%0 Journal Article
%A Depner, Sofia
%A Lederle, Wiltrud
%A Gutschalk, Claudia
%A Linde, Nina
%A Zajonz, Alexandra
%A Mueller, Margareta M
%T Cell type specific interleukin-6 induced responses in tumor keratinocytes and stromal fibroblasts are essential for invasive growth.
%J International journal of cancer
%V 135
%N 3
%@ 0020-7136
%C Bognor Regis
%I Wiley-Liss
%M DKFZ-2017-00460
%P 551-562
%D 2014
%X 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.
%K Culture Media, Conditioned (NLM Chemicals)
%K Interleukin-6 (NLM Chemicals)
%K MMP2 protein, human (NLM Chemicals)
%K Matrix Metalloproteinase 2 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:23165423
%U https://inrepo02.dkfz.de/record/119865