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Expression and regulation of the novel vascular endothelial growth factor receptor neuropilin‐1 by epidermal growth factor in human pancreatic carcinoma
Author(s) -
Parikh Alexander A.,
Liu Wen Biao,
Fan Fan,
Stoeltzing Oliver,
Reinmuth Niels,
Bruns Christiane J.,
Bucana Corazon D.,
Evans Douglas B.,
Ellis Lee M.
Publication year - 2003
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.11560
Subject(s) - epidermal growth factor , vascular endothelial growth factor , cancer research , mapk/erk pathway , endocrinology , protein kinase b , vascular endothelial growth factor a , medicine , epidermal growth factor receptor , pancreatic cancer , adenocarcinoma , growth factor receptor inhibitor , biology , growth factor , receptor , signal transduction , microbiology and biotechnology , cancer , vegf receptors
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