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Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice

Prostate cancer (PCa) is the most frequent malignancy in older men with a high propensity for bone metastases. Characteristically, PCa causes osteosclerotic lesions as a result of disrupted bone remodeling. Extracellular vesicles (EVs) participate in PCa progression by conditioning the pre-metastati...

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Autores principales: Furesi, Giulia, de Jesus Domingues, Antonio Miguel, Alexopoulou, Dimitra, Dahl, Andreas, Hackl, Matthias, Schmidt, Johannes R., Kalkhof, Stefan, Kurth, Thomas, Taipaleenmäki, Hanna, Conrad, Stefanie, Hofbauer, Christine, Rauner, Martina, Hofbauer, Lorenz C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836054/
https://www.ncbi.nlm.nih.gov/pubmed/35163219
http://dx.doi.org/10.3390/ijms23031285
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author Furesi, Giulia
de Jesus Domingues, Antonio Miguel
Alexopoulou, Dimitra
Dahl, Andreas
Hackl, Matthias
Schmidt, Johannes R.
Kalkhof, Stefan
Kurth, Thomas
Taipaleenmäki, Hanna
Conrad, Stefanie
Hofbauer, Christine
Rauner, Martina
Hofbauer, Lorenz C.
author_facet Furesi, Giulia
de Jesus Domingues, Antonio Miguel
Alexopoulou, Dimitra
Dahl, Andreas
Hackl, Matthias
Schmidt, Johannes R.
Kalkhof, Stefan
Kurth, Thomas
Taipaleenmäki, Hanna
Conrad, Stefanie
Hofbauer, Christine
Rauner, Martina
Hofbauer, Lorenz C.
author_sort Furesi, Giulia
collection PubMed
description Prostate cancer (PCa) is the most frequent malignancy in older men with a high propensity for bone metastases. Characteristically, PCa causes osteosclerotic lesions as a result of disrupted bone remodeling. Extracellular vesicles (EVs) participate in PCa progression by conditioning the pre-metastatic niche. However, how EVs mediate the cross-talk between PCa cells and osteoprogenitors in the bone microenvironment remains poorly understood. We found that EVs derived from murine PCa cell line RM1-BM increased metabolic activity, vitality, and cell proliferation of osteoblast precursors by >60%, while significantly impairing mineral deposition (−37%). The latter was further confirmed in two complementary in vivo models of ossification. Accordingly, gene and protein set enrichments of osteoprogenitors exposed to EVs displayed significant downregulation of osteogenic markers and upregulation of proinflammatory factors. Additionally, transcriptomic profiling of PCa-EVs revealed the abundance of three microRNAs, miR-26a-5p, miR-27a-3p, and miR-30e-5p involved in the suppression of BMP-2-induced osteogenesis in vivo, suggesting the critical role of these EV-derived miRNAs in PCa-mediated suppression of osteoblast activity. Taken together, our results indicate the importance of EV cargo in cancer-bone cross-talk in vitro and in vivo and suggest that exosomal miRNAs may contribute to the onset of osteosclerotic bone lesions in PCa.
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spelling pubmed-88360542022-02-12 Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice Furesi, Giulia de Jesus Domingues, Antonio Miguel Alexopoulou, Dimitra Dahl, Andreas Hackl, Matthias Schmidt, Johannes R. Kalkhof, Stefan Kurth, Thomas Taipaleenmäki, Hanna Conrad, Stefanie Hofbauer, Christine Rauner, Martina Hofbauer, Lorenz C. Int J Mol Sci Article Prostate cancer (PCa) is the most frequent malignancy in older men with a high propensity for bone metastases. Characteristically, PCa causes osteosclerotic lesions as a result of disrupted bone remodeling. Extracellular vesicles (EVs) participate in PCa progression by conditioning the pre-metastatic niche. However, how EVs mediate the cross-talk between PCa cells and osteoprogenitors in the bone microenvironment remains poorly understood. We found that EVs derived from murine PCa cell line RM1-BM increased metabolic activity, vitality, and cell proliferation of osteoblast precursors by >60%, while significantly impairing mineral deposition (−37%). The latter was further confirmed in two complementary in vivo models of ossification. Accordingly, gene and protein set enrichments of osteoprogenitors exposed to EVs displayed significant downregulation of osteogenic markers and upregulation of proinflammatory factors. Additionally, transcriptomic profiling of PCa-EVs revealed the abundance of three microRNAs, miR-26a-5p, miR-27a-3p, and miR-30e-5p involved in the suppression of BMP-2-induced osteogenesis in vivo, suggesting the critical role of these EV-derived miRNAs in PCa-mediated suppression of osteoblast activity. Taken together, our results indicate the importance of EV cargo in cancer-bone cross-talk in vitro and in vivo and suggest that exosomal miRNAs may contribute to the onset of osteosclerotic bone lesions in PCa. MDPI 2022-01-24 /pmc/articles/PMC8836054/ /pubmed/35163219 http://dx.doi.org/10.3390/ijms23031285 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Furesi, Giulia
de Jesus Domingues, Antonio Miguel
Alexopoulou, Dimitra
Dahl, Andreas
Hackl, Matthias
Schmidt, Johannes R.
Kalkhof, Stefan
Kurth, Thomas
Taipaleenmäki, Hanna
Conrad, Stefanie
Hofbauer, Christine
Rauner, Martina
Hofbauer, Lorenz C.
Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice
title Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice
title_full Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice
title_fullStr Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice
title_full_unstemmed Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice
title_short Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice
title_sort exosomal mirnas from prostate cancer impair osteoblast function in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836054/
https://www.ncbi.nlm.nih.gov/pubmed/35163219
http://dx.doi.org/10.3390/ijms23031285
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