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Mast cells induce epithelial-to-mesenchymal transition and stem cell features in human thyroid cancer cells through an IL-8–Akt–Slug pathway

Oncogene volume 34, pages 5175–5186 (2015)Cite this article

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Abstract

There is increasing evidence that mast cells (MCs) and their mediators are involved in the remodeling of the tumor microenvironment and promote tumor growth, angiogenesis and metastasis. We have found that an increased density of MCs in thyroid cancer (TC) correlates with enhanced invasiveness. However, the MC-derived factors responsible for this activity and the mechanisms by which they enhance TC invasiveness remain unidentified. Here, we report that MCs, when activated by TC cells, produce soluble factors that induce epithelial-to-mesenchymal transition (EMT) and stemness features of TC cells. We identified CXCL8/interleukin (IL)-8 as the main mediator contained in activated MC conditioned media (CM) capable of inducing both EMT and stemness of TC cells. Mechanistically, MC CM or exogenous IL-8 stimulated Akt phosphorylation and Slug expression in TC cells. The inhibition of the Akt pathway or depletion of the Slug transcription factor by RNA interference, reverted EMT and stemness responses. TC cells stably transfected with exogenous IL-8 underwent EMT, displayed increased stemness and enhanced tumorigenicity with respect to control cells. The analysis of TC surgical specimens by immunohistochemical analysis demonstrated a positive correlation between MC density (Tryptase+ cells) and stemness features (OCT4 staining). Taken together, our data identify an MC-dependent IL-8–Akt–Slug pathway that sustains EMT/stemness of TC cells. The blockade of this circuit might be exploited for the therapy of advanced TC.

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Acknowledgements

We thank A Cerrato (IEOS, CNR, Naples) for helpful discussions and technical suggestions. We thank S Sequino for assistance in animal maintenance. We are grateful to PB Gupta (Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, MA, USA) for shSlug plasmids, to M Kajita (Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Atlanta) for the Slug myc plasmid and to BP Zhou (Department of Molecular and Cellular Oncology, Breast Cancer Basic Research Program, The University of Texas M. D. Anderson Cancer Center, Houston, Texas) for the FLAG Snail wt plasmid. Associazione Italiana per la Ricerca sul Cancro (AIRC) IG grant 11827 ‘Thyroid cancer and inflammation’; Italian Health Ministry grant RF-CAM-353005 ‘Molecular diagnostic and prognostic markers of thyroid neoplasis’; Istituto Superiore di Oncologia grant (MIUR PON01_02782/12); Ministero della Salute (Ricerca Finalizzata 2009–IZSM RF 2009), Regione Campania CISI-Lab Project, CRÈME Project and TIMING Project.

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Authors and Affiliations

  1. Dipartimento di Medicina Molecolare e Biotecnologie Mediche/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR ‘G. Salvatore’, University of Naples Federico II, Naples, Italy

    C Visciano, F Liotti, G Cali', M Santoro & R M Melillo

  2. Dipartimento di Scienze Mediche Traslazionali/Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base e Cliniche, University of Naples Federico II, Naples, Italy

    N Prevete, A de Paulis & G Marone

  3. Struttura Complessa di Anatomia Patologica, Istituto Nazionale Tumori, Fondazione G. Pascale, Naples, Italy

    R Franco & F Collina

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  1. C Visciano
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Correspondence to R M Melillo.

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Visciano, C., Liotti, F., Prevete, N. et al. Mast cells induce epithelial-to-mesenchymal transition and stem cell features in human thyroid cancer cells through an IL-8–Akt–Slug pathway. Oncogene 34, 5175–5186 (2015). https://doi.org/10.1038/onc.2014.441

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