Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway

Abstract

Neuropilin-1 (NRP1) functions as a coreceptor through interaction with plexin A1 or vascular endothelial growth factor (VEGF) receptor during neuronal development and angiogenesis. NRP1 potentiates the signaling pathways stimulated by semaphorin 3A and VEGF-A in neuronal and endothelial cells, respectively. In this study, we investigate the role of tumor cell-expressed NRP1 in glioma progression. Analyses of human glioma specimens (WHO grade I-IV tumors) revealed a significant correlation of NRP1 expression with glioma progression. In tumor xenografts, overexpression of NRP1 by U87MG gliomas strongly promoted tumor growth and angiogenesis. Overexpression of NRP1 by U87MG cells stimulated cell survival through the enhancement of autocrine hepatocyte growth factor/scatter factor (HGF/SF)/c-Met signaling. NRP1 not only potentiated the activity of endogenous HGF/SF on glioma cell survival but also enhanced HGF/SFpromoted cell proliferation. Inhibition of HGF/SF, c-Met and NRP1 abrogated NRP1-potentiated autocrine HGF/SF stimulation. Furthermore, increased phosphorylation of c-Met correlated with glioma progression in human glioma biopsies in which NRP1 is upregulated and in U87MG NRP1-overexpressing tumors. Together, these data suggest that tumor cell-expressed NRP1 promotes glioma progression through potentiating the activity of the HGF/SF autocrine c-Met signaling pathway, in addition to enhancing angiogenesis, suggesting a novel mechanism of NRP1 in promoting human glioma progression.

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

“…The role of Sema3A in glioblastoma dispersal T Bagci et al Hu et al, 2007;Staton et al, 2007;Vales et al, 2007). In addition to its role as a Sema3A receptor, neuropilin-1 is a co-receptor for a specific isoform of VEGF165 and guides endothelial cell migration during vascular morphogenesis (Soker et al, 1998;Lee et al, 2002).…”

“…The role of neuropilin-1 in tumors has been mostly studied in the context of its interaction with VEGF165 and related to tumor angiogenesis and tumor cell survival (Miao et al, 2000;Bachelder et al, 2001). A recent study suggested that neuropilin-1 contributes to tumor progression by potentiating the activity of hepatocyte growth factor as well (Hu et al, 2007). However, the role of neuropilin-1 in tumor progression has not been studied in the context of its Sema3A interactions.…”

“…These data, together with our proteomic identification of neuropilin-1 as a pro-invasive protein, suggest that neuropilin-1 could contribute to GBM dispersal. To test the role of neuropilin-1 in vitro, we chose GBM cell lines with varying levels of neuropilin-1 expression (Rieger et al, 2003;Hu et al, 2007). As shown by immunoblotting, the levels of neuropilin-1 were different across cell lines: U87MG (high), A172 (moderate), U251 (low) (human umbilical vein endothelial cell, an endothelial cell line, served as positive control) (Figure 2a).…”

Pulmonary Epithelial Neuropilin-1 Deletion Enhances Development of Cigarette Smoke–induced Emphysema

“…Because epithelial cells are the primary source of VEGF in lung lavage, an alternative explanation linking conditional epithelial Nrp1 deletion and decreased lavage VEGF concentrations in CS-exposed CCSPrtTA/tetO-Cre/Nrp1 flox/flox mice could be that enhanced epithelial cell death decreases VEGF production. Furthermore, although several investigators have demonstrated that the effects of Nrp1 on cell proliferation and death may depend on how this receptor modulates the balance between VEGF and Sema3 signaling (17,26), other studies also demonstrate that Nrp1 may alter cell survival independent of its effects on VEGFR activation (22,(80)(81)(82).…”

Semaphorin, neuropilin and VEGF expression in glial tumours: SEMA3G, a prognostic marker?

“…Moreover, NRP1 overexpression was related to poor prognosis in human gliomas and with the malignancy of astrocytic tumours (Osada et al, 2004;Hu et al, 2007). Increased expression of NRP1 has also been detected in tumour cells from clinical glioma samples, suggesting a link between NRP1 expression and glioma malignancy (Ding et al, 2000).…”