title: Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform.
abstract: Secreted Semaphorin 3E (Sema3E) promotes cancer cell invasiveness and metastatic spreading. The pro-metastatic activity of Sema3E is due to its proteolytic fragment p61, capable of transactivating the oncogenic tyrosine kinase ErbB2 that associates with the Sema3E receptor PlexinD1 in cancer cells. Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61-Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading. Furthermore, Uncl-Sema3E competes with endogenous p61-Sema3E produced by tumour cells, thereby hampering their metastatic ability. Uncl-Sema3E also acts independently as a potent anti-angiogenic factor. It activates a PlexinD1-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival. The putative therapeutic potential of Uncl-Sema3E was validated in multiple orthotopic or spontaneous tumour models in vivo, where either local or systemic delivery of Uncl-Sema3E-reduced angiogenesis, growth and metastasis, even in the case of tumours refractory to treatment with a soluble vascular endothelial growth factor trap. In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading.
authors.affiliation: Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Casazza
authors.forename: Boaz
authors.initials: B
authors.lastname: Kigel
authors.forename: Federica
authors.initials: F
authors.lastname: Maione
authors.forename: Lorena
authors.initials: L
authors.lastname: Capparuccia
authors.forename: Ofra
authors.initials: O
authors.lastname: Kessler
authors.forename: Enrico
authors.initials: E
authors.lastname: Giraudo
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.forename: Gera
authors.initials: G
authors.lastname: Neufeld
authors.forename: Luca
authors.initials: L
authors.lastname: Tamagnone
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D045683:Furin / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D009389:Neovascularization, Pathologic; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D039961:Semaphorins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C493082:PLXND1 protein, human; D020033:Protein Isoforms; C494123:SEMA3E protein, human; D039961:Semaphorins; D045683:Furin