The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma

Osteosarcoma is the most frequent primary malignant bone tumour with an impressive tendency to metastasise. Highly proliferative tumour cells release a remarkable amount of protons into the extracellular space that activates the NF-kB inflammatory pathway in adjacent stromal cells. In this study, we...

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Autores principales:	Sofia Avnet, Silvia Lemma, Margherita Cortini, Gemma Di Pompo, Francesca Perut, Maria Veronica Lipreri, Laura Roncuzzi, Marta Columbaro, Costantino Errani, Alessandra Longhi, Nicoletta Zini, Dominique Heymann, Massimo Dominici, Giulia Grisendi, Giulia Golinelli, Lorena Consolino, Dario Livio Longo, Cristina Nanni, Alberto Righi, Nicola Baldini
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	osteosarcoma metastasis acid microenvironment mesenchymal stromal cells inflammatory cytokines Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/82c85e6db0a343619f2945e29d844b0d
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spelling	oai:doaj.org-article:82c85e6db0a343619f2945e29d844b0d2021-11-25T17:04:52ZThe Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma10.3390/cancers132258552072-6694https://doaj.org/article/82c85e6db0a343619f2945e29d844b0d2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5855https://doaj.org/toc/2072-6694Osteosarcoma is the most frequent primary malignant bone tumour with an impressive tendency to metastasise. Highly proliferative tumour cells release a remarkable amount of protons into the extracellular space that activates the NF-kB inflammatory pathway in adjacent stromal cells. In this study, we further validated the correlation between tumour glycolysis/acidosis and its role in metastases. In patients, at diagnosis, we found high circulating levels of inflammatory mediators (IL6, IL8 and miR-136-5p-containing extracellular vesicles). IL6 serum levels significantly correlated with disease-free survival and <sup>18</sup>F-FDG PET/CT uptake, an indirect measurement of tumour glycolysis and, hence, of acidosis. In vivo subcutaneous and orthotopic models, co-injected with mesenchymal stromal (MSC) and osteosarcoma cells, formed an acidic tumour microenvironment (mean pH 6.86, as assessed by in vivo MRI-CEST pH imaging). In these xenografts, we enlightened the expression of both IL6 and the NF-kB complex subunit in stromal cells infiltrating the tumour acidic area. The co-injection with MSC also significantly increased lung metastases. Finally, by using 3D microfluidic models, we directly showed the promotion of osteosarcoma invasiveness by acidosis via IL6 and MSC. In conclusion, osteosarcoma-associated MSC react to intratumoural acidosis by triggering an inflammatory response that, in turn, promotes tumour invasiveness at the primary site toward metastasis development.Sofia AvnetSilvia LemmaMargherita CortiniGemma Di PompoFrancesca PerutMaria Veronica LipreriLaura RoncuzziMarta ColumbaroCostantino ErraniAlessandra LonghiNicoletta ZiniDominique HeymannMassimo DominiciGiulia GrisendiGiulia GolinelliLorena ConsolinoDario Livio LongoCristina NanniAlberto RighiNicola BaldiniMDPI AGarticleosteosarcomametastasisacid microenvironmentmesenchymal stromal cellsinflammatory cytokinesNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5855, p 5855 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	osteosarcoma metastasis acid microenvironment mesenchymal stromal cells inflammatory cytokines Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	osteosarcoma metastasis acid microenvironment mesenchymal stromal cells inflammatory cytokines Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Sofia Avnet Silvia Lemma Margherita Cortini Gemma Di Pompo Francesca Perut Maria Veronica Lipreri Laura Roncuzzi Marta Columbaro Costantino Errani Alessandra Longhi Nicoletta Zini Dominique Heymann Massimo Dominici Giulia Grisendi Giulia Golinelli Lorena Consolino Dario Livio Longo Cristina Nanni Alberto Righi Nicola Baldini The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma
description	Osteosarcoma is the most frequent primary malignant bone tumour with an impressive tendency to metastasise. Highly proliferative tumour cells release a remarkable amount of protons into the extracellular space that activates the NF-kB inflammatory pathway in adjacent stromal cells. In this study, we further validated the correlation between tumour glycolysis/acidosis and its role in metastases. In patients, at diagnosis, we found high circulating levels of inflammatory mediators (IL6, IL8 and miR-136-5p-containing extracellular vesicles). IL6 serum levels significantly correlated with disease-free survival and <sup>18</sup>F-FDG PET/CT uptake, an indirect measurement of tumour glycolysis and, hence, of acidosis. In vivo subcutaneous and orthotopic models, co-injected with mesenchymal stromal (MSC) and osteosarcoma cells, formed an acidic tumour microenvironment (mean pH 6.86, as assessed by in vivo MRI-CEST pH imaging). In these xenografts, we enlightened the expression of both IL6 and the NF-kB complex subunit in stromal cells infiltrating the tumour acidic area. The co-injection with MSC also significantly increased lung metastases. Finally, by using 3D microfluidic models, we directly showed the promotion of osteosarcoma invasiveness by acidosis via IL6 and MSC. In conclusion, osteosarcoma-associated MSC react to intratumoural acidosis by triggering an inflammatory response that, in turn, promotes tumour invasiveness at the primary site toward metastasis development.
format	article
author	Sofia Avnet Silvia Lemma Margherita Cortini Gemma Di Pompo Francesca Perut Maria Veronica Lipreri Laura Roncuzzi Marta Columbaro Costantino Errani Alessandra Longhi Nicoletta Zini Dominique Heymann Massimo Dominici Giulia Grisendi Giulia Golinelli Lorena Consolino Dario Livio Longo Cristina Nanni Alberto Righi Nicola Baldini
author_facet	Sofia Avnet Silvia Lemma Margherita Cortini Gemma Di Pompo Francesca Perut Maria Veronica Lipreri Laura Roncuzzi Marta Columbaro Costantino Errani Alessandra Longhi Nicoletta Zini Dominique Heymann Massimo Dominici Giulia Grisendi Giulia Golinelli Lorena Consolino Dario Livio Longo Cristina Nanni Alberto Righi Nicola Baldini
author_sort	Sofia Avnet
title	The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma
title_short	The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma
title_full	The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma
title_fullStr	The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma
title_full_unstemmed	The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma
title_sort	release of inflammatory mediators from acid-stimulated mesenchymal stromal cells favours tumour invasiveness and metastasis in osteosarcoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/82c85e6db0a343619f2945e29d844b0d
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The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma

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