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Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling

Collagen, the main non-cellular component of the extracellular matrix (ECM), is profoundly reorganized during tumorigenesis and has a strong impact on tumor behavior. The main source of collagen in tumors is cancer-associated fibroblasts. Cancer cells can also participate in the synthesis of ECM; ho...

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Autores principales: Druzhkova, Irina, Shirmanova, Marina, Ignatova, Nadezhda, Dudenkova, Varvara, Lukina, Maria, Zagaynova, Elena, Safina, Dina, Kostrov, Sergey, Didych, Dmitry, Kuzmich, Alexey, Sharonov, George, Rakitina, Olga, Alekseenko, Irina, Sverdlov, Eugene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662237/
https://www.ncbi.nlm.nih.gov/pubmed/33143259
http://dx.doi.org/10.3390/ijms21218119
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author Druzhkova, Irina
Shirmanova, Marina
Ignatova, Nadezhda
Dudenkova, Varvara
Lukina, Maria
Zagaynova, Elena
Safina, Dina
Kostrov, Sergey
Didych, Dmitry
Kuzmich, Alexey
Sharonov, George
Rakitina, Olga
Alekseenko, Irina
Sverdlov, Eugene
author_facet Druzhkova, Irina
Shirmanova, Marina
Ignatova, Nadezhda
Dudenkova, Varvara
Lukina, Maria
Zagaynova, Elena
Safina, Dina
Kostrov, Sergey
Didych, Dmitry
Kuzmich, Alexey
Sharonov, George
Rakitina, Olga
Alekseenko, Irina
Sverdlov, Eugene
author_sort Druzhkova, Irina
collection PubMed
description Collagen, the main non-cellular component of the extracellular matrix (ECM), is profoundly reorganized during tumorigenesis and has a strong impact on tumor behavior. The main source of collagen in tumors is cancer-associated fibroblasts. Cancer cells can also participate in the synthesis of ECM; however, the contribution of both types of cells to collagen rearrangements during the tumor progression is far from being clear. Here, we investigated the processes of collagen biosynthesis and remodeling in parallel with the transcriptome changes during cancer cells and fibroblasts interactions. Combining immunofluorescence, RNA sequencing, and second harmonic generation microscopy, we have explored the relationships between the ratio of epithelial (E) and mesenchymal (M) components of hybrid E/M cancer cells, their ability to activate fibroblasts, and the contributions of both cell types to collagen remodeling. To this end, we studied (i) co-cultures of colorectal cancer cells and normal fibroblasts in a collagen matrix, (ii) patient-derived cancer-associated fibroblasts, and (iii) mouse xenograft models. We found that the activation of normal fibroblasts that form dense collagen networks consisting of large, highly oriented fibers depends on the difference in E/M ratio in the cancer cells. The more-epithelial cells activate the fibroblasts more strongly, which correlates with a dense and highly ordered collagen structure in tumors in vivo. The more-mesenchymal cells activate the fibroblasts to a lesser degree; on the other hand, this cell line has a higher innate collagen remodeling capacity. Normal fibroblasts activated by cancer cells contribute to the organization of the extracellular matrix in a way that is favorable for migratory potency. At the same time, in co-culture with epithelial cancer cells, the contribution of fibroblasts to the reorganization of ECM is more pronounced. Therefore, one can expect that targeting the ability of epithelial cancer cells to activate normal fibroblasts may provide a new anticancer therapeutic strategy.
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spelling pubmed-76622372020-11-14 Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling Druzhkova, Irina Shirmanova, Marina Ignatova, Nadezhda Dudenkova, Varvara Lukina, Maria Zagaynova, Elena Safina, Dina Kostrov, Sergey Didych, Dmitry Kuzmich, Alexey Sharonov, George Rakitina, Olga Alekseenko, Irina Sverdlov, Eugene Int J Mol Sci Article Collagen, the main non-cellular component of the extracellular matrix (ECM), is profoundly reorganized during tumorigenesis and has a strong impact on tumor behavior. The main source of collagen in tumors is cancer-associated fibroblasts. Cancer cells can also participate in the synthesis of ECM; however, the contribution of both types of cells to collagen rearrangements during the tumor progression is far from being clear. Here, we investigated the processes of collagen biosynthesis and remodeling in parallel with the transcriptome changes during cancer cells and fibroblasts interactions. Combining immunofluorescence, RNA sequencing, and second harmonic generation microscopy, we have explored the relationships between the ratio of epithelial (E) and mesenchymal (M) components of hybrid E/M cancer cells, their ability to activate fibroblasts, and the contributions of both cell types to collagen remodeling. To this end, we studied (i) co-cultures of colorectal cancer cells and normal fibroblasts in a collagen matrix, (ii) patient-derived cancer-associated fibroblasts, and (iii) mouse xenograft models. We found that the activation of normal fibroblasts that form dense collagen networks consisting of large, highly oriented fibers depends on the difference in E/M ratio in the cancer cells. The more-epithelial cells activate the fibroblasts more strongly, which correlates with a dense and highly ordered collagen structure in tumors in vivo. The more-mesenchymal cells activate the fibroblasts to a lesser degree; on the other hand, this cell line has a higher innate collagen remodeling capacity. Normal fibroblasts activated by cancer cells contribute to the organization of the extracellular matrix in a way that is favorable for migratory potency. At the same time, in co-culture with epithelial cancer cells, the contribution of fibroblasts to the reorganization of ECM is more pronounced. Therefore, one can expect that targeting the ability of epithelial cancer cells to activate normal fibroblasts may provide a new anticancer therapeutic strategy. MDPI 2020-10-30 /pmc/articles/PMC7662237/ /pubmed/33143259 http://dx.doi.org/10.3390/ijms21218119 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Druzhkova, Irina
Shirmanova, Marina
Ignatova, Nadezhda
Dudenkova, Varvara
Lukina, Maria
Zagaynova, Elena
Safina, Dina
Kostrov, Sergey
Didych, Dmitry
Kuzmich, Alexey
Sharonov, George
Rakitina, Olga
Alekseenko, Irina
Sverdlov, Eugene
Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling
title Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling
title_full Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling
title_fullStr Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling
title_full_unstemmed Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling
title_short Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling
title_sort expression of emt-related genes in hybrid e/m colorectal cancer cells determines fibroblast activation and collagen remodeling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662237/
https://www.ncbi.nlm.nih.gov/pubmed/33143259
http://dx.doi.org/10.3390/ijms21218119
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