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| Home > Publications database > Cell type specific interleukin-6 induced responses in tumor keratinocytes and stromal fibroblasts are essential for invasive growth. |
| Home > Publications database > Cell type specific interleukin-6 induced responses in tumor keratinocytes and stromal fibroblasts are essential for invasive growth. |
| Journal Article | DKFZ-2017-00460 |
; ; ; ; ;
2014
Wiley-Liss
Bognor Regis
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Abstract: Interleukin-6 (IL-6) is one of the major inflammatory interleukins that has been linked to cancer progression. In our model for human skin squamous cell carcinoma (SCC), IL-6 expression is strongly upregulated upon progression from benign tumors to highly malignant, metastasizing SCCs. We now demonstrate that IL-6 promotes malignant and invasive tumor growth in human skin SCCs by inducing cell type specific cytokine profiles in tumor keratinocytes and stromal fibroblasts, activating the latter towards a tumor associated fibroblast (TAF) phenotype. In three-dimensional organotypic cocultures in vitro invasive growth of IL-6 overexpressing tumor keratinocytes, is associated with increased expression of matrix metalloproteinase-2 (MMP-2), MMP-14 and tissue inhibitor of metalloproteinases-2, and clearly depends on IL-6 activated fibroblasts. IL-6-induced secretion of monocyte chemotactic protein-1 (MCP-1) in tumor keratinocytes and of hepatocyte growth factor in fibroblasts is crucial for regulating expression and activation of MMP-2. This functional role of IL-6 is confirmed in vivo. Here MMP-14 and MMP-2 expression occur exclusively in surface transplants of IL-6 overexpressing keratinocytes and fibroblasts are identified as important source of MMP-2. Our data indicate that tumor keratinocytes derived IL-6 activates stromal fibroblasts towards a TAF phenotype, promoting tumor invasion via enhanced expression and activation of MMP-2.
Keyword(s): Culture Media, Conditioned ; Interleukin-6 ; MMP2 protein, human ; Matrix Metalloproteinase 2
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