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Uptake-Dependent and -Independent Effects of Fibroblasts-Derived Extracellular Vesicles on Bone Marrow Endothelial Cells from Patients with Multiple Myeloma: Therapeutic and Clinical Implications
Extracellular vesicles (EVs) have emerged as important players in cell-to-cell communication within the bone marrow (BM) of multiple myeloma (MM) patients, where they mediate several tumor-associated processes. Here, we investigate the contribution of fibroblasts-derived EVs (FBEVs) in supporting BM...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10216205/ https://www.ncbi.nlm.nih.gov/pubmed/37239071 http://dx.doi.org/10.3390/biomedicines11051400 |
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author | Lamanuzzi, Aurelia Saltarella, Ilaria Reale, Antonia Melaccio, Assunta Solimando, Antonio Giovanni Altamura, Concetta Tamma, Grazia Storlazzi, Clelia Tiziana Tolomeo, Doron Desantis, Vanessa Mariggiò, Maria Addolorata Desaphy, Jean-François Spencer, Andrew Vacca, Angelo Apollonio, Benedetta Frassanito, Maria Antonia |
author_facet | Lamanuzzi, Aurelia Saltarella, Ilaria Reale, Antonia Melaccio, Assunta Solimando, Antonio Giovanni Altamura, Concetta Tamma, Grazia Storlazzi, Clelia Tiziana Tolomeo, Doron Desantis, Vanessa Mariggiò, Maria Addolorata Desaphy, Jean-François Spencer, Andrew Vacca, Angelo Apollonio, Benedetta Frassanito, Maria Antonia |
author_sort | Lamanuzzi, Aurelia |
collection | PubMed |
description | Extracellular vesicles (EVs) have emerged as important players in cell-to-cell communication within the bone marrow (BM) of multiple myeloma (MM) patients, where they mediate several tumor-associated processes. Here, we investigate the contribution of fibroblasts-derived EVs (FBEVs) in supporting BM angiogenesis. We demonstrate that FBEVs’ cargo contains several angiogenic cytokines (i.e., VEGF, HGF, and ANG-1) that promote an early over-angiogenic effect independent from EVs uptake. Interestingly, co-culture of endothelial cells from MM patients (MMECs) with FBEVs for 1 or 6 h activates the VEGF/VEGFR2, HGF/HGFR, and ANG-1/Tie2 axis, as well as the mTORC2 and Wnt/β-catenin pathways, suggesting that the early over-angiogenic effect is a cytokine-mediated process. FBEVs internalization occurs after longer exposure of MMECs to FBEVs (24 h) and induces a late over-angiogenic effect by increasing MMECs migration, chemotaxis, metalloproteases release, and capillarogenesis. FBEVs uptake activates mTORC1, MAPK, SRC, and STAT pathways that promote the release of pro-angiogenic cytokines, further supporting the pro-angiogenic milieu. Overall, our results demonstrate that FBEVs foster MM angiogenesis through dual time-related uptake-independent and uptake-dependent mechanisms that activate different intracellular pathways and transcriptional programs, providing the rationale for designing novel anti-angiogenic strategies. |
format | Online Article Text |
id | pubmed-10216205 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102162052023-05-27 Uptake-Dependent and -Independent Effects of Fibroblasts-Derived Extracellular Vesicles on Bone Marrow Endothelial Cells from Patients with Multiple Myeloma: Therapeutic and Clinical Implications Lamanuzzi, Aurelia Saltarella, Ilaria Reale, Antonia Melaccio, Assunta Solimando, Antonio Giovanni Altamura, Concetta Tamma, Grazia Storlazzi, Clelia Tiziana Tolomeo, Doron Desantis, Vanessa Mariggiò, Maria Addolorata Desaphy, Jean-François Spencer, Andrew Vacca, Angelo Apollonio, Benedetta Frassanito, Maria Antonia Biomedicines Article Extracellular vesicles (EVs) have emerged as important players in cell-to-cell communication within the bone marrow (BM) of multiple myeloma (MM) patients, where they mediate several tumor-associated processes. Here, we investigate the contribution of fibroblasts-derived EVs (FBEVs) in supporting BM angiogenesis. We demonstrate that FBEVs’ cargo contains several angiogenic cytokines (i.e., VEGF, HGF, and ANG-1) that promote an early over-angiogenic effect independent from EVs uptake. Interestingly, co-culture of endothelial cells from MM patients (MMECs) with FBEVs for 1 or 6 h activates the VEGF/VEGFR2, HGF/HGFR, and ANG-1/Tie2 axis, as well as the mTORC2 and Wnt/β-catenin pathways, suggesting that the early over-angiogenic effect is a cytokine-mediated process. FBEVs internalization occurs after longer exposure of MMECs to FBEVs (24 h) and induces a late over-angiogenic effect by increasing MMECs migration, chemotaxis, metalloproteases release, and capillarogenesis. FBEVs uptake activates mTORC1, MAPK, SRC, and STAT pathways that promote the release of pro-angiogenic cytokines, further supporting the pro-angiogenic milieu. Overall, our results demonstrate that FBEVs foster MM angiogenesis through dual time-related uptake-independent and uptake-dependent mechanisms that activate different intracellular pathways and transcriptional programs, providing the rationale for designing novel anti-angiogenic strategies. MDPI 2023-05-08 /pmc/articles/PMC10216205/ /pubmed/37239071 http://dx.doi.org/10.3390/biomedicines11051400 Text en © 2023 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 Lamanuzzi, Aurelia Saltarella, Ilaria Reale, Antonia Melaccio, Assunta Solimando, Antonio Giovanni Altamura, Concetta Tamma, Grazia Storlazzi, Clelia Tiziana Tolomeo, Doron Desantis, Vanessa Mariggiò, Maria Addolorata Desaphy, Jean-François Spencer, Andrew Vacca, Angelo Apollonio, Benedetta Frassanito, Maria Antonia Uptake-Dependent and -Independent Effects of Fibroblasts-Derived Extracellular Vesicles on Bone Marrow Endothelial Cells from Patients with Multiple Myeloma: Therapeutic and Clinical Implications |
title | Uptake-Dependent and -Independent Effects of Fibroblasts-Derived Extracellular Vesicles on Bone Marrow Endothelial Cells from Patients with Multiple Myeloma: Therapeutic and Clinical Implications |
title_full | Uptake-Dependent and -Independent Effects of Fibroblasts-Derived Extracellular Vesicles on Bone Marrow Endothelial Cells from Patients with Multiple Myeloma: Therapeutic and Clinical Implications |
title_fullStr | Uptake-Dependent and -Independent Effects of Fibroblasts-Derived Extracellular Vesicles on Bone Marrow Endothelial Cells from Patients with Multiple Myeloma: Therapeutic and Clinical Implications |
title_full_unstemmed | Uptake-Dependent and -Independent Effects of Fibroblasts-Derived Extracellular Vesicles on Bone Marrow Endothelial Cells from Patients with Multiple Myeloma: Therapeutic and Clinical Implications |
title_short | Uptake-Dependent and -Independent Effects of Fibroblasts-Derived Extracellular Vesicles on Bone Marrow Endothelial Cells from Patients with Multiple Myeloma: Therapeutic and Clinical Implications |
title_sort | uptake-dependent and -independent effects of fibroblasts-derived extracellular vesicles on bone marrow endothelial cells from patients with multiple myeloma: therapeutic and clinical implications |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10216205/ https://www.ncbi.nlm.nih.gov/pubmed/37239071 http://dx.doi.org/10.3390/biomedicines11051400 |
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