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