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  • PROGRESSION  (9)
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  • 1
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; tumor ; carcinoma ; Germany ; human ; HYBRIDIZATION ; PROTEIN ; PROTEINS ; TISSUE ; TUMORS ; PATIENT ; FAMILY ; MARKER ; hormone ; IN-SITU ; PROGRESSION ; immunohistochemistry ; PATTERNS ; prostate cancer ; PROSTATE-CANCER ; MARKERS ; BENIGN ; GLYCATION END-PRODUCTS ; RAGE ; CARCINOMAS ; adenocarcinoma ; intraepithelial neoplasia ; NEURITE OUTGROWTH ; KAPPA-B ; CANCER PATIENTS ; HEALTHY ; prostate carcinoma ; OXIDANT STRESS ; SERUM ; in situ hybridization ; ELISA ; RE ; END ; TUMORIGENESIS ; HUMAN PROSTATE ; HYPERPLASIA ; TUMOR TISSUE ; MOLECULAR-GENETICS ; HUMAN-PROSTATE ; S100 PROTEINS ; EXPRESSION PATTERNS ; SERUM-LEVELS ; TUMOR DIFFERENTIATION
    Abstract: 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, S10OA8 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 S10OA8, S100A9, and RAGE. In addition, in situ hybridization of S10OA8 and S10OA9 was done for 20 cases. An ELISA was applied to determine serum concentrations of S10OA9 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 S10OA8 and S10OA9 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
    Type of Publication: Journal article published
    PubMed ID: 16033829
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  • 2
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; GROWTH ; proliferation ; carcinoma ; CELL ; CELL-PROLIFERATION ; Germany ; LUNG ; DIAGNOSIS ; lung cancer ; LUNG-CANCER ; DEATH ; GENE ; GENES ; microarray ; PROTEIN ; cell line ; meningioma ; TISSUE ; LINES ; primary ; DOMAIN ; tumour ; SKIN ; BIOLOGY ; CELL-LINES ; MEMBER ; MOLECULAR-BIOLOGY ; SIGNAL ; PROGRESSION ; ASSAY ; INDUCED APOPTOSIS ; genetics ; COUNTRIES ; skin cancer ; CELL-LINE ; LINE ; ONCOGENE ; SUPERFAMILY ; EPITHELIAL-CELLS ; Jun ; PHENOTYPE ; STRATEGIES ; OVEREXPRESSION ; cell lines ; heredity ; LUNG-CARCINOMA ; SKIN-CANCER ; tumour suppressor gene ; ORIGIN ; molecular biology ; molecular ; ONCOLOGY ; non-small cell lung carcinoma ; SUPPRESSOR GENE ; cell proliferation ; SUPPRESSOR ; tumour suppressor ; NSCLC ; SET ; BREAST-CANCER CELLS ; DAL-1 ; ferm containing 3 ; GROWTH SUPPRESSION ; protein 4.1 ; PROTEIN 4.1B
    Abstract: Lung cancer including non-small cell lung carcinoma (NSCLC) represents a leading cause of cancer death in Western countries. Yet, understanding its pathobiology to improve early diagnosis and therapeutic strategies is still a major challenge of today's biomedical research. We analyzed a set of differentially regulated genes that were identifi. ed in skin cancer by a comprehensive microarray study, for their expression in NSCLC. We found that ferm domain containing protein 3 (FRMD3), a member of the protein 4.1 superfamily, is expressed in normal lung tissue but silenced in 54 out of 58 independent primary NSCLC tumours compared to patient-matched normal lung tissue. FRMD3 overexpression in different epithelial cell lines resulted in a decreased clonogenicity as measured by colony formation assay. Although cell attachment capabilities and cell proliferation rate remained unchanged, this phenotype was most likely owing to induced apoptosis. Our data identify FRMD3 as a novel putative tumour suppressor gene suggesting an important role in the origin and progression of lung cancer
    Type of Publication: Journal article published
    PubMed ID: 17260017
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  • 3
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; carcinoma ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; PROTEIN ; SAMPLE ; SAMPLES ; murine ; AP-1 ; CARCINOGENESIS ; tumour ; SKIN ; MOUSE ; TRANSCRIPTION FACTORS ; IDENTIFICATION ; PROGRESSION ; gene expression ; PROMOTERS ; skin carcinogenesis ; METASTASIS ; SSH ; PCR ; TRANSFORMATION ; EPITHELIAL-CELLS ; squamous cell carcinoma ; FRAGMENTS ; MULTISTAGE CARCINOGENESIS ; real-time PCR ; expression profiling ; PHORBOL ESTER ; CDNA MICROARRAY ; NMRI MOUSE SKIN ; tumour promoter
    Abstract: Malignant transformation of mouse skin by chemical carcinogens and tumour promoters, such as the phorbol ester 12-O- tetradecanoylphorbol-13-acetate (TPA), is a multi-stage process that leads to squamous cell carcinoma (SCC) formation. In an effort to identify turnour-associated genes, we studied the influence of short-term TPA-treatment on the gene expression profile of murine skin. A comprehensive microarray with some 5,000 murine gene specific cDNA fragments was established and hybridised with pooled RNA derived from control and TPA-treated dorsal skin samples. Of these genes, 54 were up- and 35 were down-regulated upon TPA application. Additionally, we performed suppression subtractive hybridisation (SSH) with respective RNA pools to generate and analyse a cDNA library enriched for TPA- inducible genes. Expression data of selected genes were confirmed by quantitative real-time PCR and Northern blot analysis. Comparison of microarray and SSH data revealed that 26% of up-regulated genes identified by expression profiling matched with those present in the SSH library. Besides numerous known genes, we identified a large set of unknown cDNAs that represent previously unrecognised TPA-regulated genes in murine skin with potential function in tumour promotion. Additionally, some TPA-induced genes, such as SprrIA, Saa3, junB, II4ralpha, Gp38, RalGDS and Slpi exhibit high basal level in advanced stages of skin carcinogenesis, suggesting that at least a subgroup of the identified TPA-regulated genes may contribute to tumour progression and metastasis. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 12640676
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; SURVIVAL ; carcinoma ; CELL ; Germany ; human ; MODEL ; PATHWAY ; PATHWAYS ; NETWORK ; SUPPORT ; DEATH ; HEPATOCELLULAR-CARCINOMA ; liver ; GENE ; GENES ; PROTEIN ; PROTEINS ; TISSUE ; NF-KAPPA-B ; ACTIVATION ; murine ; CARCINOGENESIS ; INDUCTION ; SIGNAL ; TARGET ; MOUSE ; hepatocarcinogenesis ; hepatocellular carcinoma ; PROGRESSION ; CELL-DEATH ; CELL-LINE ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; RAGE ; MOUSE MODEL ; KAPPA-B ; OXIDATIVE STRESS ; expression profiling ; inflammation ; signaling ; MOLECULAR-MECHANISMS ; cell death ; CANCER PROGRESSION ; USA ; GROWTH-CONTROL ; SUPPRESSOR-CELLS ; nuclear factor kappa B ; COEXPRESSION ; COMPENSATORY PROLIFERATION
    Abstract: The nuclear factor-kappaB (NF-kappa B) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-kappa B-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-kappa B-deficient and NF-kappa B-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-kappa B target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. Conclusion: We identified S100A8 and S100A9 as novel NF-kappa B target genes in HCC cells during inflammation-associated liver carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death. (HEPATOLOGY 2009;50: 1251-1262.)
    Type of Publication: Journal article published
    PubMed ID: 19670424
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  • 5
    Keywords: GROWTH ; LINES ; BIOLOGY ; PROGRESSION ; MIGRATION ; HUMAN-PAPILLOMAVIRUS ; HEAD ; NECK-CANCER ; NEUTRAL ENDOPEPTIDASE ; OPIORPHIN
    Abstract: Recently, increased expression of the submaxillary gland androgen-regulated protein 3A (SMR3A) was found in recurrent tumors of an orthotopic floor-of-mouth mouse tumor model after surgery. However, SMR3A expression in the pathogenesis of human malignancy and its correlation with the clinical outcome have not been addressed so far. We analyzed tissue microarrays with specimens from oropharyngeal squamous cell carcinoma (OPSCC) patients (n = 157) by immunohistochemistry and compared SMR3A expression with clinical and pathological features by statistical analysis. Strong SMR3A expression was found in almost 36 % of all primary OPSCCs. Although, SMR3A protein levels were not associated with any clinical or histopathological feature tested, univariate Kaplan-Meier analysis revealed a significant correlation between high SMR3A protein expression and poor progression-free (p = 0.02) and overall survival (p = 0.03). Furthermore, high SMR3A expression was an independent marker for poor clinical outcome [HR (SMR3A(high) vs. SMR3(low)) = 2.32; 95 % CI = 1.03-5.23] concerning overall survival in a multivariate analysis of OPSCC patients with surgery as primary therapy (n = 100). Our data demonstrate for the first time increased SMR3A protein expression in the pathogenesis of OPSCC, which serves as an unfavorable risk factor for patient survival.
    Type of Publication: Journal article published
    PubMed ID: 23053383
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  • 6
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; CELL ; Germany ; human ; IN-VIVO ; KINASE ; MODEL ; VIVO ; GENE ; GENE-EXPRESSION ; GENES ; HYBRIDIZATION ; PROTEIN ; RNA ; METABOLISM ; cell line ; LINES ; MICE ; DNA ; CARCINOGENESIS ; animals ; KERATINOCYTES ; SKIN ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CELL-LINES ; CYCLE ; DOWN-REGULATION ; MOUSE ; IDENTIFICATION ; IN-SITU ; PROGRESSION ; MALIGNANCIES ; gene expression ; EXPRESSION ANALYSIS ; HUMANS ; DESIGN ; UP-REGULATION ; MOUSE SKIN ; skin carcinogenesis ; genetics ; statistics ; CELL-LINE ; LINE ; ADHESION ; CELL-ADHESION ; ONCOGENE ; INVOLVEMENT ; RT-PCR ; KINETICS ; cell lines ; heredity ; SKIN-CANCER ; HUMAN SKIN ; in situ hybridization ; MALIGNANCY ; ONCOLOGY ; ANNOTATION ; ENHANCED EXPRESSION ; cell adhesion ; LEVEL ; analysis ; CANCER DEVELOPMENT ; cluster analysis ; S100A8 ; MAP ; in vivo ; RELEVANCE ; Oligonucleotide Array Sequence Analysis ; SPECIMENS ; animal ; Carcinoma,Squamous Cell ; SQUAMOUS-CELL ; SET ; animal model ; molecular genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Skin Neoplasms ; Cell Line,Tumor ; cytology ; DNA,Complementary ; epithelial skin cancer ; Gene Expression Regulation,Neoplastic ; HUMAN-SKIN ; Microscopy,Fluorescence ; Protein-Serine-Threonine Kinases ; RNA,Messenger ; tumour specimen
    Abstract: Chemically induced mouse skin carcinogenesis represents the most extensively utilized animal model to unravel the multistage nature of tumour development and to design novel therapeutic concepts of human epithelial neoplasia. We combined this tumour model with comprehensive gene expression analysis and could identify a large set of novel tumour-associated genes that have not been associated with epithelial skin cancer development yet. Expression data of selected genes were confirmed by semiquantitative and quantitative RT-PCR as well as in situ hybridization and immunofluorescence analysis on mouse tumour sections. Enhanced expression of genes identified in our screen was also demonstrated in mouse keratinocyte cell lines that form tumours in vivo. Self-organizing map clustering was performed to identify different kinetics of gene expression and coregulation during skin cancer progression. Detailed analysis of differential expressed genes according to their functional annotation confirmed the involvement of several biological processes, such as regulation of cell cycle, apoptosis, extracellular proteolysis and cell adhesion, during skin malignancy. Finally, we detected high transcript levels of ANXA1, LCN2 and S100A8 as well as reduced levels for NDR2 protein in human skin tumour specimens demonstrating that tumour-associated genes identified in the chemically induced tumour model might be of great relevance for the understanding of human epithelial malignancies as well
    Type of Publication: Journal article published
    PubMed ID: 16247483
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  • 7
    Keywords: PROGRESSION ; METASTASIS ; CARCINOMA-CELLS ; MIGRATION ; PHENOTYPE ; MALIGNANT-MELANOMA ; OVEREXPRESSION ; GENE FAMILY ; HUMAN TISSUE KALLIKREINS ; PROTEASE-ACTIVATED RECEPTOR-1
    Abstract: Cutaneous malignant melanoma is an aggressive disease of poor prognosis. Clinical and experimental studies have provided major insight into the pathogenesis of the disease, including the functional interaction between melanoma cells and surrounding keratinocytes, fibroblasts, and immune cells. Nevertheless, patients with metastasized melanoma have a very poor prognosis and are largely refractory to clinical therapies. Hence, diagnostic tools to monitor melanoma development, as well as therapeutic targets, are urgently needed. We investigated the expression pattern of the kallikrein-related peptidase 6 (KLK6) in human melanoma tissue sections throughout tumor development. Although KLK6 was not detectable in tumor cells, we found strong KLK6 protein expression in keratinocytes and stromal cells located adjacent to benign nevi, primary melanomas, and cutaneous metastatic lesions, suggesting a paracrine function of extracellular KLK6 during neoplastic transformation and malignant progression. Accordingly, recombinant Klk6 protein significantly induced melanoma cell migration and invasion accompanied by an accelerated intracellular Ca(2+) flux. We could further demonstrate that KLK6-induced intracellular Ca(2+) flux and tumor cell invasion critically depends on the protease-activated receptor 1 (PAR1). Our data provide experimental evidence that specific inhibition of the KLK6-PAR1 axis may interfere with the deleterious effect of tumor-microenvironment interaction and represent a potential option for translational melanoma research.
    Type of Publication: Journal article published
    PubMed ID: 21753781
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  • 8
    Keywords: RECEPTOR ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; tumor ; CELL ; Germany ; IN-VIVO ; SUPPORT ; NEW-YORK ; TISSUE ; MICE ; LIGAND ; MECHANISM ; CARCINOGENESIS ; KERATINOCYTES ; mechanisms ; SKIN ; BONE-MARROW ; PROGRESSION ; MOUSE SKIN ; skin carcinogenesis ; LIGANDS ; FACTOR-KAPPA-B ; GLYCATION END-PRODUCTS ; inflammation ; signaling ; molecular ; RE ; CANCER DEVELOPMENT ; PHASE ; USA ; BONE ; immunology ; PROMOTES ; MEDICINE ; DOUBLE-EDGED-SWORD
    Abstract: A broad range of experimental and clinical evidence has highlighted the central role of chronic inflammation in promoting tumor development. However, the molecular mechanisms converting a transient inflammatory tissue reaction into a tumor-promoting micro-environment remain largely elusive. We show that mice deficient for the receptor for advanced glycation end-products (RAGE) are resistant to DMBA/TPA-induced skin carcinogenesis and exhibit a severe defect in sustaining inflammation during the promotion phase. Accordingly, RAGE is required for TPA-induced up-regulation of proinflammatory mediators, maintenance of immune cell infiltration, 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 inflammation 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 infiltration and epidermal hyperplasia. We show that RAGE signaling drives the strength and maintenance of an inflammatory reaction during tumor promotion and provide direct genetic evidence for a novel role for RAGE in linking chronic inflammation and cancer
    Type of Publication: Journal article published
    PubMed ID: 18208974
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  • 9
    Keywords: CANCER ; GENES ; transcription ; AP-1 ; PROGRESSION ; Jun ; PTEN ; GLIOMA ; FOS ; PROMOTER METHYLATION ; PODOPLANIN ; INTEGRATED GENOMIC ANALYSIS ; HUMAN GLIOBLASTOMA
    Abstract: Recently, we found strong overexpression of the mucin-type glycoprotein podoplanin (PDPN) in human astrocytic brain tumors, specifically in primary glioblastoma multiforme (GB). In the current study, we show an inverse correlation between PDPN expression and PTEN levels in primary human GB and glioma cell lines, and we report elevated PDPN protein levels in the subventricular zone of brain tissue sections of PTEN-deficient mice. In human glioma cells lacking functional PTEN, reintroduction of wild-type PTEN, inhibition of the PTEN downstream target protein kinase B/AKT, or interference with transcription factor AP-1 function resulted in efficient downregulation of PDPN expression. In addition, we observed hypoxia-dependent PDPN transcriptional control and demonstrated that PDPN expression is subject to negative transcriptional regulation by promoter methylation in human GB and in glioma cell lines. Treatment of PTEN-negative glioma cells with demethylating agents induced expression of PDPN. Together, our findings show that increased PDPN expression in human GB is caused by loss of PTEN function and activation of the PI3K-AKT-AP-1 signaling pathway, accompanied by epigenetic regulation of PDPN promoter activity. Silencing of PDPN expression leads to reduced proliferation and migration of glioma cells, suggesting a functional role of PDPN in glioma progression and malignancy. Thus, specific targeting of PDPN expression and/or function could be a promising strategy for the treatment of patients with primary GB
    Type of Publication: Journal article published
    PubMed ID: 22394497
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