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Limited role for transforming growth factor-β pathway activation-mediated escape from VEGF inhibition in murine glioma models


Mangani, D; Weller, M; Seyed Sadr, E; Willscher, E; Seystahl, K; Reifenberger, G; Tabatabai, G; Binder, H; Schneider, H (2016). Limited role for transforming growth factor-β pathway activation-mediated escape from VEGF inhibition in murine glioma models. Neuro-Oncology, 18(12):1610-1621.

Abstract

BACKGROUND The vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β pathways regulate key biological features of glioblastoma. Here we explore whether the TGF-β pathway, which promotes angiogenesis, invasiveness, and immunosuppression, acts as an escape pathway from VEGF inhibition. METHODS The role of the TGF-β pathway in escape from VEGF inhibition was assessed in vitro and in vivo and by gene expression profiling in syngeneic mouse glioma models. RESULTS We found that TGF-β is an upstream regulator of VEGF, whereas VEGF pathway activity does not alter the TGF-β pathway in vitro. In vivo, single-agent activity was observed for the VEGF antibody B20-4.1.1 in 3 and for the TGF-β receptor 1 antagonist LY2157299 in 2 of 4 models. Reduction of tumor volume and blood vessel density, but not induction of hypoxia, correlated with benefit from B20-4.1.1. Reduction of phosphorylated (p)SMAD2 by LY2157299 was seen in all models but did not predict survival. Resistance to B20 was associated with anti-angiogenesis escape pathway gene expression, whereas resistance to LY2157299 was associated with different immune response gene signatures in SMA-497 and GL-261 on transcriptomic profiling. The combination of B20 with LY2157299 was ineffective in SMA-497 but provided prolongation of survival in GL-261, associated with early suppression of pSMAD2 in tumor and host immune cells, prolonged suppression of angiogenesis, and delayed accumulation of tumor infiltrating microglia/macrophages. CONCLUSIONS Our study highlights the biological heterogeneity of murine glioma models and illustrates that cotargeting of the VEGF and TGF-β pathways might lead to improved tumor control only in subsets of glioblastoma.

Abstract

BACKGROUND The vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β pathways regulate key biological features of glioblastoma. Here we explore whether the TGF-β pathway, which promotes angiogenesis, invasiveness, and immunosuppression, acts as an escape pathway from VEGF inhibition. METHODS The role of the TGF-β pathway in escape from VEGF inhibition was assessed in vitro and in vivo and by gene expression profiling in syngeneic mouse glioma models. RESULTS We found that TGF-β is an upstream regulator of VEGF, whereas VEGF pathway activity does not alter the TGF-β pathway in vitro. In vivo, single-agent activity was observed for the VEGF antibody B20-4.1.1 in 3 and for the TGF-β receptor 1 antagonist LY2157299 in 2 of 4 models. Reduction of tumor volume and blood vessel density, but not induction of hypoxia, correlated with benefit from B20-4.1.1. Reduction of phosphorylated (p)SMAD2 by LY2157299 was seen in all models but did not predict survival. Resistance to B20 was associated with anti-angiogenesis escape pathway gene expression, whereas resistance to LY2157299 was associated with different immune response gene signatures in SMA-497 and GL-261 on transcriptomic profiling. The combination of B20 with LY2157299 was ineffective in SMA-497 but provided prolongation of survival in GL-261, associated with early suppression of pSMAD2 in tumor and host immune cells, prolonged suppression of angiogenesis, and delayed accumulation of tumor infiltrating microglia/macrophages. CONCLUSIONS Our study highlights the biological heterogeneity of murine glioma models and illustrates that cotargeting of the VEGF and TGF-β pathways might lead to improved tumor control only in subsets of glioblastoma.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:10 June 2016
Deposited On:17 Nov 2016 10:44
Last Modified:11 Jun 2017 00:00
Publisher:Oxford University Press
ISSN:1522-8517
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/neuonc/now112
PubMed ID:27286797

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