Introduction Signal transduction Signal transduction mechanisms are used by cells to notice and to respond to signals in the environment.

These signals contain hormones, nutrients and growth factors. Growth factors bind to the cell surface receptor and mediate signal transmission from the receptor to the nucleus and regulate the activation of transcriptional programs. Many cellular functions, like divison or differentitation are controlled by signal transduction pathways mainly triggered by growth factors. Binding of a growth factor to its receptor activates a number of cytoplasmic proteins in form of a cascade in which the activation of one molecule causes activation of its downstream protein. Interleukin-6 (IL-6) IL-6 is a pleiotropic cytokine with complex biological functions and is expressed by a diverse number of cell types including fibroblasts, endothelial cells, keratinocytes as well as T and B cells [4, 5]. Under normal circumstances IL-6 production is tightly regulated with levels rising during numerous infectious, inflammatory and autoimmune diseases as well as in cancer [5, 6]. The physiological activity of IL-6 is complex, having pro- and antiinflammatory effects. It does not only elicit acute phase reactions but also the development of specific cellular and humoral immune responses, including end-stage B cell differentiation, immunoglobulin secretion and T cell activation. Additionally, IL-6 favours the transition from neutrophil to monocyte recruitment in inflammation [7, 8]. Regarding the role of IL-6 in cancer, most clinical studies have revealed that elevated serum levels correlate with disease severity and a bad clinical outcome, e.g in renal cancer, ovarian cancer, prostate cancer, plasmacytoma, and myeloma cancer [8-11]. However, anti-tumorigenic functions have also been described for IL-6, e.g. by promoting anti-tumorigenic activities of macrophages and by contributing to the production of lymphokine-activated killer cells [8]. These controversial effects became apparent in breast cancer, where IL-6 inhibits the growth of breast cancer cell lines [12], whereas in advanced breast cancer, it promotes metastasis [13] and confers multi drug resistance to breast cancer cells [14]. Additionally, IL-6 has been demonstrated to directly induce angiogenesis in ovarian cancer [15], as well as to promote angiogenesis indirectly via stimulating the release of VEGF from cervical cancer cells and glioblastoma cells [16]. These observations are strongly supported by the findings that IL-6 deficient mice show reduced angiogenesis and delayed wound healing [17]. In the HaCaT-model for human skin squamous cell carcinoma (SSC) it was shown that IL-6 plays a key role during tumor progression from a benign to a malignant invasive tumor phenotype. In this model IL-6 induces a growth factor network in the benign tumor cells by upregulating the levels of such growth factors as IL-8, GM-CSF and VEGF that in turn exert reciprocal stimulatory effects and promote proliferation and migration of tumor and stromal cells. These findings demonstrate a key function of IL-6 in skin SCC progression by the induction of a tightly regulated growth factor network [18].

IL-6 Signal Transduction IL-6 binds to a specific IL-6 receptor (IL-6R alpha chain; CD126, gp80) and this complex associates with two molecules of ubiquitously expressed gp130 (-chain, CD130), resulting in the formation of high avidity IL-6 binding receptors [8]. gp130 is a common signal transducing receptor for different cytokines of the IL-6 family (e.g. IL-6, IL-11, LIF, oncostatin M [19]), and the main pathways involved in IL-6 signalling are the JAK/STAT pathway, the MAP kinase pathway and the PI3-kinase/Akt pathway [20, 21]. After formation of ligand-receptor complex, JAK-kinases, such as JAK1 and TYK2, that are constitutively associated with gp130, are activated and in turn phosphorylate distinct tyrosine residues of the cytoplasmic region of gp130. These phosphorylated tyrosine residues serve as the docking sites for the STAT proteins (signal transducers and activators of transcription) that are also phosphorylated and activated by JAK kinases. After activation STAT proteins dissociate from the receptor, dimerize and translocate to the nucleus where they function as transcription factors and regulate the expression of different genes [5, 6, 22, 23]. Another important protein involved in the JAK/STAT pathway is SOCS3 protein (suppressors of cytokine signaling) that acts as a negative regulator of the pathway and inhibits activation of gp130 and JAKs [24]. The expression of SOCS3 is regulated by IL-6 is (figure 1).

Figure 1: IL-6 signaling pathway

The family of Janus kinases (JAKs) consists of four known members (TYK2, JAK1, JAK2 and JAK3). STAT proteins constitute a family of transcription factors and are activated by different cytokines. Therefore, the JAK-STAT pathway seems to be a key pathway to induce the specific cellular response by IL-6 cytokines [4, 5, 25]. The activation of the JAK-STAT pathway is implicated in regulation of cell growth, differentiation, survival and cross-talk between cancer and immune cells [22].

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