8829

NRP1

neuropilin 1;NRP1;neuropilin 1

neuropilin-1|transmembrane receptor|vascular endothelial cell growth factor 165 receptor

10p12

protein-coding

The majority of human melanoma cell lines secretes vascular endothelial growth factor-A (VEGF-A) and expresses its receptors VEGFR-1, VEGFR-2 and neuropilin-1 (NRP1), a co-receptor for VEGF-A that amplifies the signalling through VEGFR-2. Since it is known that the VEGF-A/VEGFR-2 autocrine loop promotes melanoma cell invasiveness, the aim of the present study was to investigate the involvement of NPR-1 in melanoma progression. Syngeneic human melanoma cell lines expressing either VEGFR-2 or NRP-1, both or none of them, were analyzed for their in vitro ability to migrate, invade the extracellular matrix (ECM) and secrete active metalloproteinase-2 (MMP-2). The results indicate that NRP-1 cooperates with VEGFR-2 in melanoma cell migration induced by VEGF-A. Moreover, NRP-1 expression is sufficient to promote MMP-2 secretion and melanoma cell invasiveness, as demonstrated by the ability of cells expressing solely NRP-1 to spontaneously invade the ECM. This ability is specifically downregulated by anti-NRP-1 antibodies or by interfering with NRP-1 expression using an shRNA construct. Investigation of the signal transduction pathways triggered by NRP-1 in melanoma cells, indicated that NRP-1-dependent promotion of cell invasiveness involves Akt activation through its phosphorylation on T308. Overall, the results demonstrate that NRP-1 is involved in melanoma progression through VEGFR-2-dependent and -independent mechanisms and suggest NRP-1 as a target for the treatment of the metastatic disease.

OBJECTIVES: Neuropilin 1 (NRP-1) appears to promote angiogenesis by acting as a coreceptor with vascular endothelial growth factor receptor. We correlated NRP-1 expression with microvessel density (MVD) and overall survival (OS) in human pancreatic ductal adenocarcinomas (PDACs). METHODS: Neuropilin 1 expression was graded semiquantitatively using immunohistochemistry in patients with resected PDAC. Moreover, MVD was determined with an anti-CD31 antibody staining. expression of NRP-1 was correlated with MVD and clinicopathologic features in patients with PDAC. Overall survival effects of NRP-1 expression were evaluated by multivariate Cox regression and Kaplan-Meier analyses. RESULTS: High NRP-1 expression was associated with advanced Union for International cancer Control stage (P = 0.046), T stage (P = 0.031), and lymph node invasion (P = 0.045). Microvessel density was significantly higher in the tumors with high NRP-1 expression than that in the tumors with low NRP-1 expression (mean, 13.9 [SD, 9.1] vs 10.2 [SD, 7.2] per high-power field; P = 0.001). The multivariate Cox regression analysis demonstrated that high NRP-1 expression was independently associated with reduced OS (hazard ratio, 2.10; 95% confidence interval, 1.19-3.70). CONCLUSIONS: Neuropilin 1 is highly expressed in PDACs, and high expression of NRP-1 is significantly correlated with angiogenesis, advanced tumor-node-metastasis stage, p T stage, node invasion, and poor postoperative OS.