Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)
The aim of this study was to assess the effects of pirfenidone (PFD) on promoting epithelial–mesenchymal-transition (EMT) and stemness features in breast carcinoma cells through targeting cancer-associated-fibroblasts (CAFs). Using The Cancer Genome Atlas (TCGA) database, we analyzed the association...
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MDPI AG
2021-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/20/5118 |
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| author | Hamidreza Aboulkheyr Es Thomas R Cox Ehsan Sarafraz-Yazdi Jean Paul Thiery Majid Ebrahimi Warkiani |
| author_facet | Hamidreza Aboulkheyr Es Thomas R Cox Ehsan Sarafraz-Yazdi Jean Paul Thiery Majid Ebrahimi Warkiani |
| author_sort | Hamidreza Aboulkheyr Es |
| collection | DOAJ |
| description | The aim of this study was to assess the effects of pirfenidone (PFD) on promoting epithelial–mesenchymal-transition (EMT) and stemness features in breast carcinoma cells through targeting cancer-associated-fibroblasts (CAFs). Using The Cancer Genome Atlas (TCGA) database, we analyzed the association between stromal index, EMT, and stemness-related genes across 1084 breast cancer patients, identifying positive correlation between YAP1, EMT, and stemness genes in samples with a high-stromal index. We monitored carcinoma cell invasion and spheroid formation co-cultured with CAFs in a 3D microfluidic device, followed by exposing carcinoma cells, spheroids, and CAFs with PFD. We depicted a positive association between the high-stromal index and the expression of EMT and stemness genes. High YAP1 expression in samples correlated with more advanced EMT status and stromal index. Additionally, we found that CAFs promoted spheroid formation and induced the expression of YAP1, VIM, and CD44 in spheroids. Treatment with PFD reduced carcinoma cell migration and decreased the expression of these genes at the protein level. The cytokine profiling showed significant depletion of various EMT- and stemness-regulated cytokines, particularly IL8, CCL17, and TNF-beta. These data highlight the potential application of PFD on inhibiting EMT and stemness in carcinoma cells through the targeting of critical cytokines. |
| first_indexed | 2024-03-10T06:40:19Z |
| format | Article |
| id | doaj.art-3f9e6720ac5b460f8ae54bc9025a0e7c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T06:40:19Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3f9e6720ac5b460f8ae54bc9025a0e7c2023-11-22T17:40:34ZengMDPI AGCancers2072-66942021-10-011320511810.3390/cancers13205118Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)Hamidreza Aboulkheyr Es0Thomas R Cox1Ehsan Sarafraz-Yazdi2Jean Paul Thiery3Majid Ebrahimi Warkiani4School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, AustraliaThe Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, AustraliaNomoCan Pharmaceuticals, New York Blood Center, New York, NY 10065, USAComprehensive Cancer Center, Institute Gustave Roussy, 94805 Villejuif, FranceSchool of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, AustraliaThe aim of this study was to assess the effects of pirfenidone (PFD) on promoting epithelial–mesenchymal-transition (EMT) and stemness features in breast carcinoma cells through targeting cancer-associated-fibroblasts (CAFs). Using The Cancer Genome Atlas (TCGA) database, we analyzed the association between stromal index, EMT, and stemness-related genes across 1084 breast cancer patients, identifying positive correlation between YAP1, EMT, and stemness genes in samples with a high-stromal index. We monitored carcinoma cell invasion and spheroid formation co-cultured with CAFs in a 3D microfluidic device, followed by exposing carcinoma cells, spheroids, and CAFs with PFD. We depicted a positive association between the high-stromal index and the expression of EMT and stemness genes. High YAP1 expression in samples correlated with more advanced EMT status and stromal index. Additionally, we found that CAFs promoted spheroid formation and induced the expression of YAP1, VIM, and CD44 in spheroids. Treatment with PFD reduced carcinoma cell migration and decreased the expression of these genes at the protein level. The cytokine profiling showed significant depletion of various EMT- and stemness-regulated cytokines, particularly IL8, CCL17, and TNF-beta. These data highlight the potential application of PFD on inhibiting EMT and stemness in carcinoma cells through the targeting of critical cytokines.https://www.mdpi.com/2072-6694/13/20/5118tumor microenvironment (TME)cancer-associated fibroblasts (CAFs)epithelial–mesenchymal transition (EMT)pirfenidone (PFD)3D microfluidic device |
| spellingShingle | Hamidreza Aboulkheyr Es Thomas R Cox Ehsan Sarafraz-Yazdi Jean Paul Thiery Majid Ebrahimi Warkiani Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs) Cancers tumor microenvironment (TME) cancer-associated fibroblasts (CAFs) epithelial–mesenchymal transition (EMT) pirfenidone (PFD) 3D microfluidic device |
| title | Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs) |
| title_full | Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs) |
| title_fullStr | Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs) |
| title_full_unstemmed | Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs) |
| title_short | Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs) |
| title_sort | pirfenidone reduces epithelial mesenchymal transition and spheroid formation in breast carcinoma through targeting cancer associated fibroblasts cafs |
| topic | tumor microenvironment (TME) cancer-associated fibroblasts (CAFs) epithelial–mesenchymal transition (EMT) pirfenidone (PFD) 3D microfluidic device |
| url | https://www.mdpi.com/2072-6694/13/20/5118 |
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