Dataset Information

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

ABSTRACT:

Background

The vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-? pathways regulate key biological features of glioblastoma. Here we explore whether the TGF-? pathway, which promotes angiogenesis, invasiveness, and immunosuppression, acts as an escape pathway from VEGF inhibition.

Methods

The role of the TGF-? 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-? is an upstream regulator of VEGF, whereas VEGF pathway activity does not alter the TGF-? pathway in vitro. In vivo, single-agent activity was observed for the VEGF antibody B20-4.1.1 in 3 and for the TGF-? 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-? pathways might lead to improved tumor control only in subsets of glioblastoma.

SUBMITTER: Mangani D

PROVIDER: S-EPMC6693192 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Mangani Davide D Weller Michael M Seyed Sadr Emad E Willscher Edith E Seystahl Katharina K Reifenberger Guido G Tabatabai Ghazaleh G Binder Hans H Schneider Hannah H

Neuro-oncology 20160610 12

<h4>Background</h4>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.<h4>Methods</h4>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.<h4> ...[more]

PMID: 27286797

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