Endothelial VEGFR Coreceptors Neuropilin-1 and Neuropilin-2 Are Essential for Tumor Angiogenesis

Abstract

Neuropilin (NRP) expression is highly correlated with poor outcome in multiple cancer subtypes. As known co-receptors for vascular endothelial growth factor receptors (VEGFRs), core drivers of angiogenesis, past investigations have alluded to their functional roles in facilitating tumorigenesis by promoting invasive vessel growth. Despite this, it remains unclear as to whether NRP1 and NRP2 act in a synergistic manner to enhance pathological angiogenesis. Here we demonstrate, using NRP1ECKO, NRP2ECKO and NRP1/NRP2ECKO mouse models, that maximum inhibition of primary tumour development and angiogenesis is achieved when both endothelial NRP1 and NRP2 are targeted simultaneously. Metastasis and secondary site angiogenesis was also significantly inhibited in NRP1/NRP2ECKO animals. Mechanistic studies revealed that co-depleting NRP1 and NRP2 in mouse-microvascular endothelial cells (ECs) stimulates rapid shuttling of VEGFR-2 to Rab7+ endosomes for proteosomal degradation. Our results highlight the importance of targeting both NRP1 and NRP2 to modulate tumour angiogenesis.

Together, Neuropilin 1 and Neuropilin 2 direct α5 integrin trafficking through GTPase-activating-protein p120RasGAP in endothelial cells to promote fibronectin fibrillogenesis

“…Fig 3A-B). Subsequent immuno-fluorescent visualisation of endogenous extra domain-A (EDA)-containing cellular FN (EDA-FN) revealed a concomitant loss of fibrillar FN in siNRP1/2 ECs compared to Ctrl ECs or ECs individually depleted for either NRP1 or NRP2 as described previously [13] (Figure 3C-D). Furthermore, the compensatory actions of αVβ3 integrin observed at 180 minutes were insufficient to rescue cell adhesion (Figure 3E).…”

“…Polarised FN secretion and directional EC migration are required for establishing a functional vascular network [3]. To determine the role of NRP1 and NRP2 during FN fibrillogenesis in vivo, we utilised NRP1 flfl .Pdgfb-iCreER T2 (NRP1 flfl .EC KO ), NRP2 flfl .Pdgfb-iCreER T2 (NRP2 flfl .EC KO ), and NRP1 flfl NRP2 flfl .Pdgfb-iCreER T2 (NRP1 flfl NRP2 flfl .EC KO ) animals, generated as previously described [13], and compared the effects of an acute endothelial-specific deletion of NRP1, NRP2, or NRP1 and NRP2 respectively during sprouting angiogenesis of the retina at postnatal day 6 (P6) . Following P2 -P5 tamoxifen administrations (Figure 8A), we first confirmed successful depletion of both NRP1 and NRP2 expression from the superficial vascular plexus (Figure 8B).…”

Orchestrating Resilience: How Neuropilin-2 and Macrophages Contribute to Cardiothoracic Disease

“…In addition, vascular expression of Nrp2 promotes angiogenesis and endothelial cell migration in pancreatic neuroendocrine tumors through a VEGF/VEGFR2-independent pathway by activating the SSH1/cofilin/actin axis [ 118 ]. Selective depletion of Nrp2 on endothelial cells ( Nrp1/2 flfl PDGFb .iCreER) inhibited primary tumor growth, as well as metastasis and secondary site angiogenesis by inducing the rapid transport and degradation of VEGFR2 to Rab7 + endosomes [ 119 ]. By contrast, Sema3-Nrp2 signaling may inhibit cancer cell migration, repressing tumor growth and metastasis [ 7 ].…”

“…Overexpression of Nrp2 in GATA2/Lmo2-deficient endothelial cells restored the response to VEGF, demonstrating that GATA2/Lmo2 regulate VEGF-induced angiogenesis via Nrp2-dependent mechanisms [ 126 ]. In addition to signaling independently of VEGFR2, Nrp2 promotes VEGF-A/VEGFR2 interactions, leading to VEGFR2 phosphorylation and enhanced cell survival and migratory signaling cascades [ 119 ].…”

The use of nanoparticles for targeted drug delivery in non-small cell lung cancer

“…In many cancers VEGF is upregulated by oncogenes and tumor hypoxia leading to an overexpression of VEGFR2, promoting angiogenesis and therefore tumor growth ( 36 ). Neuropilin1 (NRP1) is a glycoprotein receptor which can act as a co-receptor with VEGFR2 and VEFA-165 to enhance their binding and promote angiogenic signaling ( 37 , 38 ). NRP1 has been shown to be highly expressed in NSCLC is believed to correspond to poor patient prognosis, it is therefore a potential target for tumor therapy ( 39 ).…”