Expression of soluble interleukin-6 receptor in malignant ovarian tissue

Rath, Kellie S.; Funk, Holly M.; Bowling, Marcia C.; Richards, William E.; Drew, Angela F.

doi:10.1016/j.ajog.2010.03.034

Cited by 32 publications

(27 citation statements)

References 33 publications

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“…A possible explanation for the lack of staining could be that the more progressive tumors express a differentially spliced isoform of IL-6R that lacks the transmembrane 35 and as such will not be detected. However, we envision that once tumors have an autocrine production of IL-6, and can provide IL-6 needed for growth, signaling, and immunosuppressive actions, the receptor might be lost, and tumors may become more resistant.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer

et al. 2014

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y These authors contributed equally to this study.Keywords: epithelial ovarian cancer, IL-6, interleukin-6; IL-6R, interleukin-6 receptor, pSTAT3, tumor-infiltrating myeloid cells Abbreviations: DSS, disease-specific survival; EOC, epithelial ovarian cancer; IL-6R, interleukin-6, IL-6, interleukin-6 receptor; FIGO, International Federation of Gynecology and Obstetrics; MDSC, myeloid-derived suppressor cell; pSTAT3, phosphorylated signal transducer and activator of transcription 3; T reg, regulatory T cell; TMA, tissue microarray; TAM, tumor-associated macrophage; TIL, tumor-infiltrating lymphocytes; TIM, tumor-infiltrating myeloid cellAn increased level of interleukin-6 (IL-6) in epithelial ovarian cancer (EOC) is correlated with a worse prognosis. IL-6 stimulates tumor-growth and inflammation. We investigated the intricate interaction between the IL-6 signaling pathway and tumor-infiltrating myeloid cells (TIMs) to determine their prognostic impact in EOC. 160 EOC samples were analyzed for the expression of IL-6, its receptor (IL-6R) and downstream signaling via pSTAT3 by immunohistochemistry. Triple color immunofluorescence confocal microscopy was used to identify myeloid cell populations by CD14, CD33, and CD163. The relationship between these markers, tumor-infiltrating immune cells, clinical-pathological characteristics and survival was investigated. EOC displayed a dense infiltration with myeloid cells, in particular of the CD163 C type. The distribution pattern of all myeloid subtypes was comparable among the different histological subtypes. Analysis of the tumor cells revealed a high expression of IL-6R in 15% and of IL-6 in 23% of patients. Interestingly, tumors expressing IL-6 or IL-6R formed two different groups. Tumors with a high expression of IL-6R displayed low mature myeloid cell infiltration and a longer disease-specific survival (DSS), especially in late stage tumors. High expression of IL-6R was an independent prognostic factor for survival by multivariate analyses (hazard ratio D 0.474, p D 0.011). In contrast, tumors with high epithelial IL-6 expression displayed a dense infiltration of mature myeloid cells and were correlated with a shorter DSS. Furthermore, in densely CD8 C T-cell infiltrated tumors, the ratio between these lymphoid cells and CD163 C myeloid cells was predictive for survival. Thus, IL-6 and IL-6R are opposite markers for myeloid cell infiltration and survival.

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Section: Discussionmentioning

confidence: 99%

Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer

et al. 2014

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“…Increased expression of IL6 and its specific receptor IL6Rα is associated with disease stage [29]. Recent works also reported the importance of IL6 for early metastasic process in EOC.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells enhance ovarian cancer cell infiltration through IL6 secretion in an amniochorionic membrane based 3D model

et al. 2013

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BackgroundThe early peritoneal invasion of epithelial ovarian cancer (EOC) by tumoral aggregates presents in ascites is a major concern. The role of the microenvironment seems to be important in this process but the lack of adequate models to study cellular interactions between cancer cells and stromal cells does not allow to uncover the molecular pathways involved. Our goal was to study the interactions between ovarian cancer cells (OCC) and mesenchymal stem cells (MSC) using a 3D model.MethodsWe used millimetric pieces of amniochorionic membrane - referred to as amniotic membrane scaffold (AMS) - to create 3D peritoneal nodules mimicking EOC early invasion. We were able to measure the distribution and the depth of infiltration using confocal microsopy. We extracted MSC from the amniochorionic membrane using the markers CD34-, CD45-, CD73+, CD90+, CD105+ and CD29+ at the Fluorescence Activated Cell Sorting (FACS) analysis. We used transwell and wound healing tests to test OCC migration and invasion in vitro.ResultsHere we show that OCC tumors were located in regions rich in MSC (70%). The tumors infiltrated deeper within AMS in regions rich in MSC (p<0.001). In vitro tests revealed that higher IL6 secretion in a context of MSC-OCC co-culture could enhance migration and invasion of OCC. After IL6 receptor antagonism, OCC infiltration was significantly decreased, mostly in regions rich in MSCs, indicating that recruitment and tridimensional invasion of OCC was dependent of IL6 secretion.ConclusionsThe use of tridimensional models using AMS could be a useful tool to decipher early molecular events in ovarian cancer metastasis. Cytokine inhibitors interrupting the cross-talk between OCCs and MSCs such as IL6 should be investigated as a new therapeutic approach in ovarian cancer.

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“…Moreover, elevated levels of sIL-6R in malignant ascites from ovarian cancer patients are associated with poor prognosis (Lo, Cancer Res 2011;7: 424-34). The increase of IL6R expression as well as of the soluble spliced variant of IL6R in malignant ovarian tumours are regulated by cancerassociated inflammation (Rath et al, 2010). Therefore, in advanced EOC IL6R is overexpressed mainly because of increases in a sIL6R variant, which can influence its evolution and prognosis.…”

Section: Proinflammatory Cytokines In the Progression Of Eocmentioning

confidence: 99%