title: The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors.
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.
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Equipe «Différenciation endocrine et tumorigenèse», Faculté Laënnec, F-69372 Lyon, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Bollard
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Equipe «Différenciation endocrine et tumorigenèse», Faculté Laënnec, F-69372 Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Massoma
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Equipe «Différenciation endocrine et tumorigenèse», Faculté Laënnec, F-69372 Lyon, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Vercherat
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Equipe «Différenciation endocrine et tumorigenèse», Faculté Laënnec, F-69372 Lyon, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Blanc
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et de Cytologie Pathologiques, F-69437 Lyon, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Lepinasse
authors.affiliation: Université Lyon 1, Fédération de Recherche Santé Lyon-Est, ANIPATH, Faculté Laennec, F-69372 Lyon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gadot
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Equipe «Différenciation endocrine et tumorigenèse», Faculté Laënnec, F-69372 Lyon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Couderc
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, F-69437 Lyon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Poncet
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, F-69437 Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walter
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Equipe «Différenciation endocrine et tumorigenèse», Faculté Laënnec, F-69372 Lyon, France.|Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et de Cytologie Pathologiques, F-69437 Lyon, France.|Université de Lyon, Université Lyon 1, F-69622 Villeurbanne, France.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Joly
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Equipe «Différenciation endocrine et tumorigenèse», Faculté Laënnec, F-69372 Lyon, France.|Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et de Cytologie Pathologiques, F-69437 Lyon, France.|Université de Lyon, Université Lyon 1, F-69622 Villeurbanne, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Hervieu
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Equipe «Différenciation endocrine et tumorigenèse», Faculté Laënnec, F-69372 Lyon, France.|Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et de Cytologie Pathologiques, F-69437 Lyon, France.|Université Lyon 1, Fédération de Recherche Santé Lyon-Est, ANIPATH, Faculté Laennec, F-69372 Lyon, France.|Université de Lyon, Université Lyon 1, F-69622 Villeurbanne, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Equipe «Différenciation endocrine et tumorigenèse», Faculté Laënnec, F-69372 Lyon, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Roche
mesh_terms: D000818:Animals; D000071437:Axon Guidance / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D064593:Heterografts; D006801:Humans; D007078:Ileal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C491230:SEMA3F protein, human
keywords: proliferation; semaphorin; small intestine neuroendocrine tumor; tumor progression