Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells

Abstract

The epidermal growth factor receptor (EGF-R) pathway plays a pivotal role in the progression of human gastric cancer. The angiogenic factor vascular endothelial growth factor (VEGF) has been shown to be induced by EGF in various cancer cell lines. Neuropilin-1 (NRP-1) acts as a coreceptor for VEGF-165 and increases its affinity for VEGF receptor 2 (VEGFR-2) in endothelial cells. Furthermore, NRP-1 has been found to be expressed by tumour cells and has been shown to enhance tumour angiogenesis and growth in preclinical models. We examined the expression of NRP-1 mRNA and EGF-R protein in seven human gastric cancer cell lines. NRP-1 expression was expressed in five of seven cell lines, and EGF-R expression closely mirrored NRP-1 expression. Moreover, in EGF-R-positive NCI-N87 and ST-2 cells, EGF induced both NRP-1 and VEGF mRNA expression. C225, a monoclonal antibody to EGF-R, blocked EGF-induced NRP-1 and VEGF expression in NCI-N87 cells in a dose-dependent manner. The treatment of NCI-N87 cells with EGF resulted in increases in phosphorylation of Erk1/2, Akt, and P38. Blockade of the Erk, phosphatidylinositol-3 kinase/Akt, or P38 pathways in this cell line prevented EGF induction of NRP-1 and VEGF. These results suggest that regulation of NRP-1 expression in human gastric cancer is intimately associated with the EGF/EGF-R system. Activation of EGF-R might contribute to gastric cancer angiogenesis by a mechanism that involves upregulation of VEGF and NRP-1 expression via multiple signalling pathways.

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

“…Upregulation of NRP1 was found not only in endothelia but also in tumor cells in various types of primary human cancer specimens (Ding et al, 2000;Akagi et al, 2003). Overexpression of NRP1 in tumor cells has been shown to promote tumor growth and angiogenesis in xenograft models and cell survival in cancer cells.…”

The role of neuropilins in cancer

“…Insulin-like growth factor-1 increased NRP-1 expression on colon tumor cells (18,21), but tumor necrosis factor, a cytokine that has been shown to increase neuropilin in other tumor systems, failed to increase NRP-1 expression in these same cells. Activation of epidermal growth factor receptors has also been shown to upregulate NRP-1 expression in several tumor systems (18,21,22,103). Studies from our laboratory have shown that epidermal growth factor induces NRP-1 expression in human colon and pancreatic adenocarcinoma cell lines, which seems to be mediated through the phosphatidylinositol-3 kinase/Akt and P38 mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 signaling pathways (18,21).…”

Epidermal Growth Factor Potentiates Cholecystokinin/Gastrin Receptor-mediated Ca2+ Release by Activation of Mitogen-activated Protein Kinases

“…Additionally, G17 and its related peptide CCK stimulate the growth of stomach (36,37) and pancreatic cancers (38). EGF receptors and their ligands are also overexpressed and regulate the growth of the same cancers (39,40), suggesting the possibility for cross-talk between EGFR-and CCK 2 R-regulated pathways in these cancers. This hypothesis is supported by the recent findings that CCK and EGF synergically stimulate DNA synthesis, cyclin-D3 expression, and retinoblastoma phosphorylation in cells expressing both CCK 2 R and EGFR.…”