title: Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis.
abstract: Neuropilin-1 (NRP-1), a recently identified co-receptor for vascular endothelial growth factor, is expressed by several nongastrointestinal tumor types and enhances prostate cancer angiogenesis and growth in preclinical models. We investigated the expression and regulation of NRP-1 and the effect of NRP-1 overexpression on angiogenesis and growth of human colon adenocarcinoma by immunohistochemistry and in situ hybridization. NRP-1 was expressed in 20 of 20 human colon adenocarcinoma specimens but not in the adjacent nonmalignant colonic mucosa. By reverse transcriptase-polymerase chain reaction analysis, NRP-1 mRNA was expressed in seven of seven colon adenocarcinoma cell lines. Subcutaneous xenografts of stably transfected KM12SM/LM2 human colon cancer cells overexpressing NRP-1 led to increased tumor growth and angiogenesis in nude mice. In in vitro assays, conditioned medium from NRP-1-transfected cell lines led to an increase in endothelial cell migration, but did not affect endothelial cell growth. Epidermal growth factor (EGF) led to induction of NRP-1 in human colon adenocarcinoma cells and selective blockade of the epidermal growth factor receptor (EGFR) decreased constitutive and EGF-induced NRP-1 expression. Blockade of the Erk 1/2 and P38 mitogen-activated protein kinase signaling pathways also led to a decrease in constitutive and EGF-induced NRP-1 expression. These findings demonstrate the ubiquitous expression of NRP-1 in human colon cancer and suggest that NRP-1 may contribute to colon cancer angiogenesis and growth. This study also suggests that EGF and mitogen-activated protein kinase signaling pathways play an important role in NRP-1 regulation in colon cancer cells.
authors.affiliation: Departments of Surgical Oncology and Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Parikh
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Wen Biao
authors.initials: WB
authors.lastname: Liu
authors.forename: Syed A
authors.initials: SA
authors.lastname: Ahmad
authors.forename: Oliver
authors.initials: O
authors.lastname: Stoeltzing
authors.forename: Niels
authors.initials: N
authors.lastname: Reinmuth
authors.forename: Diane
authors.initials: D
authors.lastname: Bielenberg
authors.forename: Corazon D
authors.initials: CD
authors.lastname: Bucana
authors.forename: Michael
authors.initials: M
authors.lastname: Klagsbrun
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000473:pathology; D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000473:pathology; D018076:DNA, Complementary / Q000235:genetics; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D007413:Intestinal Mucosa / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology*; D039942:Neuropilin-1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000032:analysis; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: D018076:DNA, Complementary; D011994:Recombinant Proteins; D039942:Neuropilin-1; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases