IL-6 promotes malignant growth of skin SCCs by regulating a network of autocrine and paracrine cytokines

Authors

  • Wiltrud Lederle,

    1. Group Tumor and Microenvironment, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany
    2. Department of Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany
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    • W.L. and S.D. contributed equally to this work

  • Sofia Depner,

    1. Group Tumor and Microenvironment, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany
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    • W.L. and S.D. contributed equally to this work

  • Sabine Schnur,

    1. Group Tumor and Microenvironment, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany
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  • Eva Obermueller,

    1. Translational Oncology Laboratory, Barts and the London Queen Marys School of Medicine and Dentistry, John Vane Science Centre, London, United Kingdom
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  • Nicola Catone,

    1. Group Tumor and Microenvironment, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany
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  • Alexandra Just,

    1. Group Tumor and Microenvironment, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany
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  • Norbert E. Fusenig,

    1. Division of Carcinogenesis and Differentiation, German Cancer Research Center, Heidelberg, Germany
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  • Margareta M. Mueller

    Corresponding author
    1. Group Tumor and Microenvironment, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany
    2. Department of Mechanical and Process Engineering, HFU Furtwangen, Campus Villingen-Schwenningen, Villingen-Schwenningen, Germany
    • Group Tumor and Microenvironment, German Cancer Research Center, INF 280, D-69221 Heidelberg, Germany
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    • Tel.: +49-6221-424533, Fax. +49-6221-424551


Abstract

Cytokines play a crucial role in tumor initiation and progression. Here, we demonstrate that interleukin (IL)-6 is a key factor by driving tumor progression from benign to malignant, invasive tumors in the HaCaT-model of human skin carcinoma. IL-6 activates STAT3 and directly stimulates proliferation and migration of the benign noninvasive HaCaT-ras A-5 cells in vitro. Furthermore, IL-6 induces a complex, reciprocally regulated cytokine network in the tumor cells that includes inflammatory and angiogenic factors such as IL-8, GM-CSF, VEGF and MCP-1. These IL-6 effects lead to tumor cell invasion in organotypic cultures in vitro and to the formation of malignant and invasive s.c. tumors in vivo. Tumor invasion is supported by the IL-6 induced overexpression of MMP-1 in vitro and in vivo. These data demonstrate a key function of IL-6 in the progression of skin SCCs by regulating a complex cytokine and protease network and suggest new therapeutic approaches to target this central player in skin carcinogenesis.

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