Neuropilin-Mediated Signaling in Cancer and Vascular Biology

Neuropilins (NRPs) are transmembrane glycoproteins that function as multifunctional co-receptors for ligands such as vascular endothelial growth factors (VEGFs) and class III semaphorins. Two principal isoforms, NRP1 and NRP2, modulate diverse processes including angiogenesis, vascular permeability and neuronal guidance. In cancer, NRPs integrate signals from growth factor receptors and integrins to promote tumour cell survival, migration, invasion and stemness. They influence the tumour microenvironment by regulating endothelial cell function, immune cell infiltration and extracellular matrix remodelling. In vascular biology, NRPs govern endothelial tip-stalk cell specification, vessel branching and barrier integrity via cross-talk with Notch, TGF-β/BMP and VEGF receptor pathways. Organ-specific expression of NRP1 in perivascular cells further fine-tunes local responses to VEGF, resulting in context-dependent modulation of permeability and sprouting. The dual roles of NRPs in malignancy and vascular homeostasis render them attractive targets for therapeutic intervention, with emerging inhibitors demonstrating efficacy in preclinical models by disrupting key receptor interactions and downstream signalling axes.

Research from Nature Portfolio

Recent studies have elucidated that NRP1 actively represses the stalk-cell phenotype in sprouting angiogenesis by limiting Smad2/3 activation through ALK1 and ALK5. In this mechanism, Notch signalling downregulates NRP1 to relieve inhibition of TGF-β/BMP pathways, thereby driving stalk-cell behaviour and enabling tip-cell formation. This finding positions NRP1 as a pivotal modulator of endothelial heterogeneity, integrating VEGF, Notch and TGF-β/BMP inputs to orchestrate vessel branching and morphogenesis.

Neuropilin-Mediated Signaling in Cancer and Vascular Biology publication trend

The graph below shows the total number of articles in neuropilin-mediated signaling in cancer and vascular biology across all publications each year (not limited to Nature Index journals).

Technical terms

Neuropilin (NRP): A transmembrane co-receptor that binds growth factors and semaphorins to modulate signalling in vascular and neural contexts.

Co-receptor: A cell-surface molecule that associates with primary receptors to enhance ligand binding or signal transduction.

Vascular endothelial growth factor (VEGF): A family of cytokines critical for regulating angiogenesis and vascular permeability.

Epidermal growth factor receptor (EGFR): A receptor tyrosine kinase that, upon activation, initiates signalling cascades controlling cell proliferation and survival.

AKT pathway: A downstream signalling cascade of PI3K that promotes cell growth, survival and metabolism.

Juxtacrine signalling: Direct cell-to-cell communication in which membrane-bound ligands interact with adjacent cell receptors.

References

1. NRP1 promotes prostate cancer progression via modulating EGFR-dependent AKT pathway activation. Cell Death & Disease (2023).
2. Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions. Angiogenesis (2024).
3. Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch. Nature Communications (2015).