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

Abstract

BackgroundMinimal 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.MethodsWe combined meticulous in vitro profiling and tumor xenograft models to study the role of IL-6 in MSC/OCC intereactions.ResultsWe 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0787-z) contains supplementary material, which is available to authorized users.

Pathogenesis of chronic rhinosinusitis with nasal polyps: role of IL-6 in airway epithelial cell dysfunction

“…In line with our results in a chronic inflammation model, IL6 has also been reported [33] to increase epithelial tumoral cell proliferation, migration and invasion in an ovarian cancer model. Moreover, they also showed that the pro-tumoral effects can be reversed by inhibiting IL-6 both in vivo and in vitro [53]. Along the same lines of the IL-6 effect in the cancer model, IL-6 could induce up-regulation of proliferation in CRSwNP in the case of "wounded" epithelium.…”

CCL5 mediates target‐kinase independent resistance to FLT3 inhibitors in FLT3‐ITD‐positive AML

“…Microarrays for mRNA expression analysis were purchased from Affymetrix, and the analysis was conducted according to manufacturer's protocol. Briefly, RNA intensity was normalized using the Single-Channel Array Normalization (SCAN) method (Piccolo et al, 2012). Differential analysis was performed with a linear model-based approach (limma), and genes with adjusted P-value below 0.05 were considered significant (Ritchie et al, 2015).…”

“…In AML, KIT inhibition by imatinib and nilotinib was shown to be overcome in the presence of the cytokine G‐CSF (Gordon et al , ). The cytokine C‐C motif chemokine 5 (CCL5, previously known as RANTES) is physiologically a regulator of immune cell migration and was identified as constituting a distinct chemokine release cluster in AML (Bruserud et al , ) and as an important drug resistance mediator in several tumor entities: In breast, ovarian, and prostate cancer, CCL5 rendered tumor cells resistant to tamoxifen, saracatinib, cisplatin, or taxanes, respectively (Fang et al , ; Kato et al , ; Pasquier et al , ; Xiang et al , ; Yi et al , ; Zhou et al , ). In addition, CCL5 was found to contribute to tumor progression and metastasis (Azenshtein et al , ; Velasco‐Velázquez et al , ).…”

Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

“…[61]. As an example, the recent study highlighted that cancer-associated fibroblasts induced ovarian cancer cell chemoresistance in transmanner by secretion of CCL2/CCL5 and induction of IL-6 production [62]. Microenvironment-driven dynamic heterogeneity and phenotypic plasticity was recognized as mechanisms of therapy resistance in melanoma [35].…”