Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors

Abstract

The identification of novel regulators of tumor progression is a key challenge to gain knowledge on the biology of small intestinal neuroendocrine tumors (SI‐NETs). We recently identified the loss of the axon guidance protein semaphorin 3F as a protumoral event in SI‐NETs. Interestingly the expression of its receptor neuropilin‐2 (NRP‐2) was still maintained. This study aimed at deciphering the potential role of NRP‐2 as a contributor to SI‐NET progression. The role of NRP‐2 in SI‐NET progression was addressed using an approach integrating human tissue and serum samples, cell lines and in vivo models. Data obtained from human SI‐NET tissues showed that membranous NRP‐2 expression is present in a majority of tumors, and is correlated with invasion, metastatic abilities, and neovascularization. In addition, NRP‐2 soluble isoform was found elevated in serum samples from metastatic patients. In preclinical mouse models of NET progression, NRP‐2 silencing led to a sustained antitumor effect, partly driven by the downregulation of VEGFR2. In contrast, its ectopic expression conferred a gain of aggressiveness, driven by the activation of various oncogenic signaling pathways. Lastly, NRP‐2 inhibition led to a decrease of tumor cell viability, and sensitized to therapeutic agents. Overall, our results point out NRP‐2 as a potential therapeutic target for SI‐NETs, and will foster the development of innovative strategies targeting this receptor. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Vascular NRP2 triggers PNET angiogenesis by activating the SSH1-cofilin axis

“…NRP2 is primarily expressed in the nervous and vascular systems and is important for the development of embryos by enhancing VEGF-VEGFR binding [ 6 ]. Recent studies have reported that the neuropilin family is involved in tumor metastasis and is correlated with poor prognosis [ 7 , 8 ]. Moreover, NRP2 has been found to be highly expressed in pancreatic islet cells and endocrine pancreatic tumors [ 9 ].…”

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

“…In-depth analysis in preclinical mouse models of SI-NET suggested that knockdown of NRP2 imparted antitumor effects by VEGFR2 downregulation. NRP-2 inhibition led to decreased tumor cell viability and higher susceptibility towards therapeutic agents [110].…”

Angiogenesis in NENs, with a focus on gastroenteropancreatic NENs: from biology to current and future therapeutic implications

“…Semaphorins have shown both pro-and anti-angiogenic effects in NETs, and their activity is the result of the interaction with neuropilin and plexin receptors (7). Neuropilin receptors have been found in both pancreatic, intestinal and pulmonary NETs (39)(40)(41), while data on the expression of plexin receptors in NETs Schematic overview of the main pathways regulating angiogenesis in NETs. By acting on endothelial cells, VEGF stimulates both vascular endothelial mitogenesis and permeability.…”

“…Semaphorins have shown both pro- and anti-angiogenic effects in NETs, and their activity is the result of the interaction with neuropilin and plexin receptors ( 7 ). Neuropilin receptors have been found in both pancreatic, intestinal and pulmonary NETs ( 39 – 41 ), while data on the expression of plexin receptors in NETs are currently lacking. Experiments in RIP1-Tag2 mice have shown that the expression of semaphorin 3A (SEMA3A) is progressively lost during tumor progression and that the inhibition of SEMA3A during the angiogenic switch may enhance tumor formation.…”