasion. Recently, it has been suggested that cmet is activated in GBM upon bevacizumab treatment in a VEGFR and phosphotyrosine phosphatase dependent manner.In this scenario, bevacizumabinduced depletion of VEGF reduces PTPB activity and promotes cmet phosphorylation.This mechanism may therefore account at least in part for the observed therapyinduced switch to a promigratory phenotype after bevacizumab treatment. However, this putative mechanism requires the coexpression of cmet together with VEGFR on glioma cells in vivo.Whereas VEGFR can be readily detected in glioma cell lines in vitro, most studies suggest that in both murine and human glioma specimens in vivo expression of VEGFR is mainly conned to vascular endothelial cells. Several preclinical studies have shown that modulation of this pathway leads to alterations in vascular morphology and inhibition of tumor growth.Several types of angiopoietin inhibitors are now in phase IIII clinical trials. Tie is bound by three different ligands that engage the same binding site on the receptor.During vascular regression the occlusion of vessels leads to disturbed and reduced blood ow leading to KLF downregulation.Ang in turn becomes upregulated and triggers the dissociation of pericytes, the degradation of the basement membrane by inducing matrix metalloproteases and interferes with endothelial cell integrity proinammatory phenotype.Notch in concert with VEGF signaling appears to be instrumental in the tip cell versus stalk cell fate decision that is essential for the initiation of sprouting angiogenesis. The upregulation of VEGFR, which acts as a decoy receptor, further contributes to the maintenance of the VEGF gradient.This concept states that antiangiogenic treatment merely affects the immature vasculature and leaves the mature vessels unaltered.Indeed, it has been shown that VEGF withdrawal leads to selective ablation of immature blood vessels. As such, a normalized vasculature results as a consequence of antiVEGF treatment, leading to increased perfusion of the tumor and Nalmefene hydrochloride subsequent increase of Atazanavir sulfate oxygenation.Vascular normalization is thought to interrupt the vicious circle that is driven by hypoxia and that leads to upregulation of VEGF, resulting in the growth of immaturepartly unperfusedvessels and a subsequent increase in tumor hypoxia.