The Role of the Neuropilins in Tumour Angiogenesis and Tumour Progression

Abstract

Neuropilins (NRPs) are multifunctional receptors for class 3 semaphorins, which are responsible for axon guidance during the development of the nervous system in vertebrates, and for vascular endothelial growth factors (VEGFs), essential for vascular development and angiogenesis in disease. There is now a large body of evidence that NRPs also mediate tumour angiogenesis and progression, and they have also emerged as novel therapeutic targets in cancer. Many neoplastic cell types express NRPs, and NRP1 and NRP2 upregulation is positively correlated with tumour progression and poor patient prognosis in several cancer types (Pellet-Many et al., 2008). Recently, NRPs have been shown to play novel roles in the tumour stem cell niche and in regulation of tumour immunity. This chapter focuses on the role of NRPs in tumour angiogenesis and tumour progression, focusing on the role of the NRPs as modulators of VEGF function, and highlighting approaches to therapeutic targeting of NRPs in cancer. Neuropilin Structure NRP1 and NRP2 are transmembrane glycoproteins that share a similar domain structure and have 44% amino acid sequence homology. The structures of NRP1 and NRP2 are divided into 5 main domains: large extracellular regions containing two CUB (a1/a2) domain, FV/FVIII (b1/b2) domain, and cMAM domains, a single transmembrane domain, and a short cytoplasmic region of 44 amino acid residues in NRP1 and 43 in NRP2 (Kolodkin et al., 1997; Pellet-Many et al., 2008). In the extracellular region, CUB (a1/a2) domains are important for binding to semaphorins. The b1/b2 domains are required to bind VEGFA and also contribute to semaphorin binding. The role of the NRP MAM domain is unclear, but it is thought to be important for protein stability and to play a