Neuropilins in the Context of Tumor Vasculature

Abstract

Neuropilin-1 and Neuropilin-2 form a small family of plasma membrane spanning receptors originally identified by the binding of semaphorin and vascular endothelial growth factor. Having no cytosolic protein kinase domain, they function predominantly as co-receptors of other receptors for various ligands. As such, they critically modulate the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. This review highlights the diverse neuropilin ligands and interacting partners on endothelial cells, which are relevant in the context of the tumor vasculature and the tumor microenvironment. In addition to tumor cells, the latter contains cancer-associated fibroblasts, immune cells, and endothelial cells. Based on the prevalent neuropilin-mediated interactions, the suitability of various neuropilin-targeted substances for influencing tumor angiogenesis as a possible building block of a tumor therapy is discussed.

Neuropilins, as Relevant Oncology Target: Their Role in the Tumoral Microenvironment

“…SEMA3A is an angiogenesis inhibitor, that is less expressed during tumor development. Indeed, it controls pericytes recruitment to vessels (Niland and Eble, 2019). Neuropilins form a complex with SEMA receptors, the plexins.…”

“…NRPs are major regulators of the Hedgehog signaling pathway. A feedback loop exists between NRP1 and Hedgehog; Hedgehog signaling induces NRP1 expression, which promotes activation of Hedgehog targeted gene (Niland and Eble, 2019). A down-regulation of NRP1 by shRNA in ccRCC cell lines reduces sonic hedgehog (SHH) and its activator Gli1 expressions.…”

“…NRP2 expression increases during the differentiation of monocytes to macrophages (Schellenburg et al, 2017) next to inflammatory zones to induce phagocytosis. NRP2 sialylation reduces phagocytosis capacity of the macrophages (Stamatos et al, 2014;Roy et al, 2018), thus NRP2+ M2 macrophages promote tumor progression (Niland and Eble, 2019).…”

“…This new vascular network surrounding the tumor, supplies oxygen and nutrients needed for tumors growth. Tumor cells, cells from the microenvironment and NRPs expressed on both cell types influence tumor angiogenesis (Niland and Eble, 2019). The roles of NRP1 in the growth and invasiveness of prostate, colorectal, kidney, lung, breast, .…”

Micro RNAs Promoting Growth and Metastasis in Preclinical In Vivo Models of Subcutaneous Melanoma

“…Neuropilin-1 (NRP-1) has been identified as a direct target of miR-365 (149). NRP-1 is a transmembrane glycoprotein that acts as a co-receptor for various members of the VEGF family and modulates the activity of other extracellular ligands such as transforming growth factor β (TGFβ), hepatocyte growth factor (HGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF), factors modulating angiogenesis and therefore is a potential target for treatment of melanoma (150)(151)(152).…”