Endothelial VEGFR coreceptors neuropilin-1 and neuropilin-2 are essential for tumor angiogenesis

Benwell, Christopher J., Johnson, Robert T. ORCID: https://orcid.org/0000-0003-3618-238X, Taylor, James A. G. E., Price, Christopher A. and Robinson, Stephen D. ORCID: https://orcid.org/0000-0002-6606-7588 (2022) Endothelial VEGFR coreceptors neuropilin-1 and neuropilin-2 are essential for tumor angiogenesis. Cancer Research Communications, 2 (12). 1626–1640. ISSN 2767-9764

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Abstract

Neuropilin (NRP) expression is highly correlated with poor outcome in multiple cancer subtypes. As known coreceptors for 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 pathologic angiogenesis. Here we demonstrate, using NRP1ECKO, NRP2ECKO, and NRP1/NRP2ECKO mouse models, that maximum inhibition of primary tumor development and angiogenesis is achieved when both endothelial NRP1 and NRP2 are targeted simultaneously. Metastasis and secondary site angiogenesis were also significantly inhibited in NRP1/NRP2ECKO animals. Mechanistic studies revealed that codepleting NRP1 and NRP2 in mouse-microvascular endothelial cells 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 tumor angiogenesis.

Item Type:	Article
Additional Information:	Acknowledgments: This work was supported by funding from: the UKRI Biotechnology and Biological Sciences Research Council Norwich Research Park Biosciences Doctoral Training Partnership (grant numbers BB/MM011216/1 and BB/J014524/1); BHF (grant number PG/15/25/31369); and BigC (grant number 18-15R). In addition, we thank Norfolk Fundraisers, Mrs Margaret Doggett, and the Colin Wright Fund for their kind support and fundraising over the years. Robinson is also funded by the BBSRC Institute Strategic Programme Gut Microbes and Health BB/R012490/1 and its constituent project (BBS/E/F/000PR10355). Note: Supplementary data for this article are available at Cancer Research Communications Online (https://aacrjournals.org/cancerrescommun/).
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Science > School of Biological Sciences Faculty of Science > School of Pharmacy
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging Faculty of Science > Research Groups > Cells and Tissues
Depositing User:	LivePure Connector
Date Deposited:	06 Jan 2023 13:32
Last Modified:	28 Jul 2023 03:51
URI:	https://ueaeprints.uea.ac.uk/id/eprint/90451
DOI:	10.1158/2767-9764.CRC-22-0250

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