Neuropilins in neoplasms: expression, regulation, and function

Neuropilins (NRP) are membranous receptors capable of binding two disparate ligands, class 3 semaphorins (SEMA) and vascular endothelial growth factors (VEGF), and regulating two diverse systems, neuronal guidance and angiogenesis. The neuropilin genes, NRP1 and NRP2, share similar protein structure, but differ in their expression patterns, regulation, and ligand-binding specificities. NRPs vary in their expression patterns; for example, endothelial cells express both NRP1 and NRP2, lymphatic endothelial cells predominantly express NRP2, and epidermal cells predominantly express NRP1. NRP expression can be differentially regulated by transcription factors, e.g. prox-1 induces NRP2 while suppressing NRP1, or by growth factors, e.g. epidermal growth factor (EGF) induces NRP1 but not NRP2. Nearly all tumor cells express NRP1, NRP2, or both. Carcinomas express NRP1, whereas neuronal tumors and melanomas predominantly express NRP2. SEMAs play a role in neoplasms as angiogenesis inhibitors. For example, SEMA3F, which binds specifically to NRP2, inhibits tumor angiogenesis and metastasis. Metastatic tumor cells lose SEMA3F expression during progression. Therefore, SEMA3F may have therapeutic potential. This article focuses on the role of NRPs and SEMAs in tumor progression and angiogenesis.