Jubb, AM; Strickland, LA; Liu, SD; Mak, J; Schmidt, M; Koeppen, H
Neuropilin (NRP)-1 is a co-receptor for vascular
endothelial growth factor (VEGF). Preclinical data suggest that blockade of NRP1 suppresses
tumour growth by inhibiting angiogenesis, in addition to directly inhibiting tumour cell
proliferation in certain models. A humanized monoclonal antibody to NRP1 is currently being
evaluated as a potential anti-cancer therapy in clinical trials. However, the expression of NRP1
in cancer and physiological angiogenesis has yet to be systematically described. Here we
characterize the in situ expression of NRP1 in human cancer and during mammalian development. A
monoclonal antibody to human NRP1 was generated and validated for immunohistochemistry by western
blotting, use of formalin-fixed cell pellets transfected with NRP1, immunofluorescence, and
comparison with in situ hybridization. NRP1 expression was assessed in whole sections of 65
primary breast carcinomas, 95 primary colorectal adenocarcinomas, and 90 primary lung carcinomas.
An additional 59 human metastases, 16 xenografts, and three genetically engineered mouse tumour
models were also evaluated. Immunoreactivity for NRP1 was seen in vessels from normal tissues
adjacent to cancer and in 98-100% of carcinomas. Tumour cell expression of NRP1 was also observed
in 36% of primary lung carcinomas and 6% of primary breast carcinomas, but no colorectal
adenocarcinomas. NRP1 was evaluated in mouse embryos, where expression was limited to the nervous
system, endocardium, vascular smooth muscle, and, focally, endothelium on subsets of vessels.
Moreover, in a model of VEGF-dependent angiogenesis in the postnatal mouse trachea, blockade of
NRP1 signalling resulted in defective angiogenesis and recapitulated the effects of anti-VEGF
treatment. These observations confirm NRP1 as a valid anti-angiogenic target in malignancy, and
as a potential direct anti-tumour target in a subset of cancers. The data also confirm a role for
NRP1 in physiological, VEGF-mediated angiogenesis. Copyright (C) 2011 Pathological Society of
Great Britain and Ireland. Published by John Wiley & Sons, Ltd.