title: Cell type specific interleukin-6 induced responses in tumor keratinocytes and stromal fibroblasts are essential for invasive growth.
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.
authors.affiliation: Group Tumor and Microenvironment DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 280, D-69221 Heidelberg, Germany.
authors.forename: Sofia
authors.initials: S
authors.lastname: Depner
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Lederle
authors.forename: Claudia
authors.initials: C
authors.lastname: Gutschalk
authors.forename: Nina
authors.initials: N
authors.lastname: Linde
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zajonz
authors.forename: Margareta M
authors.initials: MM
authors.lastname: Mueller
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002450:Cell Communication; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D017403:In Situ Hybridization; D015850:Interleukin-6 / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D017077:Culture Media, Conditioned; D015850:Interleukin-6; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2