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Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform

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....

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Autores principales: Casazza, Andrea, Kigel, Boaz, Maione, Federica, Capparuccia, Lorena, Kessler, Ofra, Giraudo, Enrico, Mazzone, Massimiliano, Neufeld, Gera, Tamagnone, Luca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: WILEY-VCH Verlag 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376853/
https://www.ncbi.nlm.nih.gov/pubmed/22247010
http://dx.doi.org/10.1002/emmm.201100205
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author Casazza, Andrea
Kigel, Boaz
Maione, Federica
Capparuccia, Lorena
Kessler, Ofra
Giraudo, Enrico
Mazzone, Massimiliano
Neufeld, Gera
Tamagnone, Luca
author_facet Casazza, Andrea
Kigel, Boaz
Maione, Federica
Capparuccia, Lorena
Kessler, Ofra
Giraudo, Enrico
Mazzone, Massimiliano
Neufeld, Gera
Tamagnone, Luca
author_sort Casazza, Andrea
collection PubMed
description 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.
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spelling pubmed-33768532012-09-17 Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform Casazza, Andrea Kigel, Boaz Maione, Federica Capparuccia, Lorena Kessler, Ofra Giraudo, Enrico Mazzone, Massimiliano Neufeld, Gera Tamagnone, Luca EMBO Mol Med Research Article 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. WILEY-VCH Verlag 2012-03 /pmc/articles/PMC3376853/ /pubmed/22247010 http://dx.doi.org/10.1002/emmm.201100205 Text en Copyright © 2012 EMBO Molecular Medicine
spellingShingle Research Article
Casazza, Andrea
Kigel, Boaz
Maione, Federica
Capparuccia, Lorena
Kessler, Ofra
Giraudo, Enrico
Mazzone, Massimiliano
Neufeld, Gera
Tamagnone, Luca
Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform
title Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform
title_full Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform
title_fullStr Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform
title_full_unstemmed Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform
title_short Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform
title_sort tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant semaphorin 3e isoform
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376853/
https://www.ncbi.nlm.nih.gov/pubmed/22247010
http://dx.doi.org/10.1002/emmm.201100205
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