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  • GROWTH  (5)
  • 1
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; proliferation ; tumor ; carcinoma ; CELL ; CELL-PROLIFERATION ; ENDOTHELIAL GROWTH-FACTOR ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; MODEL ; PERFUSION ; imaging ; SYSTEM ; GENE ; GENES ; TUMORS ; gene therapy ; LINES ; gene transfer ; GENE-TRANSFER ; COMPLEX ; COMPLEXES ; DNA ; INDUCTION ; RAT ; ANTIGEN ; CELL-LINES ; signal transduction ; SIGNAL ; immunohistochemistry ; VECTOR ; NUMBER ; STRESS ; SIGNAL-TRANSDUCTION ; CELL-LINE ; LINE ; HEPATOMA ; EXTRACELLULAR-MATRIX ; PET ; RECEPTORS ; OXIDATIVE STRESS ; OVEREXPRESSION ; cell lines ; CELL-MIGRATION ; VASCULARIZATION ; VEGF ; HUMAN COLON-CANCER ; MATRIX ; OXIDATIVE-STRESS ; TUMOR-GROWTH ; INCREASE ; extracellular matrix ; ENHANCED EXPRESSION ; cell proliferation ; TUMOR PERFUSION ; MIGRATION INHIBITORY FACTOR ; CHIP ; functional imaging ; function ; GROWTH-FACTOR-RECEPTOR ; angiopoietin-2 ; TIE2 ; TUNEL ; UP-REGULATES ANGIOPOIETIN-2
    Abstract: Monitoring of angiogenesis-relevant approaches with functional imaging and histomorphometric analyses is desirable to evaluate the biologic effects. In this study we wished to examine the complex effects of angiopoietin-2 (Ang-2) gene transfer in a rat hepatoma model. Methods: Using a bicistronic retroviral vector for Ang-2, Morris hepatoma (MH3924A) cell lines with Ang-2 expression were generated (Ang-2-MH3924A). In human umbilical vein endothelial cells (HUVECs) cocultured with Ang-2MH3924A, the proliferative action with or without growth factors were determined. Furthermore, animal experiments were performed to measure effects on tumor growth and perfusion. Finally, tumors were examined by immunohistochemistry and DNA chip analysis. Results: Ang-2-expressing MH3924A enhanced basic fibroblast growth factor-mediated endothelial cell proliferation. Perfusion, as measured by (H2O)-O-15 PET, was increased in genetically modified tumors. Consistent with the increased perfusion, micro- and macrovascularization were increased. However, tumor growth was similar to wild-type MH3924A (WT-MH3924A). Proliferating cell nuclear antigen and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) staining revealed an increased number of positive cells, indicating a compensation of increased proliferation by enhanced apoptosis. DNA chip analysis showed an induction of angiogenesis-promoting genes, including crucial vascular growth factor receptors, as well as genes related to extracellular matrix (ECM), apoptosis, signal transduction, and oxidative stress. Conclusion: Our results suggest that Ang-2 expression increases perfusion or vascularization, especially in interaction with the vascular growth factor system, without affecting tumor growth. Simultaneous, enhanced expression of genes for ECM, apoptosis, and signal transduction indicates Ang-2's versatile role in angiogenesis including its destabilizing function on ECM and endothelium
    Type of Publication: Journal article published
    PubMed ID: 16954561
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  • 2
    Keywords: ANGIOGENESIS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; proliferation ; tumor ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; evaluation ; Germany ; IN-VIVO ; MODEL ; MODELS ; CLASSIFICATION ; DIAGNOSIS ; imaging ; LUNG-CANCER ; QUANTIFICATION ; VOLUME ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; DIFFERENTIATION ; TUMORS ; NUCLEAR-MEDICINE ; PATIENT ; CYCLE ; ASSOCIATION ; TRANSPORT ; gene expression ; PARAMETERS ; SOFT-TISSUE SARCOMAS ; BENIGN ; PET ; KINETICS ; GROWTH-FACTOR-A ; SARCOMA ; nuclear medicine ; TRACER ; PROTEOGLYCAN ; beta(2)-microglobulin ; HETEROGENEITY ; CONSTANTS ; FRACTION ; FDG PET ; F-18-FDG ; fractal dimension ; TUMOR VOLUME ; CELL TUMORS ; ACTIVATOR ; BONE-TUMORS ; FACTOR VEGF ; giant cell tumor
    Abstract: F-18-FDG kinetics were evaluated by use of compartment and noncompartment models of giant cell tumors. The kinetic data were compared with the gene expression data for a subgroup of patients. Methods: Nineteen patients with giant cell tumors were examined with PET and F-18-FDG, and tracer kinetics were assessed quantitatively. A 2-compartment model, including the transport constants k1-k4 as well as the vascular fraction (VB) for F-18-FDG, was used for evaluation of the data. A noncompartment model was used to calculate the fractal dimension of the F-18-FDG time-activity curve to assess the heterogeneity of the tracer kinetics. Furthermore, tumor specimens obtained from 5 patients were assessed with gene chip technology (U95A), and these data were compared with the quantitative F-18-FDG data. Results: The giant cell tumors showed generally enhanced 18F-FDG uptake 1 h after tracer application, with a mean 18F-FDG standardized uptake value (SUV) of 4.8 (range, 1.8-9.4). Quantitative evaluation of tracer kinetics showed a preferential increase for F-18-FDG transport, with a mean k1 of 0.340. The vascular fraction accounted for 35% of the tumor volume and was high compared with those for other tumors, such as soft-tissue sarcomas. F-18-FDG kinetics were heterogeneous, with a fractal dimension of 1.3. Gene chip analysis showed that the expression of 137 genes (1.1%) exceeded the median expression value of the reference gene, beta(2)-Microglobulin. The highest expression was observed for the gene for the small, leucine-rich proteoglycan 1 (biglycan), which is important for bone cell differentiation and proliferative activity. Correlation analysis revealed an association of F-18-FDG data with the expression of several genes. Mainly genes related to angiogenesis were associated with the compartment parameters. The SUV at 56-60 min was correlated with the expression of vascular endothelial growth factor A (angiogenesis) and cell division cycle 2 protein (proliferation). Conclusion: Despite their classification as benign tumors, giant cell tumors have generally enhanced F-18-FDG uptake, mainly attributable to an enhanced vascular fraction and increased F-18-FDG transport. A comparison of gene chip data and F-18-FDG kinetic data showed a close association of quantitative F-18-FDG results and the expression of genes related to angiogenesis
    Type of Publication: Journal article published
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  • 3
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; proliferation ; tumor ; CELL-PROLIFERATION ; FACTOR RECEPTOR ; Germany ; IN-VIVO ; INHIBITION ; MODEL ; PERFUSION ; VITRO ; imaging ; HEPATOCELLULAR-CARCINOMA ; GENE ; GENES ; METABOLISM ; TUMORS ; LINES ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; DNA ; INDUCTION ; CELL-LINES ; signal transduction ; immunohistochemistry ; MALIGNANCIES ; ASSAY ; DESIGN ; VECTOR ; NUMBER ; STRESS ; SIGNAL-TRANSDUCTION ; LINE ; positron emission tomography ; POSITRON-EMISSION-TOMOGRAPHY ; tomography ; OXIDATIVE STRESS ; cell lines ; MALIGNANCY ; OXIDATIVE-STRESS ; TUMOR-GROWTH ; monitoring ; endothelial cells ; cell proliferation ; MIGRATION INHIBITORY FACTOR ; CHIP ; computer-assisted ; functional imaging ; ANGIOGENESIS IN-VIVO ; GLIOBLASTOMA GROWTH ; IRRADIATED SKIN ; SOLUBLE FORM ; SYMPORTER GENE
    Abstract: Purpose: Inhibition of tumor angiogenesis is emerging as a promising target in the treatment of malignancies. Therefore, monitoring of antiangiogenic approaches with functional imaging and histomorphometrical analyses are desirable to evaluate the biological effects caused by this treatment modality. Experimental Design: Using a bicistronic retroviral vector for transfer of the soluble receptor for the vascular endothelial growth factor (sFLT) hepatoma (MH3924A) cell lines with sFLT expression were generated. In human umbilical vein endothelial cells cultured with conditioned medium of sFLT-expressing hepatoma cells, the inhibitory action of secreted sFLT was determined using a Coulter counter and a thymidine incorporation assay. Furthermore, in vivo experiments were done to measure the effects on tumor growth and perfusion. Finally, the tumors were examined by immunohistochemistry (including computer-assisted morphometry) and DNA chip analysis. Results: Stable sFLT-expressing hepatoma cells inhibited endothelial cell proliferation in vitro. In vivo, growth and perfusion, as measured by (H2O)-O-15 positron emission tomography, were reduced in genetically modified tumors. However, the immunohistochemically quantified microvascularization and macrovascularization, as indicated by CD31- and alpha-actin-positive area, revealed no significant changes, whereas the number of apoptotic cells was increased in sFLT-expressing tumors, although not significantly. DNA chip analysis of tumors with gene transfer showed an increase of genes related to apoptosis, signal transduction, and oxidative stress. Conclusion: Our results suggest that sFLT expression inhibits tumor growth and perfusion and enhances expression of apoptosis-related genes in this model. Enhanced expression of genes for signal transduction, stress, and metabolism indicates tumor defense reactions
    Type of Publication: Journal article published
    PubMed ID: 15788658
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  • 4
    Keywords: ANGIOGENESIS ; APOPTOSIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; proliferation ; tumor ; ANGIOSTATIN ; BLOOD ; CELL ; CELL-PROLIFERATION ; CLINICAL-TRIAL ; Germany ; human ; IN-VIVO ; INHIBITION ; MICROVESSEL DENSITY ; PERFUSION ; VITRO ; VIVO ; DENSITY ; imaging ; INFORMATION ; QUANTIFICATION ; SUPPORT ; VOLUME ; GENE ; GENES ; METABOLISM ; cell line ; TUMORS ; gene therapy ; LINES ; NUCLEAR-MEDICINE ; TRANSDUCTION ; MECHANISM ; BLOOD-FLOW ; mechanisms ; SUFFICIENT ; CELL-LINES ; signal transduction ; treatment ; SIGNAL ; ACID ; TARGET ; MALIGNANCIES ; STRESS ; SIGNAL-TRANSDUCTION ; CELL-LINE ; LINE ; HEPATOMA ; POSITRON-EMISSION-TOMOGRAPHY ; PET ; OVEREXPRESSION ; cell lines ; nuclear medicine ; TUMOR ANGIOGENESIS ; VASCULARIZATION ; INHIBITORS ; radiology ; MALIGNANCY ; TUMOR-GROWTH ; LEADS ; endothelial cell ; endothelial cells ; ARRAY ; cell proliferation ; TUMOR PERFUSION ; methods ; NUCLEAR ; USA ; EVALUATE ; in vivo ; ENDOTHELIAL-CELL ; blood supply ; MULTIPLE GENES ; blood volume ; coculture ; gene array ; LEWIS LUNG-CARCINOMA ; MEDICINE
    Abstract: Growth of malignant tumors is dependent on sufficient blood supply. Thus, inhibition of tumor angiogenesis is emerging as a promising target in the treatment of malignancies. Human angiostatin (hANG) is one of the most potent inhibitors of endothelial cell proliferation, angiogenesis, and tumor growth in vivo. However, its mechanisms operating in vivo are not well understood. Methods: To obtain more information about functional changes in the angiogenic process, we established Morris hepatoma (MH3924A) cell lines expressing hANG (hANG-MH3924A). The effects of hANG expression on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) were measured in coculture experiments in vitro. To evaluate changes in tumor perfusion and blood volume, (H2O)-O-15 and Ga-68-DOTAalbumin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N '',N'''tetraacetic acid) were used for PET studies in vivo. Additionally, immunohistologic quantification of vascularization, apoptosis, and proliferation as well as gene array analyses were performed. Results: Our in vitro experiments demonstrate reduced proliferation and increased apoptosis in HUVECs when being co-cultured with hANG-MH3924A. In support, tumor growth of hANG-MH3924A is diminished by 95% in vivo. However, tumor perfusion and blood volume are increased in hANG-MH3924A corresponding to an increased microvessel density. Furthermore, hANG-transfected tumors show changes in expression of genes related to apoptosis, stress, signal transduction, and metabolism. Conclusion: hANG expression leads to inhibition of tumor growth, increased apoptosis, and changes in the expression of multiple genes involved in stress reactions, signal transcluction, and apoptosis, which indicates a multifactorial reaction of tumors. An enhanced microvessel density is seen as part of these reactions and is associated with increased perfusion as measured by PET
    Type of Publication: Journal article published
    PubMed ID: 16513625
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  • 5
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; proliferation ; tumor ; BLOOD ; carcinoma ; CELL ; CELL-PROLIFERATION ; Germany ; human ; IN-VIVO ; INHIBITION ; PERFUSION ; THERAPY ; VIVO ; TOOL ; VOLUME ; GENE ; GENES ; TUMORS ; gene therapy ; gene transfer ; GENE-TRANSFER ; MECHANISM ; INDUCTION ; mechanisms ; MRI ; BIOLOGY ; signal transduction ; SIGNAL ; STRESS ; SIGNAL-TRANSDUCTION ; HEPATOMA ; MIGRATION ; PET ; OVEREXPRESSION ; CANCER-THERAPY ; VASCULARIZATION ; TUMOR-GROWTH ; cancer therapy ; cell proliferation ; CANCERS ; in vivo ; TOOLS ; CARTILAGE ; troponin I
    Abstract: Antiangiogenic gene transfer inhibiting growth of new blood vessels is a promising approach in cancer therapy. Human troponin I (TnI) efficiently inhibits endothelial cell proliferation, migration, as well as angiogenesis and tumor growth in vivo. However, little is known about its effects on perfusion and tumor biology. Methods: Stable Morris hepatoma (MH3924A) cells overexpressing human TO (TnI-MH3924A) were cocultured with human umbilical vein endothelial cells (HUVECs) followed by measurements of endothelial apoptosis and proliferation. Furthermore, tumor growth and perfusion were determined using (H2O)-O-15 and Ga-68-DOTA-albumin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid)PET as well as functional MRI. Additionally, histologic measurements of vascularization, apoptosis, proliferation, and gene array analyses were performed. Results: Apoptosis of HUVECs was increased and proliferation was decreased after coculture with TnI-MH3924A cells. TnI-MH3924A tumors showed a significant inhibition of growth (90%) and a decreased perfusion (25%), whereas blood volume remained unchanged. MRI investigations demonstrated a significant decrease of the rate constant k(ep). Immunohistochemical analyses showed decreased microvessel density and proliferation and significant induction of apoptosis. Furthermore, TnI-expressing hepatomas demonstrated changes in the expression of genes related to angiogenesis, apoptosis, signal transduction, or stress. Conclusion: TnI regulates tumor growth by modulating vascularization including apoptosis induction and decrease of proliferation. In addition, changes in expression of genes associated with angiogenesis, apoptosis, signal transduction, or stress were found. The upregulation of an giogenesis and stress-related genes indicates a cross-talk of different mechanisms as part of the tumor's reaction to TnI. Because the decrease of vascularization led to lower perfusion values as measured by PET and MRI, these noninvasive methods are promising tools for the monitoring of antiangiogenic gene therapy
    Type of Publication: Journal article published
    PubMed ID: 16954560
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