Pleiotropic Effects of Epithelial Mesenchymal Crosstalk on Head and Neck Cancer: EMT and beyond

J. Dudas,A. Romani,B. Kofler,H. Riechelmann,T. B. Steinbichler,D. Dejaco,D. Savic,I. I. Skvortsova

doi:10.1007/s12307-019-00228-y

J. Dudas, A. Romani + Show 6 more

Open Access

https://doi.org/10.1007/s12307-019-00228-y

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Abstract

Epithelial mesenchymal crosstalk (EMC) describes the interaction of the tumor stroma and associated fibroblasts with epithelial cancer cells. In this study we analysed the effects of EMC on head and neck cancer cells. In tumor cell lines EMC was induced using media conditioned from a mix-culture of cancer cells and fibroblasts. Cell proliferation and chemotherapy response were assessed using direct cell counting. Flow cytometry, immunohistochemistry of markers of epithelial-mesenchymal transition (EMT) and subsequent TissueFaxs™ acquisition and quantification and western blot analysis were performed. Holotomographic microscopy imaging was used to visualize the effects of EMC on Cisplatin response of SCC-25 cells. EMC induced a hybrid epithelial-mesenchymal phenotype in SCC-25 cells with co-expression of vimentin and cytokeratin. This hybrid phenotype was associated with chemotherapy resistance and increased proliferation of the cells. The EMC conditioned medium led to an activation of the IL-6/STAT3 pathway with subsequent phosphorylation of STAT3. EMC induced a hybrid epithelial-mesenchymal phenotype in HNSCC cells accompanied by increased therapy resistance and cell proliferation. The IL-6/STAT3 pathway might be one of the major pathways involved in these EMC-related effects.

Highlights

Tumor cells constantly interact with their surrounding tumor microenvironment
During direct mix culture of SCC-25 cells and Human gingival fibroblasts (HGF) fibroblasts for production of epithelialmesenchymal crosstalk (EMC)-CM, the main component was a high cytokeratin and high vimentin expressing cell population (Fig. 1 and 2), which is considered as mesenchymal trans-differentiated epithelial cell type (EMC-cell) [6]
SCC-25 cells constitutively synthesized STAT3 and Snail so these signalling factors could be found in all epithelial-mesenchymal transition (EMT) in tumor progression is nowadays considered as a reversible process, which is reversed by its contrary process, mesenchymal to epithelial transition (MET)

Summary

Introduction

Tumor cells constantly interact with their surrounding tumor microenvironment. Apart from tumor cells the tumor microenvironment consists of blood vessels, extracellular matrix, other non-malignant cells like fibroblasts, immune cells, pericytes or adipocytes and signalling molecules. Especial fibroblasts secrete growth factors and chemokines that support growth and survival of tumor cells [1]. This interaction of the tumor stroma and associated fibroblasts with tumor cells is referred to as epithelialmesenchymal crosstalk (EMC). EMC relies on paracrine signaling, cell-cell interactions and cell-matrix interactions. EMC vice versa enabling adaption to the varying requirements of tumor progression and the metastatic cascade [12, 13]

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