Zhang, QunzhouJiang, jChunmiaoShanti, Rabie MShi, ShihongChang, Ting-HanCarrasco, LeeLe, Anh DAlawi, Faizan2023-05-222023-05-222017-09-012022-06-09https://repository.upenn.edu/handle/20.500.14332/9315pithelial–mesenchymal transition (EMT), a biological process associated with cancer stem-like or cancer-initiating cell formation, contributes to the invasiveness, metastasis, drug resistance, and recurrence of the malignant tumors; it remains to be determined whether similar processes contribute to the pathogenesis and progression of ameloblastoma (AM), a benign but locally invasive odontogenic neoplasm. Here, we demonstrated that EMT- and stem cell-related genes were expressed in the epithelial islands of the most common histologic variant subtype, the follicular AM. Our results revealed elevated interleukin (IL)-6 signals that were differentially expressed in the stromal compartment of the follicular AM. To explore the stromal effect on tumor pathogenesis, we isolated and characterized both mesenchymal stromal cells (AM-MSCs) and epithelial cells (AM-EpiCs) from follicular AM and demonstrated that, in in vitro culture, AM-MSCs secreted a significantly higher level of IL-6 as compared to the counterpart AM-EpiCs. Furthermore, both in vitro and in vivo studies revealed that exogenous and AM-MSC-derived IL-6 induced the expression of EMT- and stem cell-related genes in AM-EpiCs, whereas such effects were significantly abrogated either by a specific inhibitor of STAT3 or ERK1/2, or by knockdown of Slug gene expression. These findings suggest that AM-MSC-derived IL-6 promotes tumor-stem like cell formation by inducing EMT process in AM-EpiCs through STAT3 and ERK1/2-mediated signaling pathways, implying a role in the etiology and progression of the benign but locally invasive neoplasm. Stem Cells 2017;35:2083–2094. © 2017 AlphaMed PressAmeloblastomaEpithelial CellsEpithelial–mesenchymal transitionInterleukin-6Mesenchymal stromal cellsTumor stem cellsAmeloblastomaAnimalsCarcinogenesisCell SeparationEpithelial CellsEpithelial-Mesenchymal TransitionFemaleGene Expression RegulationNeoplasticHumansInterleukin-6Mesenchymal Stromal CellsMiceNudeSignal Transduction2 (2 amino 3 methoxyphenyl)chromone2 morpholino 8 phenylchromone4 [[(4 methylphenyl)sulfonyloxy]acetamido]salicylic acidinterleukin 6mitogen activated protein kinase 1mitogen activated protein kinase 3s 3i 201STAT3 proteintranscription factor Sluginterleukin 6ameloblastomaanimal experimentanimal tissueArticlecancer patientcarcinogenesiscontrolled studyepithelial mesenchymal transitionepithelium cellfemalefollicular ameloblastomagene expressionhumanin vitro studyin vivo studymesenchymal stroma cellmousenonhumansignal transductionameloblastomaanimalcell separationepithelium cellgene expression regulationgeneticsmesenchymal stroma cellmetabolismnude mousepathologyDentistryOral and Maxillofacial SurgeryOral Biology and Oral PathologyOrthodontics and OrthodontologyArticle