Role of Neuropilin-2-mediated signaling axis in cancer progression and therapy resistance

Abstract

Neuropilins (NRPs) are transmembrane proteins involved in vascular and nervous system development by regulating angiogenesis and axon guidance cues. Several published reports have established their role in tumorigenesis. NRPs are detectable in tumor cells of several cancer types and participate in cancer progression. NRP2 is also expressed in endothelial and immune cells in the tumor microenvironment and promotes functions such as lymphangiogenesis and immune suppression important for cancer progression. In this review, we have taken a comprehensive approach to discussing various aspects of NRP2-signaling in cancer, including its regulation, functional significance in cancer progression, and how we could utilize our current knowledge to advance the studies and target NRP2 to develop effective cancer therapies.

Transcriptionally defined morphological subtypes of pancreatic ductal adenocarcinoma

“…Neuropilin-2 is known as a receptor for angiogenic growth factors. Besides its expression by endothelial cells 54 , NRP2 in PDAC cells is associated with angiogenesis, tumour growth, migration and invasion 55 . PDAC cells have also been reported to induce NRP2 expression in tumour-associated macrophages, in turn promoting tumour growth 56 .…”

Inhibition of VEGF binding to neuropilin-2 enhances chemosensitivity and inhibits metastasis in triple-negative breast cancer

“…Neuropilin-2 (NRP2) is a single-pass transmembrane protein that forms heterodimeric complexes with many other plasma membrane receptors, including growth factor receptors ( 3 , 4 ) and integrins ( 5 , 6 ). The extracellular domain (ECD) of NRP2 binds ligands, including the vascular endothelial growth factor (VEGF) and semaphorin families ( 6 ).…”

“…Neuropilin-2 (NRP2) is a single-pass transmembrane protein that forms heterodimeric complexes with many other plasma membrane receptors, including growth factor receptors ( 3 , 4 ) and integrins ( 5 , 6 ). The extracellular domain (ECD) of NRP2 binds ligands, including the vascular endothelial growth factor (VEGF) and semaphorin families ( 6 ). Its short intracellular domain does not signal directly; rather, it enhances the signaling output of growth factor receptors ( 7 ), integrins, and other co-receptors ( 6 , 8 ).…”

“…The extracellular domain (ECD) of NRP2 binds ligands, including the vascular endothelial growth factor (VEGF) and semaphorin families ( 6 ). Its short intracellular domain does not signal directly; rather, it enhances the signaling output of growth factor receptors ( 7 ), integrins, and other co-receptors ( 6 , 8 ). NRP2 expression has been detected in several human tumor types (including prostate, pancreatic, gastric, kidney, colon, bladder, and breast cancers), with the highest expression observed in aggressive, treatment-resistant tumors ( 6 , 9 ).…”

“…Its short intracellular domain does not signal directly; rather, it enhances the signaling output of growth factor receptors ( 7 ), integrins, and other co-receptors ( 6 , 8 ). NRP2 expression has been detected in several human tumor types (including prostate, pancreatic, gastric, kidney, colon, bladder, and breast cancers), with the highest expression observed in aggressive, treatment-resistant tumors ( 6 , 9 ). For example, we have shown that NRP2 is highly expressed in TNBC compared with other breast cancer subtypes ( 10 ), and other data indicate that its expression is associated with lower survival ( 11 ).…”