TY - JOUR
T1 - Endothelial VEGFR coreceptors neuropilin-1 and neuropilin-2 are essential for tumor angiogenesis
AU - Benwell, Christopher J.
AU - Johnson, Robert T.
AU - Taylor, James A. G. E.
AU - Price, Christopher A.
AU - Robinson, Stephen D.
N1 - 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/).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85150959597&partnerID=8YFLogxK
U2 - 10.1158/2767-9764.CRC-22-0250
DO - 10.1158/2767-9764.CRC-22-0250
M3 - Article
VL - 2
SP - 1626
EP - 1640
JO - Cancer Research Communications
JF - Cancer Research Communications
SN - 2767-9764
IS - 12
ER -
