Abstract
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 α 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. Cancer 2003;98:720–9. © 2003 American Cancer Society.
DOI 10.1002/cncr.11560