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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  127. Kongress der Deutschen Gesellschaft für Chirurgie; 20100420-20100423; Berlin; DOC10dgch605 /20100517/
    Publication Date: 2010-05-17
    Keywords: ddc: 610
    Type: conferenceObject
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  • 2
    Keywords: CANCER ; CANCER CELLS ; CELLS ; INHIBITOR ; tumor ; BLOOD ; CELL ; Germany ; KINASE ; MODEL ; PATHWAY ; imaging ; SYSTEM ; SYSTEMS ; liver ; GENE ; PROTEIN ; PROTEINS ; METABOLISM ; TUMORS ; NUCLEAR-MEDICINE ; PATIENT ; MECHANISM ; mechanisms ; protein kinase ; PROTEIN-KINASE ; treatment ; SIGNAL ; ANTITUMOR-ACTIVITY ; TARGET ; metastases ; RESECTION ; CANCER-CELLS ; positron emission tomography ; POSITRON-EMISSION-TOMOGRAPHY ; tomography ; GLUCOSE ; PET ; LIVER METASTASES ; imatinib ; SARCOMA ; nuclear medicine ; AKT ; GASTROINTESTINAL STROMAL TUMORS ; INHIBITORS ; targeting ; ONCOLOGY ; RE ; monitoring ; INCREASE ; F-18-FDG ; TRANSPORTER ; KINASE INHIBITORS ; LEVEL ; ENZYME ; NUCLEAR ; uptake ; female ; UNIT ; KINASE INHIBITOR ; FDG ; EMISSION-TOMOGRAPHY ; ANTITUMOR ACTIVITIES ; surgical resection ; SARCOMAS ; mTOR ; MEDICINE ; UPSTREAM ; PROTEIN-KINASE-B ; antitumor activity ; German ; EMISSION ; emission tomography ; CASCADE ; GIST ; m-TOR inhibitor ; positron ; protein kinase B ; treatment monitoring
    Abstract: Several mechanisms may influence the enhanced glucose uptake in cancer cells, including upregulation of glucose transporters, increase in the hexokinase activity and the protein kinase B, also called Akt, which appears to play key role in the control of glucose metabolism together with proteins which are involved in the signal cascade pathway, such as the mammalian target of rapamycin (mTOR). It has been demonstrated in patients with gastrointestinal stromal tumors (GIST) and other sarcomas who received treatment with imatinib that PET with F-18-FDG is appropriate for treatment monitoring. Data suggest that F-18-FDG monitoring may be used for monitoring not only imatinib but also other kinase inhibitors. A 36-year-old female patient with metastasized desmoplastic small round cells tumor after a broad surgical resection of the tumor area and due to related enzyme findings, was treated with the mTOR-inhibitor everolimus (Certican((R)), Novartis, Basel, Switzerland) at an initial dose of 3 x 0.5 mg per day targeting at a blood level of 〉 11 ng/ml. A baseline F-18-FDG-PET demonstrated an enhanced FDG uptake in three large liver metastases and in another metastatic lesion in the pelvic area. A dynamic F-18-FDG-PET study performed six weeks later, demonstrated non-response to the mTOR-inhibitor. Despite the antiproliferative activity of mTOR-inhibitors in experimental model systems, its antitumor activity in patients may be limited. In conclusion, F-18-FDG-PET seems to be a promising method for monitoring the therapeutic effect of mTOR-inhibitors
    Type of Publication: Journal article published
    PubMed ID: 17684580
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INFORMATION ; PROTEIN ; RECEPTOR EXPRESSION ; DOWN-REGULATION ; PROTEIN-KINASE ; SIGNAL-TRANSDUCTION ; UROKINASE RECEPTOR ; cell proliferation ; urokinase ; SMOOTH-MUSCLE-CELLS ; BREAST-CANCER CELLS ; PLASMINOGEN-ACTIVATOR INHIBITOR ; AMINO-TERMINAL FRAGMENT
    Abstract: The serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are involved in the control of extracellular matrix turnover, cell migration, invasion and cell signalling leading to a variety of different responses, under both physiological and pathological conditions. The urokinase receptor, binding to the growth factor-like domain of uPA, directs membrane-associated extracellular proteolysis and signals through transmembrane proteins, thus regulating tissue regeneration, angiogenesis, cancer growth and metastasis. Since these physiological and pathophysiological processes of the uPA-system are known, less informations concerning uPA-induced cell proliferation and anti-apoptotic effects of the uPA-system are available. Recent studies show a close relationship of the uPA-system and cell proliferation/apoptosis. uPA is responsible for the activation and release of different growth factors and modulates the cell proliferation/apoptosis ratio through the dynamic control of cell-matrix interactions. This article focuses on the important role of the uPA/uPAR-system for cell proliferation and apoptosis
    Type of Publication: Journal article published
    PubMed ID: 17999379
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  • 4
    Abstract: The plakophilins, members of the armadillo-repeat family, consist of three different proteins (PKP1-3) that are specifically recruited to desmosomal plaques in a highly cell type-specific manner. Using immunofluorescence, immunoelectron microscopy, and immunoblot, we found that all three plakophilins occurred in luminal and basal cells of the pseudostratified prostate epithelium. The analysis of 135 cases of prostatic adenocarcinomas grouped into tumors with low (Gleason score 〈 or = 6), intermediate (Gleason score 7), and high Gleason score (8 〈 or = Gleason score 〈 or = 10) showed that the expression of PKP1 was reduced or lost in adenocarcinomas with high Gleason scores. The expression of PKP2 was unchanged in all prostatic adenocarcinomas analyzed. In contrast, PKP3 expression was increased in carcinomas with high Gleason scores in comparison with carcinomas with low Gleason scores. In DU 145 cell lines with either overexpression or knockdown of PKP3, both imbalances resulted in fewer desmosomal cell contacts. In addition, overexpression of PKP3 in DU 145 cells led to an augmentation in proliferation rate. Our data imply that both loss of PKP1 and up-regulation of PKP3 expression are biologically important events in prostate cancer and are associated with a more aggressive phenotype.
    Type of Publication: Journal article published
    PubMed ID: 20348237
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  • 5
    Keywords: GENE-EXPRESSION ; PLAQUE PROTEIN ; MESSENGER-RNA ; SQUAMOUS-CELL CARCINOMA ; nonsense-mediated decay ; STRESS GRANULES ; X-RELATED PROTEIN ; EXON-JUNCTION COMPLEX ; POLY(A)-BINDING PROTEINS ; DESMOSOMAL PLAKOPHILINS
    Abstract: Both plakophilins (PKP) 1 and 3 play a role in the progression of prostate cancer. The RNA-binding proteins (RBPs) GAP-SH3-binding protein (G3BP), fragile-X-related protein 1 (FXR1), poly(A)-binding protein, cytoplasmic 1 (PABPC1), and up-frameshift factor 1 (UPF1) are associated with PKP3. All these RBPs have an impact on RNA metabolism. Until recently, the PKP-associated RBPs have not been analyzed in prostate cancer. In the current study, we showed by affinity purification that the PKP3-associated RBPs were also binding partners of PKP1. We examined the expression of PKP1/3-associated RBPs and PKP1/3 in prostate cell lines, tumor-free prostate, and 136 prostatic adenocarcinomas by immunofluorescence and immunoblot. All four RBPs G3BP, FXR1, UPF1, and PABPC1 were expressed in the glandular epithelium of the normal prostate. PKP1 and FXR1 were strongly reduced in tumor tissues with Gleason score 〉7 and diminished expression of PKP1 and FXR1 also appeared to be associated with a metastatic phenotype. Additionally, the predominant nuclear localization of UPF1 in normal glandular cells and low grade tumors was switched to a more cytoplasmic pattern in carcinomas with Gleason score 〉7. Our findings suggest that PKP1 and FXR1 may have a tumor-suppressive function and are downregulated in more aggressive tumors. Collectively, PKP1/3-associated RBPs FXR1 and UPF1 may have a functional role in prostate cancer progression and metastasis and highlight the potential importance of posttranscriptional regulation of gene expression and nonsense-mediated decay in cancer.
    Type of Publication: Journal article published
    PubMed ID: 23881279
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  • 6
  • 7
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; IN-VITRO ; tumor ; KINASE ; GENE-EXPRESSION ; TIME ; ACTIVATION ; MESSENGER-RNA ; BINDING ; C-JUN ; PROTEIN-KINASE ; TRANSFORMATION ; receptor tyrosine kinase ; Activator Protein 1 (AP-1) ; Axl promoter ; TIMES ; PMA
    Abstract: Background. Axl is a receptor tyrosine kinase promoting anti-apoptosis, invasion and mitogenesis, and is highly expressed in different solid cancers. Axl basal transcriptional activity is driven by Sp1/Sp3, and overexpression of MZF-1 (myeloid zinc-finger 1) induces Axl transcription and gene expression. Furthermore, Axl expression is epigenetically controlled by CpG hypermethylation; however, little is known about inducible Axl gene expression and Axl regulation in haematopoetic malignancies. Results. In the present study, we studied Axl transcriptional regulation under PMA-stimulated conditions in leukaemia cells. Luciferase analysis with sequential 5'-deletion constructs revealed that the -660/-580 region of the Axl promoter is indispensable for induced promoter activity under PMA stimulation. This region includes AP-1 (activator protein 1)/CREB [CRE (cAMP-response-element)-binding protein] motifs, five times partially overlapping TGCGTG repeats and multiple GT repeats. Mutational, supershift and ChIP (chromatin immunoprecipitation) analysis determined that AP-1 family members bind to AP-1 motifs and to the 5 X TGCGTG overlapping repeats, thus transactivating Axl promoter activity. Furthermore, specific inhibitors of PKC (protein kinase C), ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 reduced Axl expression. Additionally, mithramycin treatment abolished constitutive and PMA-induced Axl expression. Conclusions. Taken together the results of the present study suggest that PMA-induced Axl gene expression in leukaemia cells is mediated by AP-1 motifs and 5 x TGCGTG repeats within the promoter region -660/-580, and through the PKC/ERK1/2/AP-1 or PKC/p-38/AP-1 signalling axis
    Type of Publication: Journal article published
    PubMed ID: 20977427
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  • 8
    Keywords: GENE-EXPRESSION ; DIFFERENTIATION ; UP-REGULATION ; MARKERS ; HUMAN KERATINOCYTES ; epidermis ; ROLES ; SUPPRESSOR-CELLS ; MRP14 ; PROTEINS S100A8
    Abstract: S100A8 and S100A9, two heterodimer forming members of the cytosolic S100 Ca2+ signaling protein family, are overexpressed in various cancer types, including prostate cancer. They act as pro-inflammatory danger signals when secreted to the extracellular space, and are thought to play an important role during tumorigenesis, affecting inflammatory processes, proliferation, invasion and metastasis of tumor cells. Despite this fact, little is known about tumor environmental factors influencing S100A8/A9 expression. The aim of this study was to test the effect of hypoxia and its master transcriptional regulator HIF-1 on S100A8/A9 expression. Hypoxia treatment resulted in induction of S100A8/A9 protein and mRNA expression in prostate epithelial BPH-1 cells, the latter was also confirmed in the prostate cancer cell lines PC-3 and DU-145. Furthermore, overexpression of HIF-1alpha caused increase in S100A8/A9 protein and mRNA expression as well as secretion. Functional hypoxia response elements (HREs) mediating promoter activation upon HIF-1alpha overexpression were identified within the S100A8 and S100A9 promoters using promoter luciferase reporter constructs. Binding of HIF-1alpha to S100A8 and S100A9 promoters was confirmed by chromatin immunoprecipitation (ChIP). Immunohistochemical analysis of a prostate cancer tissue array showed clear correlation of S100A8 and S100A9 with HIF-1alpha expression. Multivariate proportional hazard analysis revealed association of high S100A9 level with time to prostate cancer recurrence. In conclusion, we identified hypoxia and HIF-1 as novel regulators of S100A8/A9 expression in prostate cancer. S100A9 might be useful as prognostic marker for prostate cancer recurrence after radical prostatectomy.
    Type of Publication: Journal article published
    PubMed ID: 22505354
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  • 9
    Keywords: CANCER ; EXPRESSION ; IRRADIATION ; tumor ; Germany ; DIAGNOSIS ; GENE ; HYBRIDIZATION ; TUMORS ; BREAST ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; MALIGNANCIES ; MUTATIONS ; pathology ; RECURRENT ; C-MYC ; P53 GENE ; CYTOGENETIC ANALYSIS ; soft-tissue sarcoma ; Genetic
    Abstract: Angiosarcomas (AS) are rare vascular malignancies that arise either de novo as primary tumors or secondary to irradiation or chronic lymphedema. The cytogenetics of angiosarcomas are poorly characterized. We applied array-comparative genomic hybridization as a screening method to identify recurrent alterations in 22 cases. Recurrent genetic alterations were identified only in secondary but not in primary AS. The most frequent recurrent alterations were high level amplifications on chromosome 8q24.21 (50%), followed by 10p12-33 (33%) and 5q35.3 (11%). Fluorescence in situ hybridization analysis in 28 primary and 33 secondary angiosarcomas (31 tumors secondary to irradiation, 2 tumors secondary to chronic lymphedema) confirmed high level amplification of MYC on chromosome 8q24.21 as a recurrent genetic alteration found exclusively in 55% of AS secondary to irradiation or chronic lymphedema, but not in primary AS. Amplification of MYC did not predispose to high grade morphology or increased cell turnover. In conclusion, despite their identical morphology, secondary AS are genetically different from primary AS and are characterized by a high frequency of high level amplifications of MYC. This finding may have implications both for the diagnosis and treatment of these tumors. (Am J Pathol 2010, 176:34-39; DOI: 10.2353/ajpath.2010.090637)
    Type of Publication: Journal article published
    PubMed ID: 20008140
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  • 10
    Keywords: CANCER ; GROWTH ; tumor ; CELL-PROLIFERATION ; Germany ; IN-VIVO ; THERAPY ; SYSTEM ; PROTEIN ; PROTEINS ; DRUG ; MOLECULES ; ACTIVATION ; MESSENGER-RNA ; SUPPRESSION ; antibodies ; antibody ; TARGET ; PROGRESSION ; TUMOR PROGRESSION ; PROSTATE-CANCER ; PEPTIDES ; CANCER-PATIENTS ; STRATEGIES ; MOUSE MODEL ; CANCER-THERAPY ; TUMOR-GROWTH ; development ; pharmacology ; DRUGS ; LEWIS LUNG-CARCINOMA ; STRATEGY ; hypothesis ; Lead ; AREA ; BENEFIT ; ADENOVIRUS-MEDIATED DELIVERY ; NORMAL BREAST-TISSUE ; RECEPTOR CD87
    Abstract: Areas covered in this review: Several therapeutic strategies inhibiting the uPA system have been or are currently being developed for suppression of tumor growth. This review examines the role of the uPA system in tumor progression and assesses the various therapeutic strategies developed to selectively exploit this system. What will the reader gain: We focus on the therapeutic developments of the last 15 years. In addition to antibodies and recombinant uPA- or uPAR-derived proteins, various antagonistic peptides as well as small molecules have been designed and synthesized that inhibit the uPA system, leading to reduced tumor progression. Take home message: The multifunctional potential of the uPA system in cancer has rendered this system an attractive novel target for anticancer therapy. A few novel tumor biology-based therapeutic strategies reported here, opening new ways for patient-optimized and individualized cancer therapy. It may be the right time to evaluate the hypothesis that the uPA system plays a pivotal role in cancer progression and that targeting this system will lead to clinical benefit in cancer patients
    Type of Publication: Journal article published
    PubMed ID: 20402599
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