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Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration

BACKGROUND: Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption...

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Autores principales: Odri, Guillaume, Kim, Pui-Pui, Lamoureux, François, Charrier, Céline, Battaglia, Séverine, Amiaud, Jérôme, Heymann, Dominique, Gouin, François, Redini, Françoise
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975287/
https://www.ncbi.nlm.nih.gov/pubmed/24612486
http://dx.doi.org/10.1186/1471-2407-14-169
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author Odri, Guillaume
Kim, Pui-Pui
Lamoureux, François
Charrier, Céline
Battaglia, Séverine
Amiaud, Jérôme
Heymann, Dominique
Gouin, François
Redini, Françoise
author_facet Odri, Guillaume
Kim, Pui-Pui
Lamoureux, François
Charrier, Céline
Battaglia, Séverine
Amiaud, Jérôme
Heymann, Dominique
Gouin, François
Redini, Françoise
author_sort Odri, Guillaume
collection PubMed
description BACKGROUND: Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties. METHODS: Invasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 10(6) human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology. RESULTS: ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and −9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases. CONCLUSION: These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs.
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spelling pubmed-39752872014-04-05 Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration Odri, Guillaume Kim, Pui-Pui Lamoureux, François Charrier, Céline Battaglia, Séverine Amiaud, Jérôme Heymann, Dominique Gouin, François Redini, Françoise BMC Cancer Research Article BACKGROUND: Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties. METHODS: Invasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 10(6) human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology. RESULTS: ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and −9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases. CONCLUSION: These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs. BioMed Central 2014-03-10 /pmc/articles/PMC3975287/ /pubmed/24612486 http://dx.doi.org/10.1186/1471-2407-14-169 Text en Copyright © 2014 Odri et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
spellingShingle Research Article
Odri, Guillaume
Kim, Pui-Pui
Lamoureux, François
Charrier, Céline
Battaglia, Séverine
Amiaud, Jérôme
Heymann, Dominique
Gouin, François
Redini, Françoise
Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration
title Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration
title_full Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration
title_fullStr Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration
title_full_unstemmed Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration
title_short Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration
title_sort zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of ewing’s sarcoma via inhibition of cell migration
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975287/
https://www.ncbi.nlm.nih.gov/pubmed/24612486
http://dx.doi.org/10.1186/1471-2407-14-169
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