New insights into the role of co-receptor neuropilins in tumour angiogenesis and lymphangiogenesis and targeted therapy strategies.

Local tumour sites lead to pathological angiogenesis and lymphangiogenesis due to malignant conditions such as hypoxia. Although VEGF and VEGFR are considered to be the main anti-tumour treatment targets, the problems of limited efficacy and observable side effects of some drugs relevant to this target still remain to be solved. Therefore, it is necessary to identify new therapeutic targets for angiogenesis or lymphangiogenesis. The neuropilin family is a class of single transmembrane glycoprotein receptors, including neuropilin1 (NRP1) and neuropilin2 (NRP2), which could act as co-receptors of VEGFA-165 and VEGFC and play a key role in promoting tumour proliferation, invasion and metastasis. In this review, we introduced the schematic diagram to visually reveal the function of NRP1 and NRP2 in enhancing the binding affinity of VEGFR2 to VEGFA-165 and VEGFR3 to VEGFC, respectively. We also discussed the signalling pathways that depend on the co-receptors NRP1 and NRP2 and some existing targeted therapeutic strategies, such as monoclonal antibodies, targeted peptides, microRNAs and small molecule inhibitors. It will contribute a vital foundation for the future research and development of new drugs targeting NRPs. HIGHLIGHTS NRP1 acts as a co-receptor with VEGFR2 and the pro-angiogenic factor VEGFA-165 to up-regulate tumour angiogenesis by promoting endothelial cells proliferation, survival, migration, invasion and by preventing of apoptosis. NRP2 acts as a co-receptor with VEGFR3 and the pro-lymphogenic factor VEGFC to facilitate tumour metastasis by promoting lymphangiogenesis. Although NRP1 and NRP2 do not have enzymatic signalling activity, the affinity of VEGFR2 for VEGFA-165 and VEGFR3 for VEGFC can increase in a co-receptor manner, as detailed in the schematic. The exclusive roles of NRP1 and NRP2 in signalling pathways are specifically described to emphasise the molecular regulatory mechanisms involved in co-receptors. Various studies have shown that the co-receptors NRP1 and NRP2 can be directly or indirectly targeted by different methods to prevent tumour angiogenesis and lymphangiogenesis. Therapeutic strategies targeting NRPs look promising soon as evidenced by preclinical and clinical studies.