Neuropilins: expression and roles in the epithelium

Abstract

Summary Initially found expressed in neuronal and then later in endothelial cells, it is well established that the transmembrane glycoproteins neuropilin‐1 (NRP1) and neuropilin‐2 (NRP2) play essential roles in axonal growth and guidance and in physiological and pathological angiogenesis. Neuropilin expression and function in epithelial cells has received little attention when compared with neuronal and endothelial cells. Overexpression of NRPs is shown to enhance growth, correlate with invasion and is associated with poor prognosis in various tumour types, especially those of epithelial origin. The contribution of NRP and its ligands to tumour growth and metastasis has spurred a strong interest in NRPs as novel chemotherapy drug targets. Given NRP’s role as a multifunctional co‐receptor with an ability to bind with disparate ligand families, this has sparked new areas of research implicating NRPs in diverse biological functions. Here, we review the growing body of research demonstrating NRP expression and role in the normal and neoplastic epithelium.

Enhancement of the Tumor Penetration of Monoclonal Antibody by Fusion of a Neuropilin-Targeting Peptide Improves the Antitumor Efficacy

“…1-5): (i) tumor homing by targeting NRP1/2 overexpressed on tumor-associated endothelial cells, (ii) improved extravasation due to enhanced vascular permeability, and (iii) improved tissue penetration by reducing the epithelial barrier. Fc-/mAbA22p rapidly and extensively localized to tumor vessels compared with the respective parental format, suggesting that NRP1/2 serve as tumor-homing targets due to their overexpression, not only on tumor endothelium, but also on many types of cancer cells (11,15). Because NRP1/2 are also expressed at low levels in normal tissue vessels (11), however, additional in vivo studies to address normal tissue distribution and any systemic cytotoxicity of Fc-/ mAb-A22p are necessary.…”

“…We achieved this by fusing mAbs to a tumor-penetrating peptide that targets tumor-associated proteins. For the target protein, we chose a neuropilin receptor (NRP) because NRPs are abundantly expressed on the surface of many tumor endothelial and epithelial cells (11) and can increase vascular permeability upon activation by their intrinsic ligands (12,13). Further, some NRP-binding peptides have been shown to improve tumor tissue penetration of coadministered anticancer drugs, including mAbs (8,14).…”

“…Further, some NRP-binding peptides have been shown to improve tumor tissue penetration of coadministered anticancer drugs, including mAbs (8,14). Human NRP1 and NRP2 (NRP1/2), which share 44% sequence identity, are coreceptors of plexin receptors for secreted class 3 semaphorin (Sema3) ligands, and are coreceptors of VEGF receptors (VEGF-R) for VEGF ligands (11,15). In addition to the ligand-specificity determining a1a2 domains, NRP1/2 have a specific C-terminal arginine-binding pocket on the b1 domain, which is the shared binding site for furin-processed Sema3 and VEGF ligands with a C-terminal Arg residue (see Supplementary Fig.…”

Neuropilin 1 in uterine leiomyosarcoma. Clinical and pathological analysis

“…In the first case, with the contribution of VEGFR-2, the endothelial cells migration is stimulated. In the second case, neuropilin 1 together with plaxin A causes the opposite reaction [15].…”

PAX2 regulates NRP-1 expression in renal tubular epithelial cellsto promote epithelial-to-mesenchymal transition and renal fibrosis

“…We observed that when PAX2 was overexpressed in the renal tubular epithelial cells, the mRNA expression of neuropilin-1 (NRP-1) was upregulated by 4.06 fold (the data is not published). NRP-1, initially discovered in the developing nerve fiber axons, is a receptor of semaphorin 3A and vascular endothelial growth factor (VEGF)-165 and is mainly expressed in glomerular epithelial cells and collecting ducts [9] . Studies have suggested that NRP-1 can induce EMT in tumor cells [10] , and its expression is increased in hepatic fibrosis [11,12] .…”