TY  - JOUR
AU  - Depner, Sofia
AU  - Lederle, Wiltrud
AU  - Gutschalk, Claudia
AU  - Linde, Nina
AU  - Zajonz, Alexandra
AU  - Mueller, Margareta M
TI  - Cell type specific interleukin-6 induced responses in tumor keratinocytes and stromal fibroblasts are essential for invasive growth.
JO  - International journal of cancer
VL  - 135
IS  - 3
SN  - 0020-7136
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2017-00460
SP  - 551-562
PY  - 2014
AB  - 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.
KW  - Culture Media, Conditioned (NLM Chemicals)
KW  - Interleukin-6 (NLM Chemicals)
KW  - MMP2 protein, human (NLM Chemicals)
KW  - Matrix Metalloproteinase 2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23165423
UR  - https://inrepo02.dkfz.de/record/119865
ER  -