Cancer-associated fibroblasts induce epithelial-mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling

Cancer-associated fibroblasts induce epithelial-mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling

Cancer-associated fibroblasts (CAFs), activated by tumour cells, are the predominant type of stromal cells in cancer tissue and play an important role in interacting with neoplastic cells to promote cancer progression. Epithelial-mesenchymal transition (EMT) is a key feature of metastatic cells. How...

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Bibliographic Details
Published in:BMC cancer Vol. 19; no. 1; pp. 137 - 13
Main Authors: Goulet, Cassandra Ringuette, Champagne, Audrey, Bernard, Geneviève, Vandal, Dominique, Chabaud, Stéphane, Pouliot, Frédéric, Bolduc, Stéphane
Format: Journal Article
Language:English
Published: England BioMed Central Ltd 11-02-2019
BioMed Central
BMC
Subjects:
Anopheles
Antibodies
Bladder cancer
CAFs
Cancer
Cancer cells
Cancer metastasis
Cell adhesion & migration
Cell culture
Cell growth
Cell migration
Cell proliferation
Cytokines
DNA binding proteins
E-cadherin
EMT
Enzyme-linked immunosorbent assay
Exosomes
Fibroblasts
Gene expression
Genes
Genetic aspects
IL-6
Interleukin 6
Kinases
Mesenchyme
Metastases
Metastasis
N-Cadherin
Paracrine signalling
Phenotypes
Phosphorylation
Proteins
Stem cells
Stromal cells
Transcription factors
Tumors
Vimentin
CAFs
Bladder cancer
EMT
IL-6
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Summary:Cancer-associated fibroblasts (CAFs), activated by tumour cells, are the predominant type of stromal cells in cancer tissue and play an important role in interacting with neoplastic cells to promote cancer progression. Epithelial-mesenchymal transition (EMT) is a key feature of metastatic cells. However, the mechanism by which CAFs induce EMT program in bladder cancer cells remains unclear. To investigate the role of CAFs in bladder cancer progression, healthy primary bladder fibroblasts (HFs) were induced into CAFs (iCAFs) by bladder cancer-derived exosomes. Effect of conditioned medium from iCAFs (CM ) on EMT markers expression of non-invasive RT4 bladder cancer cell line was determined by qPCR and Western blot. IL6 expression in iCAFs was evaluated by ELISA and Western blot. RT4 cell proliferation, migration and invasion were assessed in CM +/- anti-IL6 neutralizing antibody using cyQUANT assay, scratch test and transwell chamber respectively. We investigated IL6 expression relevance for bladder cancer progression by querying gene expression datasets of human bladder cancer specimens from TCGA and GEO genomic data platforms. Cancer exosome-treated HFs showed CAFs characteristics with high expression levels of αSMA and FAP. We showed that the CM induces the upregulation of mesenchymal markers, such as N-cadherin and vimentin, while repressing epithelial markers E-cadherin and p-ß-catenin expression in non-invasive RT4 cells. Moreover, EMT transcription factors SNAIL1, TWIST1 and ZEB1 were upregulated in CM -cultured RT4 cells compared to control. We also showed that the IL-6 cytokine was highly expressed by CAFs, and its receptor IL-6R was found on RT4 bladder cancer cells. The culture of RT4 bladder cancer cells with CM resulted in markedly promoted cell growth, migration and invasion. Importantly, inhibition of CAFs-secreted IL-6 by neutralizing antibody significantly reversed the IL-6-induced EMT phenotype, suggesting that this cytokine is necessary for CAF-induced EMT in the progression of human bladder cancer. Finally, we observed that IL6 expression is up-regulated in aggressive bladder cancer and correlate with CAF marker ACTA2. We conclude that CAFs promote aggressive phenotypes of non-invasive bladder cancer cells through an EMT induced by the secretion of IL-6.
ISSN:1471-2407
1471-2407
DOI:10.1186/s12885-019-5353-6