Neuropilin-2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors
Menée in vitro et à l'aide de modèles murins de tumeurs neuroendocrines de l'intestin grêle, cette étude met en évidence le rôle de la neuropiline-2, le récepteur de la sémaphorine 3F, dans la progression tumorale
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-NET). We recently identified the loss of the axon guidance protein semaphorin 3F as a pro-tumoral 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. This article is protected by copyright. All rights reserved.