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J Pathol ; 249(3): 343-355, 2019 11.
Article in English | MEDLINE | ID: mdl-31257576

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.


Subject(s)
Carcinoma, Neuroendocrine/metabolism , Intestinal Neoplasms/metabolism , Intestine, Small/metabolism , Neuropilin-2/metabolism , Aged , Animals , Antineoplastic Agents/pharmacology , Apoptosis , Carcinoma, Neuroendocrine/drug therapy , Carcinoma, Neuroendocrine/genetics , Carcinoma, Neuroendocrine/secondary , Cell Line, Tumor , Cell Movement , Everolimus/pharmacology , Female , Gene Expression Regulation, Neoplastic , Humans , Intestinal Neoplasms/drug therapy , Intestinal Neoplasms/genetics , Intestinal Neoplasms/pathology , Intestine, Small/pathology , Male , Mice, Nude , Neoplasm Invasiveness , Neovascularization, Pathologic , Neuropilin-2/blood , Neuropilin-2/genetics , Protein Kinase Inhibitors/pharmacology , Signal Transduction , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolism
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