CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer
Abstract Background Minimal residual disease is the main issue of advanced ovarian cancer treatment. According to the literature and previous results, we hypothesized that Mesenchymal Stromal Cells (MSC) could support this minimal residual disease by protecting ovarian cancer cells (OCC) from chemot...
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| Format: | Article |
| Language: | English |
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BMC
2018-02-01
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| Series: | Molecular Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12943-018-0787-z |
| _version_ | 1818994869192884224 |
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| author | Jennifer Pasquier Marie Gosset Caroline Geyl Jessica Hoarau-Véchot Audrey Chevrot Marc Pocard Massoud Mirshahi Raphael Lis Arash Rafii Cyril Touboul |
| author_facet | Jennifer Pasquier Marie Gosset Caroline Geyl Jessica Hoarau-Véchot Audrey Chevrot Marc Pocard Massoud Mirshahi Raphael Lis Arash Rafii Cyril Touboul |
| author_sort | Jennifer Pasquier |
| collection | DOAJ |
| description | Abstract Background Minimal residual disease is the main issue of advanced ovarian cancer treatment. According to the literature and previous results, we hypothesized that Mesenchymal Stromal Cells (MSC) could support this minimal residual disease by protecting ovarian cancer cells (OCC) from chemotherapy. In vitro study confirmed that MSC could induce OCC chemoresistance without contact using transwell setting. Further experiments showed that this induced chemoresistance was dependent on IL-6 OCC stimulation. Methods We combined meticulous in vitro profiling and tumor xenograft models to study the role of IL-6 in MSC/OCC intereactions. Results We demonstrated that Tocilizumab® (anti-IL-6R therapy) in association with chemotherapy significantly reduced the peritoneal carcinosis index (PCI) than chemotherapy alone in mice xenografted with OCCs+MSCs. Further experiments showed that CCL2 and CCL5 are released by MSC in transwell co-culture and induce OCCs IL-6 secretion and chemoresistance. Finally, we found that IL-6 induced chemoresistance was dependent on PYK2 phosphorylation. Conclusions These findings highlight the potential key role of the stroma in protecting minimal residual disease from chemotherapy, thus favoring recurrences. Future clinical trials targeting stroma could use anti-IL-6 therapy in association with chemotherapy. |
| first_indexed | 2024-12-20T21:04:48Z |
| format | Article |
| id | doaj.art-519f9acd55434623844a7719a97fc606 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-20T21:04:48Z |
| publishDate | 2018-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-519f9acd55434623844a7719a97fc6062022-12-21T19:26:38ZengBMCMolecular Cancer1476-45982018-02-0117111410.1186/s12943-018-0787-zCCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancerJennifer Pasquier0Marie Gosset1Caroline Geyl2Jessica Hoarau-Véchot3Audrey Chevrot4Marc Pocard5Massoud Mirshahi6Raphael Lis7Arash Rafii8Cyril Touboul9Stem cell and microenvironment laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar FoundationUMR INSERM U965: Angiogenèse et Recherche translationnelle. Hôpital LariboisièreUMR INSERM U965: Angiogenèse et Recherche translationnelle. Hôpital LariboisièreStem cell and microenvironment laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar FoundationUMR INSERM U965: Angiogenèse et Recherche translationnelle. Hôpital LariboisièreUMR INSERM U965: Angiogenèse et Recherche translationnelle. Hôpital LariboisièreUMR INSERM U965: Angiogenèse et Recherche translationnelle. Hôpital LariboisièreDepartment Genetic Medicine, Weill Cornell Medical CollegeStem cell and microenvironment laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar FoundationUMR INSERM U965: Angiogenèse et Recherche translationnelle. Hôpital LariboisièreAbstract Background Minimal residual disease is the main issue of advanced ovarian cancer treatment. According to the literature and previous results, we hypothesized that Mesenchymal Stromal Cells (MSC) could support this minimal residual disease by protecting ovarian cancer cells (OCC) from chemotherapy. In vitro study confirmed that MSC could induce OCC chemoresistance without contact using transwell setting. Further experiments showed that this induced chemoresistance was dependent on IL-6 OCC stimulation. Methods We combined meticulous in vitro profiling and tumor xenograft models to study the role of IL-6 in MSC/OCC intereactions. Results We demonstrated that Tocilizumab® (anti-IL-6R therapy) in association with chemotherapy significantly reduced the peritoneal carcinosis index (PCI) than chemotherapy alone in mice xenografted with OCCs+MSCs. Further experiments showed that CCL2 and CCL5 are released by MSC in transwell co-culture and induce OCCs IL-6 secretion and chemoresistance. Finally, we found that IL-6 induced chemoresistance was dependent on PYK2 phosphorylation. Conclusions These findings highlight the potential key role of the stroma in protecting minimal residual disease from chemotherapy, thus favoring recurrences. Future clinical trials targeting stroma could use anti-IL-6 therapy in association with chemotherapy.http://link.springer.com/article/10.1186/s12943-018-0787-zOvarian cancerChemoresistanceIl-6Mesenchymal stromal cellMouse |
| spellingShingle | Jennifer Pasquier Marie Gosset Caroline Geyl Jessica Hoarau-Véchot Audrey Chevrot Marc Pocard Massoud Mirshahi Raphael Lis Arash Rafii Cyril Touboul CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer Molecular Cancer Ovarian cancer Chemoresistance Il-6 Mesenchymal stromal cell Mouse |
| title | CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer |
| title_full | CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer |
| title_fullStr | CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer |
| title_full_unstemmed | CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer |
| title_short | CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer |
| title_sort | ccl2 ccl5 secreted by the stroma induce il 6 pyk2 dependent chemoresistance in ovarian cancer |
| topic | Ovarian cancer Chemoresistance Il-6 Mesenchymal stromal cell Mouse |
| url | http://link.springer.com/article/10.1186/s12943-018-0787-z |
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