Abstract 1031: Blockade of radiation-induced neuropilin-1 in glioblastoma cells impairs migration of endothelial cells

Abstract

Abstract Neuropilin-1 (NRP-1) is an isoform specific receptor for vascular endothelial growth factor (VEGF), that regulates the development of the nervous system and also promotes angiogenesis in endothelial cells. Glioblastoma multiforme (GBM) is a malignant tumor characterized by robust neoangiogenesis with an aberrant elevation of VEGF. Recent evidence suggests that the majority of GBMs after radiation therapy (IR) exhibit an angiogenic regeneration process, which contributes phenotypic plasticity and therapeutic resistance. A high expression of NRP-1 in GBM correlates with disease progression. In this study, we show that the IR-induced NRP-1 role in the VEGFR-2 mediated signaling cascade promotes migration of endothelial cells. We observed that IR (8Gy) significantly elevated levels of VEGF and NRP-1 expression in 4910 and 5310 human GBM xenograft cells. Endothelial cells cultured on tumor- conditioned media from IR induced xenograft cells showed a significant increase in migration of endothelial cells; whereas, conditioned medium (CM) from NRP-1 knockdown xenograft cells inhibited IR-induced migration effects in endothelial cells. Further, CM from NRP-1 inhibited cells downregulated IR-induced expression of VEGFR-2 and its downstream molecules Sema3A, Plexin-A1 and E-cadherin in endothelial cells. Immunoflourescence co-localization studies revealed that the interaction of NRP-1 and VEGFR-2 were significantly decreased in endothelial cells cultured on CM from NRP-1-siRNA-transfected xenograft cells compared to mock- and SV-transfected cells. Collectively, our data indicate that NRP-1 plays a significant role in the regulation of VEGF/VEGFR-2 signaling and migration in endothelial cells, and thereby suggests NRP-1 as an important therapeutic target for glioma patients receiving radiation therapy. Citation Format: Dilip Rajasekhar Maddirela, Divya Kesanakurti, Venkateswara R. Gogineni, Chandramu Chetty. Blockade of radiation-induced neuropilin-1 in glioblastoma cells impairs migration of endothelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1031. doi:10.1158/1538-7445.AM2014-1031