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Osteotropism of neuroendocrine tumors: role of the CXCL12/CXCR4 pathway in promoting EMT in vitro

Neuroendocrine tumors (NETs) metastasize to the skeleton in approximately 20% of patients. We have previously shown that the epithelial-mesenchymal transition (EMT) regulates the NET osteotropism and that CXCR4 overexpression predicts bone spreading. Here, we unravel the molecular mechanisms linking...

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Autores principales: Cives, Mauro, Quaresmini, Davide, Rizzo, Francesca Maria, Felici, Claudia, D'Oronzo, Stella, Simone, Valeria, Silvestris, Franco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410243/
https://www.ncbi.nlm.nih.gov/pubmed/28186979
http://dx.doi.org/10.18632/oncotarget.15122
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author Cives, Mauro
Quaresmini, Davide
Rizzo, Francesca Maria
Felici, Claudia
D'Oronzo, Stella
Simone, Valeria
Silvestris, Franco
author_facet Cives, Mauro
Quaresmini, Davide
Rizzo, Francesca Maria
Felici, Claudia
D'Oronzo, Stella
Simone, Valeria
Silvestris, Franco
author_sort Cives, Mauro
collection PubMed
description Neuroendocrine tumors (NETs) metastasize to the skeleton in approximately 20% of patients. We have previously shown that the epithelial-mesenchymal transition (EMT) regulates the NET osteotropism and that CXCR4 overexpression predicts bone spreading. Here, we unravel the molecular mechanisms linking the activation of the CXCL12/CXCR4 axis to the bone colonization of NETs using cell lines representative of pancreatic (BON1, CM, QGP1), intestinal (CNDT 2.5), and bronchial origin (H727). By combining flow cytometry and ELISA, BON1, CM and QGP1 cells were defined as CXCR4(high)/CXCL12(low), while H727 and CNDT 2.5 were CXCR4(low)/CXCL12(high). CXCL12 was inert on cell proliferation, but significantly increased the in vitro osteotropism of CXCR4(high)/CXCL12(low) cells, as assessed by transwell assays with or without Matrigel membranes. In these cells, CXCL12 induced in vitro a marked EMT-like transcriptional shift with acquirement of a mesenchymal shape. The nuclei of CXCR4(high)/CXCL12(low) NET cells were typically enriched in non-phosphorylated CXCR4, particularly upon agonist stimulation. Silencing of CXCR4 via siRNA prevented the CXCL12-induced EMT in CXCR4(high)/CXCL12(low) NET cell lines resulting in the abrogation of both migration and transcriptional mesenchymal patterns. Our data suggest that CXCL12 conveys EMT-promoting signals in NET cells through CXCR4, which in turn regulates transcriptional, morphologic and functional modifications resulting in enhanced in vitro osteotropism of NET cells. Unique functions of CXCR4 may be segregated in relation to its subcellular localization and may acquire potential relevance in future in vivo studies.
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spelling pubmed-54102432017-05-04 Osteotropism of neuroendocrine tumors: role of the CXCL12/CXCR4 pathway in promoting EMT in vitro Cives, Mauro Quaresmini, Davide Rizzo, Francesca Maria Felici, Claudia D'Oronzo, Stella Simone, Valeria Silvestris, Franco Oncotarget Research Paper Neuroendocrine tumors (NETs) metastasize to the skeleton in approximately 20% of patients. We have previously shown that the epithelial-mesenchymal transition (EMT) regulates the NET osteotropism and that CXCR4 overexpression predicts bone spreading. Here, we unravel the molecular mechanisms linking the activation of the CXCL12/CXCR4 axis to the bone colonization of NETs using cell lines representative of pancreatic (BON1, CM, QGP1), intestinal (CNDT 2.5), and bronchial origin (H727). By combining flow cytometry and ELISA, BON1, CM and QGP1 cells were defined as CXCR4(high)/CXCL12(low), while H727 and CNDT 2.5 were CXCR4(low)/CXCL12(high). CXCL12 was inert on cell proliferation, but significantly increased the in vitro osteotropism of CXCR4(high)/CXCL12(low) cells, as assessed by transwell assays with or without Matrigel membranes. In these cells, CXCL12 induced in vitro a marked EMT-like transcriptional shift with acquirement of a mesenchymal shape. The nuclei of CXCR4(high)/CXCL12(low) NET cells were typically enriched in non-phosphorylated CXCR4, particularly upon agonist stimulation. Silencing of CXCR4 via siRNA prevented the CXCL12-induced EMT in CXCR4(high)/CXCL12(low) NET cell lines resulting in the abrogation of both migration and transcriptional mesenchymal patterns. Our data suggest that CXCL12 conveys EMT-promoting signals in NET cells through CXCR4, which in turn regulates transcriptional, morphologic and functional modifications resulting in enhanced in vitro osteotropism of NET cells. Unique functions of CXCR4 may be segregated in relation to its subcellular localization and may acquire potential relevance in future in vivo studies. Impact Journals LLC 2017-02-06 /pmc/articles/PMC5410243/ /pubmed/28186979 http://dx.doi.org/10.18632/oncotarget.15122 Text en Copyright: © 2017 Cives et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Cives, Mauro
Quaresmini, Davide
Rizzo, Francesca Maria
Felici, Claudia
D'Oronzo, Stella
Simone, Valeria
Silvestris, Franco
Osteotropism of neuroendocrine tumors: role of the CXCL12/CXCR4 pathway in promoting EMT in vitro
title Osteotropism of neuroendocrine tumors: role of the CXCL12/CXCR4 pathway in promoting EMT in vitro
title_full Osteotropism of neuroendocrine tumors: role of the CXCL12/CXCR4 pathway in promoting EMT in vitro
title_fullStr Osteotropism of neuroendocrine tumors: role of the CXCL12/CXCR4 pathway in promoting EMT in vitro
title_full_unstemmed Osteotropism of neuroendocrine tumors: role of the CXCL12/CXCR4 pathway in promoting EMT in vitro
title_short Osteotropism of neuroendocrine tumors: role of the CXCL12/CXCR4 pathway in promoting EMT in vitro
title_sort osteotropism of neuroendocrine tumors: role of the cxcl12/cxcr4 pathway in promoting emt in vitro
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410243/
https://www.ncbi.nlm.nih.gov/pubmed/28186979
http://dx.doi.org/10.18632/oncotarget.15122
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