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Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment

Multiple myeloma develops primarily inside the bone marrow microenvironment, that confers pro-survival signals and drug resistance. 3D cultures that reproduce multiple myeloma-bone marrow interactions are needed to fully investigate multiple myeloma pathogenesis and response to drugs. To this purpos...

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Autores principales: Belloni, Daniela, Heltai, Silvia, Ponzoni, Maurilio, Villa, Antonello, Vergani, Barbara, Pecciarini, Lorenza, Marcatti, Magda, Girlanda, Stefania, Tonon, Giovanni, Ciceri, Fabio, Caligaris-Cappio, Federico, Ferrarini, Marina, Ferrero, Elisabetta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865414/
https://www.ncbi.nlm.nih.gov/pubmed/29326121
http://dx.doi.org/10.3324/haematol.2017.167486
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author Belloni, Daniela
Heltai, Silvia
Ponzoni, Maurilio
Villa, Antonello
Vergani, Barbara
Pecciarini, Lorenza
Marcatti, Magda
Girlanda, Stefania
Tonon, Giovanni
Ciceri, Fabio
Caligaris-Cappio, Federico
Ferrarini, Marina
Ferrero, Elisabetta
author_facet Belloni, Daniela
Heltai, Silvia
Ponzoni, Maurilio
Villa, Antonello
Vergani, Barbara
Pecciarini, Lorenza
Marcatti, Magda
Girlanda, Stefania
Tonon, Giovanni
Ciceri, Fabio
Caligaris-Cappio, Federico
Ferrarini, Marina
Ferrero, Elisabetta
author_sort Belloni, Daniela
collection PubMed
description Multiple myeloma develops primarily inside the bone marrow microenvironment, that confers pro-survival signals and drug resistance. 3D cultures that reproduce multiple myeloma-bone marrow interactions are needed to fully investigate multiple myeloma pathogenesis and response to drugs. To this purpose, we exploited the 3D Rotary Cell Culture System bioreactor technology for myeloma-bone marrow co-cultures in gelatin scaffolds. The model was validated with myeloma cell lines that, as assessed by histochemical and electron-microscopic analyses, engaged contacts with stromal cells and endothelial cells. Consistently, pro-survival signaling and also cell adhesion-mediated drug resistance were significantly higher in 3D than in 2D parallel co-cultures. The contribution of the VLA-4/VCAM1 pathway to resistance to bortezomib was modeled by the use of VCAM1 transfectants. Soluble factor-mediated drug resistance could be also demonstrated in both 2D and 3D co-cultures. The system was then successfully applied to co-cultures of primary myeloma cells-primary myeloma bone marrow stromal cells from patients and endothelial cells, allowing the development of functional myeloma-stroma interactions and MM cell long-term survival. Significantly, genomic analysis performed in a high-risk myeloma patient demonstrated that culture in bioreactor paralleled the expansion of the clone that ultimately dominated in vivo. Finally, the impact of bortezomib on myeloma cells and on specialized functions of the microenvironment could be evaluated. Our findings indicate that 3D dynamic culture of reconstructed human multiple myeloma microenvironments in bioreactor may represent a useful platform for drug testing and for studying tumor-stroma molecular interactions.
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spelling pubmed-58654142018-04-01 Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment Belloni, Daniela Heltai, Silvia Ponzoni, Maurilio Villa, Antonello Vergani, Barbara Pecciarini, Lorenza Marcatti, Magda Girlanda, Stefania Tonon, Giovanni Ciceri, Fabio Caligaris-Cappio, Federico Ferrarini, Marina Ferrero, Elisabetta Haematologica Article Multiple myeloma develops primarily inside the bone marrow microenvironment, that confers pro-survival signals and drug resistance. 3D cultures that reproduce multiple myeloma-bone marrow interactions are needed to fully investigate multiple myeloma pathogenesis and response to drugs. To this purpose, we exploited the 3D Rotary Cell Culture System bioreactor technology for myeloma-bone marrow co-cultures in gelatin scaffolds. The model was validated with myeloma cell lines that, as assessed by histochemical and electron-microscopic analyses, engaged contacts with stromal cells and endothelial cells. Consistently, pro-survival signaling and also cell adhesion-mediated drug resistance were significantly higher in 3D than in 2D parallel co-cultures. The contribution of the VLA-4/VCAM1 pathway to resistance to bortezomib was modeled by the use of VCAM1 transfectants. Soluble factor-mediated drug resistance could be also demonstrated in both 2D and 3D co-cultures. The system was then successfully applied to co-cultures of primary myeloma cells-primary myeloma bone marrow stromal cells from patients and endothelial cells, allowing the development of functional myeloma-stroma interactions and MM cell long-term survival. Significantly, genomic analysis performed in a high-risk myeloma patient demonstrated that culture in bioreactor paralleled the expansion of the clone that ultimately dominated in vivo. Finally, the impact of bortezomib on myeloma cells and on specialized functions of the microenvironment could be evaluated. Our findings indicate that 3D dynamic culture of reconstructed human multiple myeloma microenvironments in bioreactor may represent a useful platform for drug testing and for studying tumor-stroma molecular interactions. Ferrata Storti Foundation 2018-04 /pmc/articles/PMC5865414/ /pubmed/29326121 http://dx.doi.org/10.3324/haematol.2017.167486 Text en Copyright© 2018 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
spellingShingle Article
Belloni, Daniela
Heltai, Silvia
Ponzoni, Maurilio
Villa, Antonello
Vergani, Barbara
Pecciarini, Lorenza
Marcatti, Magda
Girlanda, Stefania
Tonon, Giovanni
Ciceri, Fabio
Caligaris-Cappio, Federico
Ferrarini, Marina
Ferrero, Elisabetta
Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment
title Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment
title_full Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment
title_fullStr Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment
title_full_unstemmed Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment
title_short Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment
title_sort modeling multiple myeloma-bone marrow interactions and response to drugs in a 3d surrogate microenvironment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865414/
https://www.ncbi.nlm.nih.gov/pubmed/29326121
http://dx.doi.org/10.3324/haematol.2017.167486
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