Research Papers:

Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation

Valentina Doldi _, Maurizio Callari, Elisa Giannoni, Francesca D’Aiuto, Massimo Maffezzini, Riccardo Valdagni, Paola Chiarugi, Paolo Gandellini and Nadia Zaffaroni

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Oncotarget. 2015; 6:31441-31460. https://doi.org/10.18632/oncotarget.5056

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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

Correspondence to:

Paolo Gandellini, e-mail: paolo.gandellini@istitutotumori.mi.it

Nadia Zaffaroni, e-mail: nadia.zaffaroni@istitutotumori.mi.it

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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