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.

Streptozotocin-based chemotherapy is the first-line chemotherapy recommended for advanced pancreatic neuroendocrine tumors (pNETs), whereas targeted therapies, including mTOR inhibitors, are available in second-line treatment. Unfortunately, objective response rates to both treatments are limited. Because mTOR pathway activation, commonly observed in pNETs, has been reported as one of the major mechanisms accounting for chemoresistance, we investigated the potential benefit of mTOR inhibition combined with streptozotocin treatment in a subset of pNETs, namely insulinomas. To evaluate the potential of mTOR inhibition in combination with streptozotocin, we selected four different inhibitors acting at various levels of the pathway (everolimus: inhibition of mTORC1; MK-2206: inhibition of AKT; BKM120: inhibition of PI3K, mTORC1, and mTORC2; and BEZ235: inhibition of mTORC1 and mTORC2). Effects on cell viability and apoptosis were assessed in insulinoma cell lines INS-1E (rat) and MIN6 (mouse) and were confirmed by using a mouse model of hepatic tumor dissemination after intrasplenic xenograft. , all four combinations display synergistic effects. These combinations lead to heterogeneous mTOR pathway inhibition, in agreement with their respective target, and increased apoptosis., tumor growth in the liver was significantly inhibited by combining streptozotocin with everolimus ( = 0.0014), BKM120 ( = 0.0092), or BEZ235 ( = 0.008) as compared to each agent alone. These results suggest that targeting the mTOR pathway in combination with streptozotocin could be of potential benefit for insulinomas and pNET patients and thus support further clinical investigations. .