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Molecular Cancer
Published in: Molecular Cancer 1/2018

Open Access 01-12-2018 | Research

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

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

Published in: Molecular Cancer | Issue 1/2018

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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.
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Metadata
Title
CCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer
Authors
Jennifer Pasquier
Marie Gosset
Caroline Geyl
Jessica Hoarau-Véchot
Audrey Chevrot
Marc Pocard
Massoud Mirshahi
Raphael Lis
Arash Rafii
Cyril Touboul
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2018
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-018-0787-z

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