CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer - Université Sorbonne Paris Cité Accéder directement au contenu
Article Dans Une Revue Revue Européenne des Éléments Finis Année : 2018

CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer

Résumé

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.
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Origine : Publication financée par une institution
Origine : Publication financée par une institution
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Dates et versions

inserm-01716892 , version 1 (25-02-2018)

Identifiants

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Jennifer Pasquier, Marie Gosset, Caroline Geyl, Jessica Hoarau-Véchot, Audrey Chevrot, et al.. CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer. Revue Européenne des Éléments Finis, 2018, 17 (1), pp.47. ⟨10.1186/s12943-018-0787-z⟩. ⟨inserm-01716892⟩
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