Neuropilin-1 modulates TGFβ signaling to drive glioblastoma growth and recurrence after anti-angiogenic therapy.

Sam C Kwiatkowski,Manish Aghi,John E Morales,Joseph H Mccarty,Paola A Guerrero,Shinya Hirota,Zhihua Chen,Guido Serini

doi:10.1371/journal.pone.0185065

Abstract

Glioblastoma (GBM) is a rapidly progressive brain cancer that exploits the neural microenvironment, and particularly blood vessels, for selective growth and survival. Anti-angiogenic agents such as the vascular endothelial growth factor-A (VEGF-A) blocking antibody bevacizumab yield short-term benefits to patients due to blood vessel regression and stabilization of vascular permeability. However, tumor recurrence is common, and this is associated with acquired resistance to bevacizumab. The mechanisms that drive acquired resistance and tumor recurrence in response to anti-angiogenic therapy remain largely unknown. Here, we report that Neuropilin-1 (Nrp1) regulates GBM growth and invasion by balancing tumor cell responses to VEGF-A and transforming growth factor βs (TGFβs). Nrp1 is expressed in GBM cells where it promotes TGFβ receptor internalization and signaling via Smad transcription factors. GBM that recur after bevacizumab treatment show down-regulation of Nrp1 expression, indicating that altering the balance between VEGF-A and TGFβ signaling is one mechanism that promotes resistance to anti-angiogenic agents. Collectively, these data reveal that Nrp1 plays a critical role in balancing responsiveness to VEGF-A versus TGFβ to regulate GBM growth, progression, and recurrence after anti-vascular therapy.

Highlights

GBM is a malignant brain cancer that is distinguished from lower grade tumors, in part, by the development of hallmark angiogenesis pathologies, including florid microvascular cell proliferation and breakdown of the intratumoral blood-brain barrier [1]
Mesenchymal tumors are distinguished from other molecular subtypes by enhanced expression of genes involved in pathological angiogenesis, hypoxia, and necrosis, including vascular endothelial growth factor-A (VEGF-A) and extracellular matrix (ECM) components such as fibronectins and angiopoietins [28,29,30]
We sought to elucidate the roles for this pathway in human LN229 GBM cells that express Nrp1 and show transforming growth factor βs (TGFβs)-responsive signaling

Summary

Introduction

GBM is a malignant brain cancer that is distinguished from lower grade tumors, in part, by the development of hallmark angiogenesis pathologies, including florid microvascular cell proliferation and breakdown of the intratumoral blood-brain barrier [1]. GBM cells are highly invasive, and often utilize blood vessels and their extracellular matrix (ECM)-rich basement membranes to disperse throughout the brain [2]. Invasive GBM cells often escape surgical resection and invariably contribute to tumor recurrence. Various ECM and growth factor signaling pathways that promote pathological angiogenesis and perivascular GBM cell invasion have been identified, including components of the VEGF-A and TGFβ signaling pathways [3]. VEGF-A is a potent inducer of angiogenesis in GBM via activation of VEGFR1 and VEGFR2.

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Results

Conclusion