title: Mast cells induce epithelial-to-mesenchymal transition and stem cell features in human thyroid cancer cells through an IL-8-Akt-Slug pathway.
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.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR 'G. Salvatore', University of Naples Federico II, Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Visciano
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR 'G. Salvatore', University of Naples Federico II, Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Liotti
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali/Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base e Cliniche, University of Naples Federico II, Naples, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Prevete
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR 'G. Salvatore', University of Naples Federico II, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cali'
authors.affiliation: Struttura Complessa di Anatomia Patologica, Istituto Nazionale Tumori, Fondazione G. Pascale, Naples, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Franco
authors.affiliation: Struttura Complessa di Anatomia Patologica, Istituto Nazionale Tumori, Fondazione G. Pascale, Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Collina
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali/Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base e Cliniche, University of Naples Federico II, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: de Paulis
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali/Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base e Cliniche, University of Naples Federico II, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Marone
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR 'G. Salvatore', University of Naples Federico II, Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Santoro
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR 'G. Salvatore', University of Naples Federico II, Naples, Italy.
authors.forename: R M
authors.initials: RM
authors.lastname: Melillo
mesh_terms: D000818:Animals; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D013964:Thyroid Neoplasms / Q000473:pathology*; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt