title: Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation.
abstract: 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.
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Doldi
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Callari
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Aiuto
authors.affiliation: Department of Urology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Maffezzini
authors.affiliation: Department of Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy.|Prostate Program, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Valdagni
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gandellini
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D045744:Cell Line, Tumor; D030541:Databases, Genetic; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053263:Gene Regulatory Networks; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D060066:Protein Interaction Maps; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D015850:Interleukin-6; C548234:MIRN133 microRNA, human; D035683:MicroRNAs; D016212:Transforming Growth Factor beta
keywords: cancer associated fibroblasts; gene expression; interleukin-6; microRNA; prostate cancer