Hartman Institute for Therapeutic Organ Regeneration

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

TitleCCL2/CCL5 secreted by the stroma induce IL-6/PYK2 dependent chemoresistance in ovarian cancer.
Publication TypeJournal Article
Year of Publication2018
AuthorsPasquier J, Gosset M, Geyl C, Hoarau-VĂ©chot J, Chevrot A, Pocard M, Mirshahi M, Lis R, Rafii A, Touboul C
JournalMol Cancer
Volume17
Issue1
Pagination47
Date Published2018 Feb 19
ISSN1476-4598
KeywordsAnimals, Antibodies, Monoclonal, Humanized, Cell Line, Tumor, Cell Movement, Chemokine CCL2, Chemokine CCL5, Coculture Techniques, Female, Focal Adhesion Kinase 2, Humans, Interleukin-6, Mice, Ovarian Neoplasms, Signal Transduction
Abstract

<p><b>BACKGROUND: </b>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.</p><p><b>METHODS: </b>We combined meticulous in vitro profiling and tumor xenograft models to study the role of IL-6 in MSC/OCC intereactions.</p><p><b>RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>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.</p>

DOI10.1186/s12943-018-0787-z
Alternate JournalMol Cancer
PubMed ID29455640
PubMed Central IDPMC5817856

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
1300 York Ave, Box 136 New York, NY 10065