Mesenchymal Stromal Cell‐Derived Interleukin‐6 Promotes Epithelial–Mesenchymal Transition and Acquisition of Epithelial Stem‐Like Cell Properties in Ameloblastoma Epithelial Cells

Epithelial-mesenchymal transition (EMT), a biological process associated with cancer stem-like or cancer-initiating cell (CSC) 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, 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 ameloblastoma. Our results revealed elevated IL-6 signals that were differentially expressed in the stromal compartment of the follicular ameloblastoma. To explore the stromal effect on tumor pathogenesis, we isolated and characterized both mesenchymal stromal (AM-MSCs) and epithelial cells (AM-EpiCs) from follicular ameloblastoma and demonstrated that, in in vitro culture, AM-MSCs secreted a significantly higher level of IL-6 as compared to the counterpart AM-EpiCs. Further, 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. This article is protected by copyright. All rights reserved.