The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors

// Julien Bollard 1, * , Patrick Massoma 1, * , Cecile Vercherat 1 , Martine Blanc 1 , Florian Lepinasse 2 , Nicolas Gadot 3 , Christophe Couderc 1 , Gilles Poncet 4 , Thomas Walter 4 , Marie-Odile Joly 1, 2, 5 , Valerie Hervieu 1, 2, 5 , Jean-Yves Scoazec 1, 2, 3, 5 , Colette Roche 1 1 Centre de Recherche en Cancerologie de Lyon, INSERM U1052, CNRS UMR5286, Equipe «Differenciation endocrine et tumorigenese», Faculte Laennec, F-69372 Lyon, France 2 Hospices Civils de Lyon, Hopital Edouard Herriot, Service Central d’Anatomie et de Cytologie Pathologiques, F-69437 Lyon, France 3 Universite Lyon 1, Federation de Recherche Sante Lyon-Est, ANIPATH, Faculte Laennec, F-69372 Lyon, France 4 Hospices Civils de Lyon, Hopital Edouard Herriot, Federation des Specialites Digestives, F-69437 Lyon, France 5 Universite de Lyon, Universite Lyon 1, F-69622 Villeurbanne, France * These authors have contributed equally to this work Correspondence to: Colette Roche, e-mail: colette.roche@inserm.fr Keywords: small intestine neuroendocrine tumor, semaphorin, proliferation, tumor progression Received: May 20, 2015      Accepted: September 21, 2015      Published: October 02, 2015 ABSTRACT Gastro-intestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, frequently metastatic, raising difficult clinical and therapeutic challenges due to a poor knowledge of their biology. As neuroendocrine cells express both epithelial and neural cell markers, we studied the possible involvement in GI-NETs of axon guidance molecules, which have been shown to decrease tumor cell proliferation and metastatic dissemination in several tumor types. We focused on the role of Semaphorin 3F (SEMA3F) in ileal NETs, one of the most frequent subtypes of GI-NETs. SEMA3F expression was detected in normal neuroendocrine cells but was lost in most of human primary tumors and all their metastases. SEMA3F loss of expression was associated with promoter gene methylation. After increasing endogenous SEMA3F levels through stable transfection, enteroendocrine cell lines STC-1 and GluTag showed a reduced proliferation rate in vitro . In two different xenograft mouse models, SEMA3F-overexpressing cells exhibited a reduced ability to form tumors and a hampered liver dissemination potential in vivo . This resulted, at least in part, from the inhibition of mTOR and MAPK signaling pathways. This study demonstrates an anti-tumoral role of SEMA3F in ileal NETs. We thus suggest that SEMA3F and/or its cellular signaling pathway could represent a target for ileal NET therapy.