Expression and regulation of the novel vascular endothelial growth factor receptor neuropilin-1 by epidermal growth factor in human pancreatic carcinoma.

Parikh AA, Liu WB, Fan F, Stoeltzing O, Reinmuth N, Bruns CJ, Bucana CD, Evans DB, Ellis LM
Cancer. 2003 98 (4): 720-9

PMID: 12910515 · DOI:10.1002/cncr.11560

BACKGROUND - It was recently shown that neuropilin-1 (NRP-1), which was described originally as a receptor for the semaphorins/collapsins (ligands involved in neuronal guidance), is a coreceptor for vascular endothelial growth factor (VEGF) and increases the affinity of specific isoforms of VEGF to its receptor, VEGF-R2.

METHODS - The authors investigated the expression and regulation of NRP-1 in human pancreatic adenocarcinoma specimens and cell lines.

RESULTS - Immunohistochemical analysis revealed that NRP-1 was expressed in 12 of 12 human pancreatic adenocarcinoma specimens but was absent in nonmalignant pancreatic tissue. Northern blot analysis revealed NRP-1 mRNA expression in 8 of 11 human pancreatic adenocarcinoma cell lines. NRP-1 mRNA expression was increased by epidermal growth factor (EGF) but not by tumor necrosis factor alpha in several of the human pancreatic adenocarcinoma cell lines studied. Treating human Panc-48 adenocarcinoma cells with EGF activated Akt and Erk but not P-38. Blockade of the phosphatidylinositol-3 kinase (PI-3K)/Akt, mitogen-activated protein kinase (MAPK)/Erk, or P-38 pathways abrogated EGF-induced NRP-1 expression. Finally, EGF receptor blockade in vivo led to a decrease in NRP-1 expression in an orthotopic model of human pancreatic carcinoma.

CONCLUSIONS - NRP-1 is expressed in most human pancreatic adenocarcinomas and cell lines but not in nonmalignant pancreatic tissue. EGF regulates NRP-1 expression through the PI-3K/Akt and MAPK/Erk signaling pathways, and blockade of the EGF receptor is associated with decreased expression of NRP-1 in vivo. NRP-1 may act as a coreceptor for VEGF in pancreatic carcinoma, as it does in other tumor systems, thereby enhancing angiogenesis and the effect of VEGF on the growth of pancreatic adenocarcinoma.

Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11560

MeSH Terms (17)

Adenocarcinoma Blotting, Northern Dose-Response Relationship, Drug Epidermal Growth Factor Humans Immunohistochemistry Keratins Mitogen-Activated Protein Kinases Neuropilin-1 Pancreas Pancreatic Neoplasms Phosphatidylinositol 3-Kinases Receptors, Vascular Endothelial Growth Factor RNA, Messenger Signal Transduction Tumor Cells, Cultured Tumor Necrosis Factor-alpha

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