The AP-1 transcription factor is mainly composed of Jun, Fos and ATF protein dimers. It mediates gene regulation in response to a plethora of physiological and pathological stimuli, including cytokines, growth factors, stress signals, bacterial and viral infections, as well as oncogenic stimuli. Studies in genetically modified mice and cells have highlighted a crucial role for AP-1 in a variety of cellular events involved in normal development or neoplastic transformation causing cancer. However, emerging evidence indicates that the contribution of AP-1 to determination of cell fates critically depends on the relative abundance of AP-1 subunits, the composition of AP-1 dimers, the quality of stimulus, the cell type and the cellular environment. Therefore, AP-1-mediated regulation of processes such as proliferation, differentiation, apoptosis and transformation should be considered within the context of a complex dynamic network of signalling pathways and other nuclear factors that respond simultaneously.

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A broad range of experimental and clinical evidence has highlighted the central role of chronic infl ammation in promoting tumor development. However, the molecular mechanisms converting a transient infl ammatory tissue reaction into a tumor-promoting microenvironment remain largely elusive. We show that mice defi cient for the receptor for advanced glycation end-products (RAGE) are resistant to DMBA/TPA-induced skin carcinogenesis and exhibit a severe defect in sustaining infl ammation during the promotion phase. Accordingly, RAGE is required for TPA-induced up-regulation of proinfl ammatory mediators, maintenance of immune cell infi ltration, and epidermal hyperplasia. RAGE-dependent up-regulation of its potential ligands S100a8 and S100a9 supports the existence of an S100/RAGE-driven feed-forward loop in chronic infl ammation and tumor promotion. Finally, bone marrow chimera experiments revealed that RAGE expression on immune cells, but not keratinocytes or endothelial cells, is essential for TPA-induced dermal infi ltration and epidermal hyperplasia. We show that RAGE signaling drives the strength and maintenance of an infl ammatory reaction during tumor promotion and provide direct genetic evidence for a novel role for RAGE in linking chronic infl ammation and cancer.

The receptor for advanced glycation end products (RAGE) is a single transmembrane receptor of the immunoglobulin superfamily that is mainly expressed on immune cells, neurons, activated endothelial and vascular smooth muscle cells, bone forming cells, and a variety of cancer cells. RAGE is a multifunctional receptor that binds a broad repertoire of ligands and mediates responses to cell damage and stress conditions. It activates programs responsible for acute and chronic inflammation, and is implicated in a number of pathological diseases, including diabetic complications, stroke, atheriosclerosis, arthritis, and neurodegenerative disorders. The availability of Rage knockout mice has not only advanced our knowledge on signalling pathways within these pathophysiological conditions, but also on the functional importance of the receptor in processes of cancer. Here, we will summarize molecular mechanisms through which RAGE signalling contributes to the establishment of a pro-tumourigenic microenvironment. Moreover, we will review recent findings that provide genetic evidence for an important role of RAGE in bridging inflammation and cancer.

Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA1 RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and

Purpose: S100 proteins comprise a family of calcium-modulated proteins that have recently been associated with epithelial tumors. We examined the expression of two members of this family, S100A8 and S100A9, together with the S100 receptor RAGE (receptor for advanced glycation end products) in human prostate adenocarcinomas and in prostatic intraepithelial neoplasia. Experimental Design:Tissue specimens of 75 patients with organ-confined prostate cancer of different grades were analyzed by immunohistochemistry for expression of S100A8, S100A9, and RAGE. In addition, in situ hybridization of S100A8 and S100A9 was done for 20 cases. An ELISA was applied to determine serum concentrations of S100A9 in cancer patients compared with healthy controls or to patients with benign prostatic hyperplasia (BPH). Results: S100A8, S100A9, and RAGE were up-regulated in prostatic intraepithelial neoplasia and preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed weak expression of the proteins. There was a high degree of overlap of S100A8 and S100A9 expression patterns and of S100A8 or S100A9 and RAGE, respectively. Frequently, a gradient within the tumor tissue with an increased expression toward the invaded stroma of the prostate was observed. S100A9 serum levels were significantly elevated in cancer patients compared with BPH patients or healthy individuals. Conclusion: Our data suggest that enhanced expression of S100A8, S100A9, and RAGE is an early event in prostate tumorigenesis and may contribute to development and progression or extension of prostate carcinomas. Furthermore, S100A9 in serum may serve as useful marker to discriminate between prostate cancer and BPH.

Interstitial collagenase (collagenase-3, MMP13) is a member of the large family of matrix metalloproteinases that play a decisive role in the degradation of components of the extracellular matrix, particularly the collagens. It degrades collagen type II most efficiently but also collagens type I, III, and X, which are the major components of cartilage and bone (1). MMP13 is expressed in hypertrophic chondrocytes and osteoblasts during embryogenesis and in the adult bone and is thought to be involved in endochondral ossification and bone remodeling (2-4). The level of MMP13 expression depends on the exposure to a variety of systemic and local factors including hormones and cytokines present in the bone microenvironment (5-9). High constitutive levels of MMP13 were observed in osteosarcomas and chondrosarcomas, suggesting a critical role in the formation of bone tumors (2, 10).Parathyroid hormone (PTH) 1 has been shown to stimulate MMP13 expression in vivo as well as in vitro cultures of primary bone cells and osteoblast-derived osteosarcoma cell lines (8, 9, 11). PTH is secreted by the parathyroid gland and is a major regulator of calcium homeostasis. Intracellular signaling initiated by ligand-activated PTH/PTHrP receptor present on the plasma membrane of osteoblasts (12) is mediated predominantly by activation of adenylate cyclase, resulting in enhanced concentration of cAMP and activation of the protein kinase A (PKA) (13,14).We and others have identified the minimal PTH-responsive region within the mmp13 promoter (8, 9). This region contains a conserved AP-1 binding site and an osteoblast-specific element 2 (OSE2), which is recognized by members of the Cbfa/ Runt family of transcription factors. Both elements act cooperatively and are absolutely required for PTH-dependent promoter activation. In agreement with the crucial role of AP-1 and Cbfa/Runt transcription factors in osteosarcoma cell lines, expression of MMP13 is reduced in mice lacking c-fos and is completely absent in cbfa1 Ϫ/Ϫ embryos (9, 15).

Recently, we described phorbol ester-induced expression of the brain and skin serine proteinase Bssp/kallikrein 6 (Klk6), the mouse orthologue of human KLK6, in mouse back skin and in advanced tumor stages of a well-established multistage tumor model. Here, we show KLK6 up-regulation in squamous skin tumors of human patients and in tumors of other epithelial tissues. Ectopic Klk6 expression in mouse keratinocyte cell lines induces a spindle-like morphology associated with accelerated proliferation, migration, and invasion capacity. We found reduced E-cadherin protein levels in the cell membrane and nuclear translocation of B-catenin in Klk6-expressing mouse keratinocytes and human HEK293 cells transfected with a KLK6 expression plasmid. Additionally, HEK293 cells exhibited induced T-cell factor-dependent transcription and impaired cell-cell adhesion in the presence of KLK6, which was accompanied by induced E-cadherin ectodomain shedding. Interestingly, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 interfere with KLK6-induced E-cadherin ectodomain shedding and rescue the cell-cell adhesion defect in vitro, suggesting the involvement of matrix metalloproteinase and/or a disintegrin and metalloproteinase (ADAM) proteolytic activity. In line with this assumption, we found increased levels of the mature 62-kDa ADAM10 proteinase in cells expressing ectopic KLK6 compared with mock controls. Finally, enhanced epidermal keratinocyte proliferation and migration in concert with decreased E-cadherin protein levels are confirmed in an in vivo Klk6 transgenic mouse model. [Cancer Res 2007; 67(17):8198-206]