Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation
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Valentina Doldi1,*, Maurizio Callari1,*, Elisa Giannoni2, Francesca D’Aiuto1, Massimo Maffezzini3, Riccardo Valdagni4,5, Paola Chiarugi2, Paolo Gandellini1,**, Nadia Zaffaroni1,**
1Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy
2Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy
3Department of Urology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy
4Department of Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy
5Prostate Program, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy
*These authors have contributed equally to this work
**These authors share senior authorship
Paolo Gandellini, e-mail: email@example.com
Nadia Zaffaroni, e-mail: firstname.lastname@example.org
Keywords: prostate cancer, cancer associated fibroblasts, interleukin-6, microRNA, gene expression
Received: April 16, 2015 Accepted: August 28, 2015 Published: September 08, 2015
Tumor microenvironment coevolves with and simultaneously sustains cancer progression. In prostate carcinoma (PCa), cancer associated fibroblasts (CAF) have been shown to fuel tumor development and metastasis by mutually interacting with tumor cells. Molecular mechanisms leading to activation of CAFs from tissue-resident fibroblasts, circulating bone marrow-derived fibroblast progenitors or mesenchymal stem cells are largely unknown. Through integrated gene and microRNA expression profiling, we showed that PCa-derived CAF transcriptome strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus proving evidence, for the first time, that the cytokine is able per se to induce most of the transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGFβ-related signatures, indicating that either signal, depending on the context, may concur to fibroblast activation. Our analyses also highlighted novel pathways potentially relevant for induction of a reactive stroma. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression.
Overall, we provided insights into the molecular mechanisms driving fibroblast activation in PCa, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment.
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