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

Jennifer Pasquier, Marie Gosset, Caroline Geyl, Jessica Hoarau, Audrey Chevrot, Marc Pocard, Massoud Mirshahi, Raphael Lis, Arash Rafii Tabrizi, Cyril Touboul

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17 Citations (Scopus)

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.

Original languageEnglish
Article number47
JournalMolecular Cancer
Volume17
Issue number1
DOIs
Publication statusPublished - 19 Feb 2018

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Keywords

  • Chemoresistance
  • Il-6
  • Mesenchymal stromal cell
  • Mouse
  • Ovarian cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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