Neuropilin-1 modulates TGF beta signaling to drive glioblastoma growth and recurrence after anti-angiogenic therapy

作者：Kwiatkowski Sam C; Guerrero Paola A; Hirota Shinya; Chen Zhihua; Morales John E; Aghi Manish; McCarty Joseph H^*

来源：PLos One, 2017, 12(9): 0185065.

DOI：10.1371/journal.pone.0185065

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 beta s (TGF beta s). Nrp1 is expressed in GBM cells where it promotes TGF beta 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 TGF beta 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 TGF beta to regulate GBM growth, progression, and recurrence after anti-vascular therapy.

• 出版日期2017-9-22