Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling
Within the ovarian cancer tumor microenvironment, cancer stem-like cells (CSC) interact with carcinoma associated mesenchymal stem/stromal cells (CA-MSC) through multiple secreted cytokines and growth factors. These paracrine interactions have been revealed to cause enrichment of CSC and their chemo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/8/2063 |
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| author | Shreya Raghavan Catherine S. Snyder Anni Wang Karen McLean Dmitriy Zamarin Ronald J. Buckanovich Geeta Mehta |
| author_facet | Shreya Raghavan Catherine S. Snyder Anni Wang Karen McLean Dmitriy Zamarin Ronald J. Buckanovich Geeta Mehta |
| author_sort | Shreya Raghavan |
| collection | DOAJ |
| description | Within the ovarian cancer tumor microenvironment, cancer stem-like cells (CSC) interact with carcinoma associated mesenchymal stem/stromal cells (CA-MSC) through multiple secreted cytokines and growth factors. These paracrine interactions have been revealed to cause enrichment of CSC and their chemoprotection; however, it is still not known if platelet-derived growth factor (PDGF) signaling is involved in facilitating these responses. In order to probe this undiscovered bidirectional communication, we created a model of ovarian malignant ascites in the three-dimensional (3D) hanging drop heterospheroid array, with CSC and CA-MSC. We hypothesized that PDGF secretion by CA-MSC increases self-renewal, migration, epithelial to mesenchymal transition (EMT) and chemoresistance in ovarian CSC. Our results indicate that PDGF signaling in the CSC-MSC heterospheroids significantly increased stemness, metastatic potential and chemoresistance of CSC. Knockdown of <i>PDGFB</i> in MSC resulted in abrogation of these phenotypes in the heterospheroids. Our studies also reveal a cross-talk between PDGF and Hedgehog signaling in ovarian cancer. Overall, our data suggest that when the stromal signaling via PDGF to ovarian CSC is blocked in addition to chemotherapy pressure, the tumor cells are significantly more sensitive to chemotherapy. Our results emphasize the importance of disrupting the signals from the microenvironment to the tumor cells, in order to improve response rates. These findings may lead to the development of combination therapies targeting stromal signaling (such as PDGF and Hedgehog) that can abrogate the tumorigenic, metastatic and platinum resistant phenotypes of ovarian CSC through additional investigations. |
| first_indexed | 2024-03-10T18:12:36Z |
| format | Article |
| id | doaj.art-fabbfba168ce4982ac53df8127d020d7 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T18:12:36Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fabbfba168ce4982ac53df8127d020d72023-11-20T08:02:31ZengMDPI AGCancers2072-66942020-07-01128206310.3390/cancers12082063Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF SignalingShreya Raghavan0Catherine S. Snyder1Anni Wang2Karen McLean3Dmitriy Zamarin4Ronald J. Buckanovich5Geeta Mehta6Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USADepartment of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USADepartment of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USADepartment of Obstetrics and Gynecology, Division of Gynecologic Oncology, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USADepartment of Gynecologic Medical Oncology and Immunotherapeutics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USADirector of Ovarian Cancer Research, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15260, USADepartment of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USAWithin the ovarian cancer tumor microenvironment, cancer stem-like cells (CSC) interact with carcinoma associated mesenchymal stem/stromal cells (CA-MSC) through multiple secreted cytokines and growth factors. These paracrine interactions have been revealed to cause enrichment of CSC and their chemoprotection; however, it is still not known if platelet-derived growth factor (PDGF) signaling is involved in facilitating these responses. In order to probe this undiscovered bidirectional communication, we created a model of ovarian malignant ascites in the three-dimensional (3D) hanging drop heterospheroid array, with CSC and CA-MSC. We hypothesized that PDGF secretion by CA-MSC increases self-renewal, migration, epithelial to mesenchymal transition (EMT) and chemoresistance in ovarian CSC. Our results indicate that PDGF signaling in the CSC-MSC heterospheroids significantly increased stemness, metastatic potential and chemoresistance of CSC. Knockdown of <i>PDGFB</i> in MSC resulted in abrogation of these phenotypes in the heterospheroids. Our studies also reveal a cross-talk between PDGF and Hedgehog signaling in ovarian cancer. Overall, our data suggest that when the stromal signaling via PDGF to ovarian CSC is blocked in addition to chemotherapy pressure, the tumor cells are significantly more sensitive to chemotherapy. Our results emphasize the importance of disrupting the signals from the microenvironment to the tumor cells, in order to improve response rates. These findings may lead to the development of combination therapies targeting stromal signaling (such as PDGF and Hedgehog) that can abrogate the tumorigenic, metastatic and platinum resistant phenotypes of ovarian CSC through additional investigations.https://www.mdpi.com/2072-6694/12/8/2063ovarian cancercancer stem-like cells (CSC)carcinoma associated mesenchymal stem cells (CA-MSC)platelet derived growth factor (PDGF)stemnesschemoresistance |
| spellingShingle | Shreya Raghavan Catherine S. Snyder Anni Wang Karen McLean Dmitriy Zamarin Ronald J. Buckanovich Geeta Mehta Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling Cancers ovarian cancer cancer stem-like cells (CSC) carcinoma associated mesenchymal stem cells (CA-MSC) platelet derived growth factor (PDGF) stemness chemoresistance |
| title | Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling |
| title_full | Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling |
| title_fullStr | Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling |
| title_full_unstemmed | Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling |
| title_short | Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling |
| title_sort | carcinoma associated mesenchymal stem cells promote chemoresistance in ovarian cancer stem cells via pdgf signaling |
| topic | ovarian cancer cancer stem-like cells (CSC) carcinoma associated mesenchymal stem cells (CA-MSC) platelet derived growth factor (PDGF) stemness chemoresistance |
| url | https://www.mdpi.com/2072-6694/12/8/2063 |
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