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  • DKFZ Publication Database  (19)
  • EXPRESSION  (12)
  • PROGRESSION  (11)
  • PROSTATE-CANCER  (7)
  • molecular  (6)
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  • DKFZ Publication Database  (19)
Keywords
  • 1
    Keywords: CANCER ; tumor ; Germany ; PROSTATE ; LUNG-CANCER ; AMPLIFICATION ; microarrays ; prostate cancer ; PROSTATE-CANCER ; EFFICIENT ; MUTATIONS ; OVEREXPRESSION ; molecular ; HER2 ; GEFITINIB
    Type of Publication: Journal article published
    PubMed ID: 17628772
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  • 2
    Keywords: CANCER ; Germany ; human ; PROSTATE ; THERAPY ; DIAGNOSIS ; GENE ; GENES ; PROTEIN ; PROTEINS ; validation ; MARKER ; BIOMARKERS ; TARGET ; IDENTIFICATION ; PROGRESSION ; prostate cancer ; PROSTATE-CANCER ; FUSION ; MARKERS ; PREDICTION ; TARGETS ; HUMAN GENES ; molecular biology ; molecular ; THERAPIES ; TISSUE MICROARRAYS ; LEVEL ; biomarker ; analysis ; HIGH-THROUGHPUT ; technique ; CANCERS ; CHALLENGES ; TARGETED THERAPY ; CLINICAL-PRACTICE ; gene protein
    Abstract: Significant cellular alterations required for the development and progression of cancers are detectable at the molecular level and represent potential targets for gene-specific therapies. Modern chip techniques allow the parallel analysis of virtually all known human genes and proteins in a single experiment. Using modern high-throughput techniques, numerous potential new biomarkers for the diagnosis and prediction of prostate cancer have been identified. However, so far none of these markers has improved clinical practice. One of the most important challenges in the coming years is the extensive clinical validation of molecular data using clinically relevant end points. For this venture the pivotal prerequisite is the availability of large, comprehensively annotated and standardized high-quality bioresources
    Type of Publication: Journal article published
    PubMed ID: 18712514
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  • 3
    Keywords: CANCER ; EXPRESSION ; Germany ; human ; PROSTATE ; THERAPY ; DIAGNOSIS ; GENE ; GENES ; PROTEIN ; PROTEINS ; validation ; BIOMARKERS ; IDENTIFICATION ; PROGRESSION ; prostate cancer ; PROSTATE-CANCER ; FUSION ; TARGETS ; SINGLE ; molecular biology ; THERAPIES ; TISSUE MICROARRAYS ; development ; HIGH-THROUGHPUT ; USA ; CANCERS ; TARGETED THERAPY ; ANNEXIN A3
    Abstract: Significant cellular alterations required for the development and progression of cancers are detectable at the molecular level and represent potential targets for gene-specific therapies. Modern chip techniques allow the parallel analysis of virtually all known human genes and proteins in a single experiment. Using modern high-throughput techniques, numerous potential new biomarkers for the diagnosis and prediction of prostate cancer have been identified. However, so far none of these markers has improved clinical practice. One of the most important challenges in the coming years is the extensive clinical validation of molecular data using clinically relevant end points. For this venture the pivotal prerequisite is the availability of large, comprehensively annotated and standardized high-quality bioresources
    Type of Publication: Journal article published
    PubMed ID: 19139898
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  • 4
    Keywords: EXPRESSION ; GROWTH ; carcinoma ; PATHWAY ; PROTEINS ; transcription ; GROWTH-FACTOR-BETA ; prostate carcinoma ; PROTEASOME ; MULTIPLE-MYELOMA ; TRANSFORMING GROWTH-FACTOR-BETA-1 ; BREAST-CANCER CELLS ; BORTEZOMIB ; DEPENDENT DEGRADATION ; E3 ubiquitin ligase ; SMAD2 ; SMURF2 ; tumour marker
    Abstract: The purpose of this work was to investigate the role of the ubiquitin-proteasome network (UPN) in prostate cancer (PCA) and to elicit potential markers for this disease. The UPN represents a key factor in the maintenance of cellular homoeostasis as a result of its fundamental function in the regulation of intracellular protein degradation. Members of this network have a role in the biology of haematological and solid tumours. Tumour cells and normal epithelial cells from 22 prostatectomy specimens were isolated by laser microdissection. Prostate biopsy samples from healthy individuals served for technical calibration and as controls. Transcript levels of eight selected genes with E3 ubiquitin ligase activity (labelling target proteins for proteasome degradation) and two genes belonging to the proteasome-multienzyme complex itself were analysed by quantitative real-time RT-PCR. The proteasome genes PSMC4 and PSMB5 and the E3 ubiquitin ligase NEDD4L were significantly and coherently upregulated in PCA cells compared with the corresponding adjacent normal prostate tissue. Transcription of the E3 ubiquitin ligase SMURF2 was significantly higher in organ-confined tumours (pT2) compared with non-organ-confined cancers (pT3). The results indicate a role for PSMC4 and PSMB5 and the E3 ubiquitin ligase NEDD4L in prostate tumourigenesis, whereas SMURF2 downregulation could be associated with clinical progression. NEDD4L and SMURF2 both target transforming growth factor (TGF)-beta for degradation. This reflects the pleiotropic role of the TGF-beta signalling pathway acting as a tumour suppressor in normal and pre-cancerous cells, but having oncogenic properties in progressing cancer. Further studies have to elucidate whether these alterations could represent clinically relevant PCA-diagnostic and progression markers.
    Type of Publication: Journal article published
    PubMed ID: 21102547
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  • 5
    Keywords: EXPRESSION ; prognosis ; BIOMARKERS ; PROGRESSION ; statistics ; PROTEOMIC ANALYSIS ; ANDROGEN RECEPTOR ; ARGINASE-II ; PEROXIREDOXINS ; PRINCIPLE
    Abstract: Prostate cancer (PCa) is the most common type of cancer found in men and among the leading causes of cancer death in the western world. In the present study, we compared the individual protein expression patterns from histologically characterized PCa and the surrounding benign tissue obtained by manual micro dissection using highly sensitive two-dimensional differential gel electrophoresis (2D-DIGE) coupled with mass spectrometry. Proteomic data revealed 118 protein spots to be differentially expressed in cancer (n = 24) compared to benign (n = 21) prostate tissue. These spots were analysed by MALDI-TOF-MS/MS and 79 different proteins were identified. Using principal component analysis we could clearly separate tumor and normal tissue and two distinct tumor groups based on the protein expression pattern. By using a systems biology approach, we could map many of these proteins both into major pathways involved in PCa progression as well as into a group of potential diagnostic and/or prognostic markers. Due to complexity of the highly interconnected shortest pathway network, the functional sub networks revealed some of the potential candidate biomarker proteins for further validation. By using a systems biology approach, our study revealed novel proteins and molecular networks with altered expression in PCa. Further functional validation of individual proteins is ongoing and might provide new insights in PCa progression potentially leading to the design of novel diagnostic and therapeutic strategies.
    Type of Publication: Journal article published
    PubMed ID: 21347291
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  • 6
    Keywords: EXPRESSION ; GROWTH ; carcinoma ; CELL LUNG-CANCER ; MOLECULES ; CLINICAL-IMPLICATIONS ; MYC ; field cancerization ; miR-16
    Abstract: We analyzed the levels of selected micro-RNAs in normal prostate tissue to assess their potential to indicate tumor foci elsewhere in the prostate. Histologically normal prostate tissue samples from 31 prostate cancer patients and two cancer negative control groups with either unsuspicious or elevated prostate specific antigen (PSA) levels (14 and 17 individuals, respectively) were analyzed. Based on the expression analysis of 157 microRNAs in a pool of prostate tissue samples and information from data bases/literature, we selected eight microRNAs for quantification by real-time polymerase chain reactions (RT-PCRs). Selected miRNAs were analyzed in histologically tumor-free biopsy samples from patients and healthy controls. We identified seven microRNAs (miR-124a, miR-146a & b, miR-185, miR-16 and let-7a & b), which displayed significant differential expression in normal prostate tissue from men with prostate cancer compared to both cancer negative control groups. Four microRNAs (miR-185, miR-16 and let-7a and let-7b) remained to significantly discriminate normal tissues from prostate cancer patients from those of the cancer negative control group with elevated PSA levels. The transcript levels of these microRNAs were highly indicative for the presence of cancer in the prostates, independently of the PSA level. Our results suggest a microRNA-pattern in histologically normal prostate tissue, indicating prostate cancer elsewhere in the organ.
    Type of Publication: Journal article published
    PubMed ID: 23459235
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  • 7
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; tumor ; carcinoma ; COMBINATION ; Germany ; PROSTATE ; VITRO ; POPULATION ; CDNA ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; microarray ; PROTEIN ; RNA ; transcription ; TISSUE ; MECHANISM ; BIOMARKERS ; mechanisms ; DOWN-REGULATION ; PROGRESSION ; gene expression ; microarrays ; prostate cancer ; PROSTATE-CANCER ; LOCALIZATION ; CARCINOMAS ; CDNA MICROARRAYS ; microdissection ; prostate carcinoma ; QUANTITIES ; MANAGEMENT ; CDNA MICROARRAY ; HETEROGENEITY ; molecular ; RADICAL PROSTATECTOMY ; EXTRACTION ; PROTOCOL ; MOLECULAR-MECHANISMS ; biomarker ; RECOVERY ; RNAS ; PRESERVATION ; HIGH-GRADE ; NEEDLE BIOPSIES ; ALTERNATE READING FRAME ; COA RACEMASE P504S ; ISCHEMIA TIME ; laser microdissection ; tissue banking
    Abstract: Molecular analyses of early-stage prostate cancers are necessary to assess their potential clinical significance based on established and/or novel biomarkers for tailored clinical management. A prerequisite for the application of RNA-based analyses of such, mostly macroscopically-undetectable, small prostate carcinomas is the recovery and preservation of sufficient RNA quantities and quality. Furthermore, in prostate cancer, heterogeneity is a common phenomenon that includes a juxtaposition of different tissue compositions and variable histological grades within the same tumor focus. To better understand the molecular mechanisms of prostate cancer, it is essential to correlate molecular data with a specific cell type. Here, we present a tissue collecting protocol which is aligned with the preoperative evaluation of tumor localization. In combination with the technique of laser microdissection and pressure catapulting, we are able to preserve RNA of high quality from homogeneous cell populations of macroscopically-undetectable small prostate carcinomas. To obtain the necessary RNA quantities for whole genome cDNA microarrays, the isolated total RNAs were amplified by T7-based RNA-polymerase in vitro transcription. The microarray analyses (Human Unigene Set RZPD3.1) resulted in 216 differentially expressed genes (191 down-regulated, 25 Up-regulated). Among these were several known prostate cancer relevant genes, such as AMACR, TARP, LIM, GPR160 (all up-regulated), CAVI, NTNI, MTIX; CLU, TRIM29, SPARCLI and HSPB8 (,all down-regulated)
    Type of Publication: Journal article published
    PubMed ID: 16077921
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  • 8
    Keywords: EXPRESSION ; TUMOR-CELLS ; PROGRESSION ; IN-SITU HYBRIDIZATION ; OVEREXPRESSION ; POOR-PROGNOSIS ; PTEN ; ANDROGEN RECEPTOR ; ETS FAMILY ; TMPRSS2-ERG GENE FUSION
    Abstract: PURPOSE: About 50% of prostate cancers have TMPRSS2-ERG fusions with concurrent ERG overexpression. The aim of this study was to determine whether clinical differences exist between ERG-positive and ERG-negative cancers in surgically treated patients not exposed to antihormonal therapy. A secondary aim was to search for differences between these tumor classes. EXPERIMENTAL DESIGN: A tissue microarray containing samples from more than 2,800 prostate cancers with clinical data was analyzed for ERG alterations by immunohistochemistry and FISH. Results were compared with tumor phenotype, biochemical recurrence, and molecular features considered important for prostate cancer. The effect of ERG on androgen receptor (AR)-dependent transcription was analyzed in cell lines. RESULTS: ERG expression was found in 52.4% of 2,805 cancers with a 95% concordance between ERG expression and ERG gene rearrangement detected by FISH. ERG expression was unrelated to clinical outcome and tumor phenotype. Differences in AMACR, Annexin A3, Bcl2, CD10, ALCAM, chromogranin A, epidermal growth factor receptor, HER2, mTOR, p53, and synaptophysin status were significant but minimal in absolute numbers. The most striking difference was found for AR expression, which was markedly higher in ERG-positive cancers. In vitro studies showed ERG-dependent impairment of AR-mediated transcriptional activity. CONCLUSIONS: The striking similarities between these two types of prostate cancers rules out a major impact of ERG on tumor aggressiveness in early, not hormonally treated cancer. The marked difference in AR levels between ERG-positive and -negative cancers supports a systematic difference in potential response to hormonal therapy as previously observed in clinical trials.
    Type of Publication: Journal article published
    PubMed ID: 21791629
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  • 9
    Keywords: EXPRESSION ; GENE ; PROTEIN ; HIGH-RISK ; POOR-PROGNOSIS ; AKT ; IMMUNOHISTOCHEMICAL DETECTION ; PTEN/MMAC1 ; SUPPRESSOR ; FISH ANALYSIS
    Abstract: The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene is often altered in prostate cancer. To determine the prevalence and clinical significance of the different mechanisms of PTEN inactivation, we analyzed PTEN deletions in TMAs containing 4699 hormone-naive and 57 hormone-refractory prostate cancers using fluorescence in situ hybridization analysis. PTEN mutations and methylation were analyzed in subsets of 149 and 34 tumors, respectively. PTEN deletions were present in 20.2% (458/2266) of prostate cancers, including 8.1% heterozygous and 12.1% homozygous deletions, and were linked to advanced tumor stage (P 〈 0.0001), high Gleason grade (P 〈 0.0001), presence of lymph node metastasis (P = 0.0002), hormone-refractory disease (P 〈 0.0001), presence of ERG gene fusion (P 〈 0.0001), and nuclear p53 accumulation (P 〈 0.0001). PTEN deletions were also associated with early prostate-specific antigen recurrence in univariate (P 〈 0.0001) and multivariate (P = 0.0158) analyses. The prognostic impact of PTEN deletion was seen in both ERG fusion-positive and ERG fusion-negative tumors. PTEN mutations were found in 4 (12.9%) of 31 cancers with heterozygous PTEN deletions but in only 1 (2%) of 59 cancers without PTEN deletion (P = 0.027). Aberrant PTEN promoter methylation was not detected in 34 tumors. The results of this study demonstrate that biallelic PTEN inactivation, by either homozygous deletion or deletion of one allele and mutation of the other, occurs in most PTEN-defective cancers and characterizes a particularly aggressive subset of metastatic and hormone-refractory prostate cancers.
    Type of Publication: Journal article published
    PubMed ID: 22705054
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  • 10
    Keywords: CELLS ; EXPRESSION ; GROWTH ; DIFFERENTIATION ; PROGRESSION ; REPRESSION ; NASOPHARYNGEAL CARCINOMA ; GROUP PROTEIN EZH2 ; POLYCOMB ; GENE FUSIONS
    Abstract: Prostate cancer is the second most common cancer among men worldwide. Alterations in the DNA methylation pattern can be one of the leading causes for prostate cancer formation. This study is the first high-throughput sequencing study investigating genome-wide DNA methylation patterns in a large cohort of 51 tumor and 53 benign prostate samples using methylated DNA immunoprecipitation sequencing. Comparative analyses identified more than 147,000 cancer-associated epigenetic alterations. In addition, global methylation patterns show significant differences based on the TMPRSS2-ERG rearrangement status. We propose the hypermethylation of miR-26a as an alternative pathway of ERG rearrangement-independent EZH2 activation. The observed increase in differential methylation events in fusion-negative tumors can explain the tumorigenic process in the absence of genomic rearrangements. SIGNIFICANCE: In contrast to TMPRSS2-ERG -rearranged tumors, the pathomechanism for gene fusion-negative tumors is completely unclear. Using a sequencing-based approach, our work uncovers significant global epigenetic alterations in TMPRSS2-ERG gene fusion-negative tumors and provides a mechanistic explanation for the tumor formation process.
    Type of Publication: Journal article published
    PubMed ID: 22930729
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