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The metastatic capacity of high-grade serous ovarian cancer cells changes along disease progression: inhibition by mifepristone

BACKGROUND: Simplistic two-dimensional (2D) in vitro assays have long been the standard for studying the metastatic abilities of cancer cells. However, tri-dimensional (3D) organotypic models provide a more complex environment, closer to that seen in patients, and thereby provide a more accurate rep...

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Autores principales: Ritch, Sabrina J., Noman, Abu Shadat M., Goyeneche, Alicia A., Telleria, Carlos M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9733158/
https://www.ncbi.nlm.nih.gov/pubmed/36494669
http://dx.doi.org/10.1186/s12935-022-02822-5
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author Ritch, Sabrina J.
Noman, Abu Shadat M.
Goyeneche, Alicia A.
Telleria, Carlos M.
author_facet Ritch, Sabrina J.
Noman, Abu Shadat M.
Goyeneche, Alicia A.
Telleria, Carlos M.
author_sort Ritch, Sabrina J.
collection PubMed
description BACKGROUND: Simplistic two-dimensional (2D) in vitro assays have long been the standard for studying the metastatic abilities of cancer cells. However, tri-dimensional (3D) organotypic models provide a more complex environment, closer to that seen in patients, and thereby provide a more accurate representation of their true capabilities. Our laboratory has previously shown that the antiprogestin and antiglucocorticoid mifepristone can reduce the growth, adhesion, migration, and invasion of various aggressive cancer cells assessed using 2D assays. In this study, we characterize the metastatic capabilities of high-grade serous ovarian cancer cells generated along disease progression, in both 2D and 3D assays, and the ability of cytostatic doses of mifepristone to inhibit them. METHODS: High-grade serous ovarian cancer cells collected from two separate patients at different stages of their disease were used throughout the study. The 2D wound healing and Boyden chamber assays were used to study migration, while a layer of extracellular matrix was added to the Boyden chamber to study invasion. A 3D organotypic model, composed of fibroblasts embedded in collagen I and topped with a monolayer of mesothelial cells was used to further study cancer cell adhesion and mesothelial displacement. All assays were studied in cells, which were originally harvested from two patients at different stages of disease progression, in the absence or presence of cytostatic doses of mifepristone. RESULTS: 2D in vitro assays demonstrated that the migration and invasive rates of the cells isolated from both patients decreased along disease progression. Conversely, in both patients, cells representing late-stage disease demonstrated a higher adhesion capacity to the 3D organotypic model than those representing an early-stage disease. This adhesive behavior is associated with the in vivo tumor capacity of the cells. Regardless of these differences in adhesive, migratory, and invasive behavior among the experimental protocols used, cytostatic doses of mifepristone were able to inhibit the adhesion, migration, and invasion rates of all cells studied, regardless of their basal capabilities over simplistic or organotypic metastatic in vitro model systems. Finally, we demonstrate that when cells acquire the capacity to grow spontaneously as spheroids, they do attach to a 3D organotypic model system when pre-incubated with conditioned media. Of relevance, mifepristone was able to cause dissociation of these multicellular structures. CONCLUSION: Differences in cellular behaviours were observed between 2 and 3D assays when studying the metastatic capabilities of high-grade serous ovarian cancer cells representing disease progression. Mifepristone inhibited these metastatic capabilities in all assays studied. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-022-02822-5.
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spelling pubmed-97331582022-12-10 The metastatic capacity of high-grade serous ovarian cancer cells changes along disease progression: inhibition by mifepristone Ritch, Sabrina J. Noman, Abu Shadat M. Goyeneche, Alicia A. Telleria, Carlos M. Cancer Cell Int Research BACKGROUND: Simplistic two-dimensional (2D) in vitro assays have long been the standard for studying the metastatic abilities of cancer cells. However, tri-dimensional (3D) organotypic models provide a more complex environment, closer to that seen in patients, and thereby provide a more accurate representation of their true capabilities. Our laboratory has previously shown that the antiprogestin and antiglucocorticoid mifepristone can reduce the growth, adhesion, migration, and invasion of various aggressive cancer cells assessed using 2D assays. In this study, we characterize the metastatic capabilities of high-grade serous ovarian cancer cells generated along disease progression, in both 2D and 3D assays, and the ability of cytostatic doses of mifepristone to inhibit them. METHODS: High-grade serous ovarian cancer cells collected from two separate patients at different stages of their disease were used throughout the study. The 2D wound healing and Boyden chamber assays were used to study migration, while a layer of extracellular matrix was added to the Boyden chamber to study invasion. A 3D organotypic model, composed of fibroblasts embedded in collagen I and topped with a monolayer of mesothelial cells was used to further study cancer cell adhesion and mesothelial displacement. All assays were studied in cells, which were originally harvested from two patients at different stages of disease progression, in the absence or presence of cytostatic doses of mifepristone. RESULTS: 2D in vitro assays demonstrated that the migration and invasive rates of the cells isolated from both patients decreased along disease progression. Conversely, in both patients, cells representing late-stage disease demonstrated a higher adhesion capacity to the 3D organotypic model than those representing an early-stage disease. This adhesive behavior is associated with the in vivo tumor capacity of the cells. Regardless of these differences in adhesive, migratory, and invasive behavior among the experimental protocols used, cytostatic doses of mifepristone were able to inhibit the adhesion, migration, and invasion rates of all cells studied, regardless of their basal capabilities over simplistic or organotypic metastatic in vitro model systems. Finally, we demonstrate that when cells acquire the capacity to grow spontaneously as spheroids, they do attach to a 3D organotypic model system when pre-incubated with conditioned media. Of relevance, mifepristone was able to cause dissociation of these multicellular structures. CONCLUSION: Differences in cellular behaviours were observed between 2 and 3D assays when studying the metastatic capabilities of high-grade serous ovarian cancer cells representing disease progression. Mifepristone inhibited these metastatic capabilities in all assays studied. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-022-02822-5. BioMed Central 2022-12-09 /pmc/articles/PMC9733158/ /pubmed/36494669 http://dx.doi.org/10.1186/s12935-022-02822-5 Text en © Crown 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Ritch, Sabrina J.
Noman, Abu Shadat M.
Goyeneche, Alicia A.
Telleria, Carlos M.
The metastatic capacity of high-grade serous ovarian cancer cells changes along disease progression: inhibition by mifepristone
title The metastatic capacity of high-grade serous ovarian cancer cells changes along disease progression: inhibition by mifepristone
title_full The metastatic capacity of high-grade serous ovarian cancer cells changes along disease progression: inhibition by mifepristone
title_fullStr The metastatic capacity of high-grade serous ovarian cancer cells changes along disease progression: inhibition by mifepristone
title_full_unstemmed The metastatic capacity of high-grade serous ovarian cancer cells changes along disease progression: inhibition by mifepristone
title_short The metastatic capacity of high-grade serous ovarian cancer cells changes along disease progression: inhibition by mifepristone
title_sort metastatic capacity of high-grade serous ovarian cancer cells changes along disease progression: inhibition by mifepristone
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9733158/
https://www.ncbi.nlm.nih.gov/pubmed/36494669
http://dx.doi.org/10.1186/s12935-022-02822-5
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