Abstract

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.

摘要

由于缺氧等恶性条件，局部肿瘤部位导致病理性血管生成和淋巴管生成。尽管VEGF和VEGFR被认为是主要的抗肿瘤治疗靶点，但与该靶点相关的一些药物的疗效有限和副作用明显等问题仍有待解决。因此，有必要为血管生成或淋巴管生成确定新的治疗靶点。神经纤毛蛋白家族是一类单跨膜糖蛋白受体，包括神经纤毛蛋白1（NRP1）和神经纤毛蛋白2（NRP2），可作为VEGFA-165和VEGFC的共同受体，在促进肿瘤增殖、侵袭和转移中起关键作用。在这次审查中，我们引入了示意图，直观地揭示了 NRP1 和 NRP2 分别增强 VEGFR2 与 VEGFA-165 和 VEGFR3 与 VEGFC 的结合亲和力的功能。我们还讨论了依赖于共同受体 NRP1 和 NRP2 的信号通路以及一些现有的靶向治疗策略，例如单克隆抗体、靶向肽、microRNA 和小分子抑制剂。它将为未来靶向NRPs的新药研发奠定重要基础。

• 强调

• NRP1 作为 VEGFR2 和促血管生成因子 VEGFA-165 的共同受体，通过促进内皮细胞增殖、存活、迁移、侵袭和防止细胞凋亡来上调肿瘤血管生成。

• NRP2 作为 VEGFR3 和促淋巴生成因子 VEGFC 的共同受体，通过促进淋巴管生成促进肿瘤转移。

• 虽然 NRP1 和 NRP2 没有酶信号活性，但 VEGFR2 对 VEGFA-165 和 VEGFR3 对 VEGFC 的亲和力可以共同受体的方式增加，如示意图中详述。

• 专门描述了 NRP1 和 NRP2 在信号通路中的独特作用，以强调共同受体中涉及的分子调节机制。

• 各种研究表明，共同受体 NRP1 和 NRP2 可以通过不同的方法直接或间接靶向，以防止肿瘤血管生成和淋巴管生成。

• 临床前和临床研究证明，针对 NRP 的治疗策略很快看起来很有希望。