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  • 1
    Keywords: brain ; CANCER ; BLOOD ; Germany ; LUNG ; MODEL ; MODELS ; PERFUSION ; THERAPY ; chest ; CT ; imaging ; lung cancer ; LUNG-CANCER ; SYSTEM ; SYSTEMS ; TOOL ; VISUALIZATION ; VOLUME ; DISEASE ; liver ; TISSUE ; computed tomography ; RESOLUTION ; MICE ; kidney ; RAT ; PROGRESSION ; EFFICACY ; tomography ; COMPUTED-TOMOGRAPHY ; STROKE ; ANIMAL-MODELS ; fibrosis ; TUMOR-GROWTH ; monitoring ; HIGH-RESOLUTION ; PNEUMONITIS ; lung fibrosis ; LEVEL ; IMAGE QUALITY ; ABILITY ; SIZE ; TECHNOLOGY ; ANIMAL-MODEL ; contrast-enhanced ; DISEASE PROGRESSION ; flat-panel detector ; lung carcinoma
    Abstract: Noninvasive radiologic imaging has recently gained considerable interest in basic and preclinical research for monitoring disease progression and therapeutic efficacy. In this report, we introduce flat-panel volumetric computed tomography (fpVCT) as a powerful new tool for noninvasive imaging of different organ systems in preclinical research. The three-dimensional visualization that is achieved by isotropic high-resolution datasets is illustrated for the skeleton, chest, abdominal organs, and brain of mice. The high image quality of chest scans enables the visualization of small lung nodules in an orthotopic lung cancer model and the reliable imaging of therapy side effects such as lung fibrosis. Using contrast-enhanced scans, fpVCT displayed the vascular trees of the brain, liver, and kidney down to the subsegmental level. Functional application of fpVCT in dynamic contrast-enhanced scans of the rat brain delivered physiologically reliable data of perfusion and tissue blood volume. Beyond scanning of small animal models as demonstrated here, fpVCT provides the ability to image animals up to the size of primates
    Type of Publication: Journal article published
    PubMed ID: 16207475
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  • 2
    Keywords: brain ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; Germany ; GENE ; transcription ; TISSUE ; LINES ; FAMILY ; mechanisms ; CELL-LINES ; MOLECULE ; METASTASIS ; LINE ; inactivation ; POLYMERASE-CHAIN-REACTION ; ORGANIZATION ; cell lines ; METHYLATION ; HYPERMETHYLATION ; AGENT ; E-cadherin ; IV ; GLIOMA ; astrocytoma ; SCREEN ; SUPPRESSOR ; sequencing ; PROMOTER REGION ; CPG-ISLAND METHYLATION ; cRT-PCR ; NERVOUS-SYSTEM TUMORS ; PCDH-gamma-A11
    Abstract: In a microarray-based methylation analysis of astrocytomas [World Health Organization (WHO) grade II], we identified a CpG island within the first exon of the protocadherin-gamma subfamily All 1 (PCDH-gamma-A11) gene that showed hypermethylation compared to normal brain tissue. Bisulfite sequencing and combined bisulfite restriction analysis (COBRA) was performed to screen low- and high-grade astrocytomas for the methylation status of this CpG island. Hypermethylation was detected in 30 of 34 (88%) astrocytomas (WHO grades II and III), 20 of 23 (87%) glioblastomas (WHO grade IV), and 8 of 8 (100%) glioma cell lines. There was a highly significant correlation (P = .00028) between PCDH-gamma-A11 hypermethylation and decreased transcription as determined by competitive reverse transcription polymerase chain reaction in WHO grades II and III astrocytomas. After treatment of glioma cell lines with a demethylating agent, transcription of PCDH-gamma-A11 was restored. In summary, we have identified PCDH-gamma-A11 as a new target silenced epigenetically in astrocytic gliomas. The inactivation of this cell-cell contact molecule might be involved in the invasive growth of astrocytoma cells into normal brain parenchyma
    Type of Publication: Journal article published
    PubMed ID: 15799819
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  • 3
    Keywords: ANGIOGENESIS, animal, animals, antibodies, BONE, BONE METASTASES, BREAST, breast cancer, BREAST-CANC
    Abstract: The aim of this study was to evaluate the effect of an antiangiogenic treatment with the vascular endothelial growth factor antibody bevacizumab in an experimental model of breast cancer bone metastasis and to monitor osteolysis, soft tissue tumor, and angiogenesis in bone metastasis noninvasively by volumetric computed tomography (VCT) and magnetic resonance imaging (MRI). After inoculation of MDA-MB-231 human breast cancer cells into nude rats, bone metastasis was monitored with contrast-enhanced VCT and MRI from day 30 to day 70 after tumor cell inoculation, respectively. Thereby, animals of the treatment group (10 mg/kg bevacizumab IV weekly, n = 15) were compared with sham-treated animals (n = 17). Treatment with bevacizumab resulted in a significant difference versus control in osteolytic as well as soft tissue lesion sizes (days 50 to 70 and 40 to 70 after tumor cell inoculation, respectively; P 〈 .05). This observation was paralleled with significantly reduced vascularization in the treatment group as shown by reduced increase in relative signal intensity in dynamic contrast-enhanced MRI from days 40 to 70 (P 〈 .05). Contrast-enhanced VCT and histology confirmed decreased angiogenesis as well as new bone formation after application of bevacizumab. In conclusion, bevacizumab significantly inhibited osteolysis, surrounding soft tissue tumor growth, and angiogenesis in an experimental model of breast cancer bone metastasis as visualized by VCT and MRI
    Type of Publication: Journal article published
    PubMed ID: 18472968
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  • 4
    Keywords: ENVIRONMENT ; ANGIOGENESIS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; tumor ; CELL ; evaluation ; Germany ; IN-VIVO ; tumor growth ; VITRO ; VIVO ; SUPPORT ; DRUG ; MICE ; IMPACT ; INDUCTION ; ALPHA ; resistance ; CANCER-CELLS ; BETA ; ADHESION ; RECRUITMENT ; IMMUNE-RESPONSE ; DRUG-RESISTANCE ; SARCOMA ; chemokine ; inflammation ; CROSS-TALK ; MATRIX ; ONCOLOGY ; RE ; TUMOR-GROWTH ; TUMORIGENICITY ; INFLAMMATORY CYTOKINES ; USA ; MOTILITY ; IL-1 receptor antagonist ; fibrosarcoma ; matrix metalloproteinase ; host ; MATRIX-METALLOPROTEINASE ; systemic ; LEWIS LUNG-CARCINOMA ; myeloid cells ; SUPPRESSOR-CELLS ; TUMOR-HOST INTERACTIONS ; ANCHORAGE-INDEPENDENT GROWTH ; SYSTEMIC INFLAMMATION
    Abstract: Analyzing the growth of fibrosarcoma lines derived from IL-1 alpha-, IL-1 beta-, or IL-1 alpha beta-knockout((-/-)) mice in the immunocompetent host revealed that tumor-derived IL-1 alpha and IL-1 beta exert strong and opposing effects on immune response induction, which prohibited the evaluation of a potential impact on tumorigenicity. Therefore, in vivo growth of IL-1-deficient tumor lines was evaluated in nu/nu mice and was compared with in vitro growth characteristics. All IL-1-deficient fibrosarcoma lines grow in immunocompromised mice. However, IL-1 alpha(-/-)beta-competent ( comp) lines grow more aggressively, efficiently induce angiogenesis, and recruit inflammatory cells. Despite stronger tumorigenicity of IL-1 beta(comp) lines, IL-1 alpha strengthens anchorage-independent growth, but both IL-1a and IL-1 beta support drug resistance. Corresponding to the aggressive growth, IL-1 beta(comp) cells display increased matrix adhesion, motility, and cable formation on matrigel, likely supported by elevated alpha(v)/beta(3) and matrix metalloproteinase expression. Recruitment of myeloid cells requires IL-1 beta but is regulated by IL-1 alpha, because inflammatory chemokine and cytokine expression is stronger in IL-1 alpha(-/-)beta(comp) than in IL-1(wt) lines. This regulatory effect of tumor-derived IL-1 alpha is restricted to the tumor environment and does not affect systemic inflammatory response induction by tumor-derived IL-1 beta. Both sarcoma cell-derived IL-1 alpha and IL-1 beta promote tumor growth. However, IL- 1 alpha exerts regulatory activity on the tumor cell-matrix cross-talk, and only IL-1 beta initiates systemic inflammation
    Type of Publication: Journal article published
    PubMed ID: 18516292
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  • 5
    Keywords: APOPTOSIS ; EXPRESSION ; GROWTH ; proliferation ; tumor ; carcinoma ; CELL ; FACTOR RECEPTOR ; Germany ; human ; KINASE ; PATHWAY ; PATHWAYS ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; PROTEIN ; PROTEINS ; SAMPLE ; SAMPLES ; TISSUE ; ACTIVATION ; primary ; PROTEIN-KINASE ; ASSOCIATION ; MAP KINASE ; score ; STAGE ; NEOPLASIA ; immunohistochemistry ; gene expression ; metastases ; ABERRATIONS ; SIGNALING PATHWAY ; RELIABILITY ; HEAD ; squamous cell carcinoma ; GROWTH-FACTOR-BETA ; MICROARRAY ANALYSIS ; gene expression profiling ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; protein expression ; EPIDERMAL-GROWTH-FACTOR ; NECK-CANCER ; signaling ; molecular ; CELL CARCINOMA ; ONCOLOGY ; INCREASE ; analysis ; CHIP ; USA ; lymph node metastases ; SQUAMOUS-CELL ; HUMAN HEPATOCELLULAR-CARCINOMA ; SET ; COLLECTION ; DETECT ; MAP-KINASE ; GENE-ONTOLOGY
    Abstract: In an attempt to further elucidate the pathomechanisms in oral squamous cell carcinoma (OSCC), gene expression profiling was performed using a whole-transcriptome chip that contains 35,035 gene-specific 70mere oligonucleotides (Human OligoSet 4.0; Operon, Cologne, Germany) to a set of 35 primary OSCCs. Altogether, 7390 genes were found differentially expressed between OSCC tumor samples and oral mucosa. To characterize the major biologic processes in this tumor collection, MAPPFinder, a component of GenMAPP version 2.1, was applied to this data set to generate a statistically ranked list of molecular signaling pathways. Among others, cancer-related pathways, such as mitogen-activated protein (MAP) kinase signaling (z score = 4.6, P 〈 .001), transforming growth factor-beta signaling (z score = 3.0, P = .015), and signaling pathways involved in apoptosis (z score = 2.1, P = .037), were found deregulated in the OSCC collection analyzed. Focusing on the MAP kinase signaling pathway, subsequent tissue microarray analyses by immunohistochemistry revealed an increase in protein expression of MAP kinase-related proteins ERK1 in 22.8% (48 of 209) and ERK5 in 27.4% (76 of 277), respectively. An association of high ERK5 but not of high ERK1 expression with advanced tumor stage and the presence of lymph node metastases was found (P = .008 and P = .016, respectively). Our analysis demonstrates the reliability of the combined approach of gene expression profiling, signaling pathway analyses, and tissue microarray analysis to detect novel distinct molecular aberrations in OSCC
    Type of Publication: Journal article published
    PubMed ID: 18472963
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  • 6
    Abstract: EphB receptors and their ephrinB ligands play a key role in the formation of a regular vascular system. Recent studies have also shown the involvement of Eph/ephrin interactions in malignant tumor progression and angiogenesis. We have generated soluble monomeric EphB4 (sEphB4)-expressing A375 melanoma cells to study the effect of dominant negatively acting sEphB4 on tumor growth and angiogenesis. Soluble EphB4-expressing A375 tumors grown subcutaneously in nude mice show dramatically reduced tumor growth compared to control tumors. The proliferative capacity of sEphB4-expressing cells in monolayer culture is not altered. Yet, sEphB4-expressing A375 cells cannot establish proper cell-cell contacts in three-dimensional spheroids. However, sEphB4 transfectants have reduced proliferation and apoptosis rates when grown in three-dimensional culture in vitro or in subcutaneous tumors in vivo. Analysis of the vascular phenotype of the tumors revealed a reduction of intratumoral microvessel density in sEphB4-expressing tumors. Corresponding to these mouse experiments, a matched pair analysis of EphB4 and ephrinB2 expression in human colon carcinomas revealed significantly upregulated levels of EphB4 expression compared to adjacent normal tissue. Taken together, the data identify dual effects of sEphB4 on the tumor and the vascular compartment that collectively inhibit tumor growth.
    Type of Publication: Journal article published
    PubMed ID: 15153337
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  • 7
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    Neoplasia 15 (3), 281-295 
    Keywords: ACTIVATION ; MECHANISM ; METASTASIS ; MELANOMA ; CANCER-CELLS ; CARCINOMA-CELLS ; RAT-TUMOR ; CD44 ; tetraspanins ; PROMOTE
    Abstract: Tumor exosomes educate selected host tissues toward a prometastatic phenotype. We demonstrated this for exosomes of the metastatic rat adenocarcinoma BSp73ASML (ASML), which modulate draining lymph nodes and lung tissue to support settlement of poorly metastatic BSp73ASML-CD44v4-v7 knockdown (ASML-CD44v(kd)) cells. Now, we profiled mRNA and microRNA (miRNA) of ASML(wt) and ASML-CD44v(kd) exosomes to define the pathway(s), whereby exosomes prepare the premetastatic niche. ASML exosomes, recovered in draining lymph nodes after subcutaneous injection, preferentially are taken up by lymph node stroma cells (LnStr) and lung fibroblasts (LuFb) that were chosen as exosome targets. ASML(wt) and ASML-CD44v(kd) exosomes contain a restricted mRNA and miRNA repertoire that differs significantly between the two lines and exosomes thereof due to CD44v6 influencing gene and miRNA transcription/posttranscriptional regulation. Exosomal mRNA and miRNA are recovered in target cells, where transferred miRNA significantly affected mRNA translation. Besides others, this was exemplified for abundant ASML(wt)-exosomal miR-494 and miR-542-3p, which target cadherin-17 (cdh17). Concomitantly, matrix metalloproteinase transcription, accompanying cdh17 down-regulation, was upregulated in LnStr transfected with miR-494 or miR-542-3p or co-cultured with tumor exosomes. Thus, tumor exosomes target non-transformed cells in premetastatic organs and modulate premetastatic organ cells predominantly through transferred miRNA, where miRNA from a metastasizing tumor prepares premetastatic organ stroma cells for tumor cell hosting. Fitting the demands of metastasizing tumor cells, transferred exosomal miRNA mostly affected proteases, adhesion molecules, chemokine ligands, cell cycle- and angiogenesis-promoting genes, and genes engaged in oxidative stress response. The demonstration of function-competent exosomal miRNA in host target cells encourages exploiting exosomes as a therapeutic gene delivery system.
    Type of Publication: Journal article published
    PubMed ID: 23479506
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  • 8
    Keywords: BREAST-CANCER ; EXTRACELLULAR-MATRIX ; TISSUE FACTOR ; STROMAL CELLS ; MEDIATED TRANSFER ; GROWTH-FACTORS ; CLINICAL-APPLICATIONS ; MESENCHYMAL STEM-CELLS ; PREMETASTATIC NICHE ; CELL-DERIVED-EXOSOMES
    Abstract: Exosomes are important intercellular communicators, where tumor exosomes (TEX) severely influence hematopoiesis and premetastatic organ cells. With the extracellular matrix (ECM) being an essential constituent of non-transformed tissues and tumors, we asked whether exosomes from a metastatic rat tumor also affect the organization of the ECM and whether this has consequences on host and tumor cell motility. TEX bind to individual components of the ECM, the preferential partner depending on the exosomes' adhesion molecule profile such that high CD44 expression is accompanied by hyaluronic acid binding and high alpha6beta4 expression by laminin (LN) 332 binding, which findings were confirmed by antibody blocking. TEX can bind to the tumor matrix already during exosome delivery but also come in contact with distinct organ matrices. Being rich in proteases, TEX modulate the ECM as demonstrated for degradation of collagens, LNs, and fibronectin. Matrix degradation by TEX has severe consequences on tumor and host cell adhesion, motility, and invasiveness. By ECM degradation, TEX also promote host cell proliferation and apoptosis resistance. Taken together, the host tissue ECM modulation by TEX is an important factor in the cross talk between a tumor and the host including premetastatic niche preparation and the recruitment of hematopoietic cells. Reorganization of the ECM by exosomes likely also contributes to organogenesis, physiological and pathologic angiogenesis, wound healing, and clotting after vessel disruption.
    Type of Publication: Journal article published
    PubMed ID: 23908589
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  • 9
    Abstract: The CCL2-CCR2 chemokine axis has an important role in cancer progression where it contributes to metastatic dissemination of several cancer types (e.g., colon, breast, prostate). Tumor cell-derived CCL2 was shown to promote the recruitment of CCR2(+)/Ly6C(hi) monocytes and to induce vascular permeability of CCR2(+) endothelial cells in the lungs. Here we describe a novel decoy protein consisting of a CCL2 mutant protein fused to human serum albumin (dnCCL2-HSA chimera) with enhanced binding affinity to glycosaminoglycans that was tested in vivo. The monocyte-mediated tumor cell transendothelial migration was strongly reduced upon unfused dnCCL2 mutant treatment in vitro. dnCCL2-HSA chimera had an extended serum half-life and thus a prolonged exposure in vivo compared with the dnCCL2 mutant. dnCCL2-HSA chimera bound to the lung vasculature but caused minimal alterations in the leukocyte recruitment to the lungs. However, dnCCL2-HSA chimera treatment strongly reduced both lung vascular permeability and tumor cell seeding. Metastasis of MC-38GFP, 3LL, and LLC1 cells was significantly attenuated upon dnCCL2-HSA chimera treatment. Tumor cell seeding to the lungs resulted in enhanced expression of a proteoglycan syndecan-4 by endothelial cells that correlated with accumulation of the dnCCL2-HSA chimera in the vicinity of tumor cells. These findings demonstrate that the CCL2-based decoy protein effectively binds to the activated endothelium in lungs and blocks tumor cell extravasation through inhibition of vascular permeability.
    Type of Publication: Journal article published
    PubMed ID: 26806351
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  • 10
    Keywords: CANCER ; EXPRESSION ; carcinoma ; Germany ; DISEASE ; GENE ; TUMORS ; PATIENT ; FREQUENCY ; LESIONS ; MUTATION ; meta-analysis ; PCR ; MUTATIONS ; POLYMERASE-CHAIN-REACTION ; adenocarcinoma ; intraepithelial neoplasia ; K-RAS ; chronic pancreatitis ; ALLELIC LOSS ; K-ras mutation ; pancreatic ductal carcinoma ; molecular ; DUCTAL ADENOCARCINOMA ; KRAS MUTATIONS ; METAANALYSIS ; CODON ; DNA ADDUCT ; duration ; K-RAS MUTATIONS ; KRAS ; GENETIC PROGRESSION ; ONCOGENE ACTIVATION ; pancreatic intraepithelial neoplasia
    Abstract: Molecular analyses have demonstrated mutations in the K-ras gene at codon 12 in the majority of pancreatic ductal adenocarcinomas (PDACs). In order to determine whether the K-ras mutation rate increases parallel to the grade of dysplasia in duct lesions, we performed a meta-analysis of the studies published between 1988 and 2003 that provide information on K-ras mutations in hyperplastic and dysplastic duct lesions in the pancreas. The described duct lesions were reclassified according to the nomenclature for pancreatic intraepithelial neoplasia (PanIN), and the molecular methods for detecting K-ras were reviewed. In PanIN lesions from pancreata of patients with PDAC, there was a stepwise increase in K-ras mutations that correlated with the grade of dysplasia of the PanIN lesion. K-ras mutations were found in 36%, 44%, and 87% of PanIN-1a, 1b, and 2-3 lesions, respectively (trend statistic P 〈 .001). Mutation-enriched polymerase chain reaction (PCR) resulted in higher rates of K-ras mutations in PanIN than plain PCR did. The incidence of K-ras mutations in PanIN lesions associated with chronic pancreatitis (CP) or normal pancreas was low (around 10%). In CP, K-ras mutations were only found after a disease duration of 3 years. The correlation of the incidence of K-ras mutations with the grade of dysplasia in PanIN and the occurrence of these mutations in CP with a duration of more than 3 years underlines the importance of this genetic change for the development of PDAC
    Type of Publication: Journal article published
    PubMed ID: 15720814
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