Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large-and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.angiogenesis | glioma | metabolism | perfusion G lioblastomas (GBMs) are highly vascularized brain tumors and are therefore attractive targets for anti-angiogenic therapies (1). In particular, vascular endothelial growth factor (VEGF) has been identified as a critical regulator of angiogenesis, and currently a number of clinical trials targeting the VEGFsignaling pathways are under development (2, 3). Bevacizumab (bev), a humanized anti-VEGF antibody, has shown promising results in exploratory phase II trials of recurrent GBM. Alone or in combination with irinotecan, it is well tolerated and shows a high radiological response rate and possibly an increase in median progression-free survival compared with historical controls (4-7), although no impact on overall survival has been reported (8). However, these results are based on small patient cohorts and, because anti-angiogenic agents directly affect vessel permeability, the imaging response assessment based on contrast enhancement (CE) is highly ambiguous (9). Indeed, a direct antitumor effect of bev has remained elusive and the infiltrative part of the tumor may even increase (10,11). In addition to a lack of robust clinical data, the cellular and molecular consequences of anti-VEGF treatment have not been outlined (12). Detailed information on how bev affects ...

We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants of BRCA2-K3326X (rs11571833; odds ratio [OR]=2.47, P=4.74×10−20) and of CHEK2-I157T (rs17879961; OR=0.38 P=1.27×10−13). We also showed an association between common variation at 3q28 (TP63; rs13314271; OR=1.13, P=7.22×10−10) and lung adenocarcinoma previously only reported in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants having substantive effects on cancer risk from pre-existing GWAS data.

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The results suggest that VEGF(165) content in tumor cytosols is a predictor of RFS and OS in primary NPBC. VEGF content might also predict outcome after adjuvant endocrine treatment, but further studies in a prospective setting with homologous treatments are required.