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  • 1
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; FLK-1/KDR ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; INVASION ; IONIZING-RADIATION ; IRRADIATION ; proliferation ; PROTECTION ; radiotherapy ; SURVIVAL ; tumor ; TUMOR-CELLS
    Abstract: In recent decades, radiation research has concentrated primarily on the cancer cell compartment. Much less is known about the effect of ionizing radiation on the endothelial cell compartment and the complex interaction between tumor cells and their microenvironment. Here we report that ionizing radiation is a potent antiangiogenic agent that inhibits endothelial cell survival, proliferation, tube formation and invasion. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor were able to reduce the radiosensitivity of endothelial cells. Yet, it is also found that radiation induces angiogenic factor production by tumor cells that can be abrogated by the addition of antiangiogenic agents. Receptor tyrosine kinase inhibitors of Flk-1/KDR/VEGFR2, FGFR1 and PDGFRbeta, SU5416, and SU6668 enhanced the antiangiogenic effects of direct radiation of the endothelial cells. In a coculture system of PC3 prostate cancer cells and endothelial cells, isolated irradiation of the PC3 cells enhanced endothelial cell invasiveness through a Matrigel matrix, which was inhibited by SU5416 and SU6668. Furthermore, ionizing radiation up-regulated VEGF and basic fibroblast growth factor in PC3 cells and VEGFR2 in endothelial cells. Together these findings suggest a radiation-inducible protective role for tumor cells in the support of their associated vasculature that may be down- regulated by coadministration of angiogenesis inhibitors., These results rationalize concurrent administration of angiogenesis inhibitors and radiotherapy in cancer treatment
    Type of Publication: Journal article published
    PubMed ID: 12839971
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  • 2
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; IN-VITRO ; INHIBITOR ; IONIZING-RADIATION ; IRRADIATION ; proliferation ; radiotherapy ; SURVIVAL ; tumor ; TUMOR-CELLS ; AGENTS ; CELL ; COMBINATION ; Germany ; human ; INHIBITION ; KINASE ; MODEL ; MODELS ; PROSTATE ; THERAPY ; TYROSINE KINASE ; VITRO ; EXPOSURE ; NEW-YORK ; DRUG ; cell line ; LINES ; radiation ; ACTIVATION ; DNA ; primary ; FLOW ; CELL-LINES ; PHOSPHORYLATION ; treatment ; ASSAY ; EFFICACY ; prostate cancer ; PROSTATE-CANCER ; CELL-LINE ; chemotherapy ; LINE ; CANCER-CELLS ; INVOLVEMENT ; STRATEGIES ; FLOW-CYTOMETRY ; TUMOR CELLS ; TUMOR-CELL-LINES ; NECK-CANCER ; alimta ; ANGIOGENESIS INHIBITION ; antiangiogenesis ; CONCURRENT ; MEDICAL PROGRESS ; MULTITARGETED ANTIFOLATE ; pemetrexed ; SU5416 ; triple combination ; XENOGRAFTS
    Abstract: Purpose: This is the first preclinical report evaluating a trimodal therapy consisting of irradiation, chemotherapy, antiangiogenesis in the context of a multimodal anticancer strategy. The combination of the folate antimetabolite pemetrexed, SU5416, a receptor tyrosine kinase inhibitor of VEGFR2, and irradiation was investigated in human endothelial cells and tumor cell lines. Methods and Materials: Primary isolated human umbilical vein endothelial cells (HUVEC), human dermal microvascular endothelial cells (HDMEC), and human glioblastoma (U87) and prostate cancer cells (PC3) were exposed to pemetrexed (2 h) alone and in combination with SU5416 (2 h). When combined with irradiation up to 8 Gy, fixed concentrations of pemetrexed (1.06 muM) and SU5416 (1.0 muM) were used. Proliferation and clonogenic assays were conducted with endothelial and tumor cells. The migration/invasion ability of endothelial cells and the ability to produce tubular structures were tested in Matrigel and tube formation assays. Apoptosis was measured by sub-G1 DNA and caspase-3 flow cytometry. To investigate underlying cell signaling, immunocytochemistry was used to detect Akt survival signaling involvement. Results: Triple combination using only a low-toxicity drug exposure of pemetrexed and SU5416 results in greater response than each treatment alone or than each combination of two modalities in all tested endothelial and tumor cell models. Triple combination substantially inhibits proliferation, migration/invasion, tube formation, and clonogenic survival. Triple combination also induced the highest rate of apoptosis in HDMEC and HUVEC as indicated by sub-1 G1 and caspase-3 assessment. Interestingly, triple combination therapy also reduces proliferation and clonogenic survival significantly in U87 and PC3 tumor cell lines. SU5416 potently inhibited Akt phosphorylation which could be induced by radiation and radiochemotherapy in human endothelial cells. Conclusions: Our findings demonstrate the high antiendothelial/antitumoral efficacy of the concurrent administration of irradiation, chemotherapy, and angiogenesis inhibition in vitro. A potential explanation for the favorable combination would be that VEGF signaling inhibition downregulates Akt survival signaling upon activation by radiation and/or chemotherapy. The data also suggest that endothelial cell apoptosis may have an important role in the benefits of the presented therapy. (C) 2004 Elsevier Inc
    Type of Publication: Journal article published
    PubMed ID: 15519795
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  • 3
    Keywords: CANCER ; tumor ; carcinoma ; CLASSIFICATION ; COHORT ; DISTINCT ; GENE ; GENES ; TUMORS ; PATIENT ; prognosis ; treatment ; FREQUENCY ; SUSCEPTIBILITY ; BREAST ; DESIGN ; AGE ; BRCA1 ; OVARIAN-CANCER ; WOMEN ; MUTATION ; REPRODUCIBILITY ; p53 ; MUTATIONS ; MORPHOLOGY ; adenocarcinoma ; CARRIERS ; CANCER-RESEARCH ; SERIES ; POOR-PROGNOSIS ; FEATURES ; BRCA2 GENE ; GRADE ; MUTATION CARRIERS ; GERM-LINE MUTATIONS ; FAMILIAL BREAST-CANCER
    Abstract: Purpose: Germline mutations in the BRCA1 and BRCA2 genes confer increased susceptibility to ovarian cancer. There is evidence that tumors in carriers may exhibit a distinct distribution of pathological features, but previous studies on the pathology of such tumors have been small. Our aim was to evaluate the morphologies and immunophenotypes in a large cohort of patients with familial ovarian cancer.Experimental Design: We performed a systematic review of ovarian tumors from 178 BRCA1 mutation carriers, 29 BRCA2 mutation carriers, and 235 controls with a similar age distribution. Tumors were evaluated by four pathologists blinded to mutation status. Both morphological features and immunochemical staining for p53 and HER2 were evaluated.Results: Tumors in BRCA1 mutation carriers were more likely than tumors in age-matched controls to be invasive serous adenocarcinomas (odds ratio, 1.84; 95% confidence interval, 1.21-2.79) and unlikely to be borderline or mucinous tumors. Tumors in BRCA1 carriers were of higher grade (P 〈 0.0001), had a higher percentage solid component (P 0.001), and were more likely to stain strongly for p53 (P = 0.018). The distribution of pathological features in BRCA2 carriers was similar to that in BRCA1 carriers.Conclusions: Use of pathological features can substantially improve the targeting of predictive genetic testing. Results also suggest that BRCA1 and BRCA2 tumors are relatively. aggressive and may be expected to have poor prognosis, although this may be treatment dependent
    Type of Publication: Journal article published
    PubMed ID: 15073127
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  • 4
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    Radiologe 44 (2), 177-179 
    Keywords: CANCER
    Type of Publication: Journal article published
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  • 5
    Keywords: CANCER ; Germany ; CLASSIFICATION ; DIAGNOSIS ; IMAGES ; TISSUE ; ACCURACY ; CONTRAST ; MAGNETIC-RESONANCE ; BREAST ; LESIONS ; REGION ; PARAMETERS ; BENIGN ; CURVES ; GD-DTPA ; TRACER ; SUBSET ; ENHANCEMENT ; BREAST-TUMORS ; contrast-enhanced ; ARTIFICIAL NEURAL-NETWORKS ; breast lesions ; MR mammography ; MR-MAMMOGRAPHY
    Abstract: Objective: This study compares the performance of quantitative methods for the characterization of signal-time curves acquired by dynamic contrast-enhanced magnetic resonance mammography from 253 females. Materials and Methods: Signal-time curves obtained from 105 parenchyma, 162 malignant, and 91 benign tissue regions were examined (243 lesions were histopathologically validated). A neural network, a nearest-neighbor, and a threshold classifier were applied to either the entire signal-time curve or pharmacokinetic and descriptive parameters calculated from the curves to differentiate between 2 (malignant or benign) or 3 tissue classes (malignant, benign, or parenchyma). The classifiers were tuned and evaluated according to their performance on 2 distinct subsets of the curves. Results: The accuracy determined for the neural network and the nearest-neighbor classifiers was nearly identical (approximately 80% in case of 3 tissue classes, and approximately 76% in case of the 2 classes). In contrast, the accuracy of the threshold classifier applied to the discrimination of 3 classes was low (65%). Conclusion: Quantitative classifiers can support the radiologist in the diagnosis of breast lesions
    Type of Publication: Journal article published
    PubMed ID: 15973136
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  • 6
    Keywords: CANCER ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; INHIBITION ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; RNA ; cell line ; MOLECULES ; LINES ; ACTIVATION ; DNA ; MECHANISM ; prognosis ; mechanisms ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CELL-LINES ; CYCLE ; DOWN-REGULATION ; FREQUENCY ; FREQUENCIES ; MOLECULE ; TARGET ; IDENTIFICATION ; PATTERNS ; gene expression ; CELL-LINE ; LINE ; DNA methylation ; DEGRADATION ; TARGETS ; cell lines ; METHYLATION ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; HUMAN CANCER ; TUMORIGENESIS ; CPG ISLANDS ; analysis ; HUMAN CANCER-CELLS ; USA ; function ; HUMAN CANCERS ; CPG-ISLAND METHYLATION ; CANDIDATE ; CANCERS ; CpG island ; DNA-METHYLATION ; MICRORNA ; epimutation
    Abstract: MicroRNAs ( miRNAs) are small RNA molecules that control gene expression by inhibition of protein translation or by degradation of cognate target mRNAs. Even though strict developmental and tissue-specific regulation appears to be critical for miRNA function, very little is known about the mechanisms governing miRNA gene expression. Several recent studies have shown that miRNA genes can be regulated by DNA methylation and other epigenetic mechanisms. The observation of altered miRNA gene methylation patterns in human cancers also suggested that miRNA gene methylation is functionally relevant for tumorigenesis. We have now performed a comprehensive analysis of miRNA genes and found that about half of these genes are associated with CpG islands and thus represent candidate targets of the DNA methylation machinery. An expanded analysis of several miRNA-associated CpG islands in five cell lines indicated that miRNA gene methylation is detectable at high frequencies, both in normal and malignant cells. Possible explanations for this phenomenon include the specific structure of miRNA genes and/or their requirement for strict expression regulation
    Type of Publication: Journal article published
    PubMed ID: 17457051
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  • 7
    Keywords: CANCER ; evaluation ; Germany ; AUSTRALIA ; comparison
    Type of Publication: Journal article published
    PubMed ID: 17676295
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  • 8
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    Journal of Nuclear Medicine 49 (Suppl. 2), 43S-63S 
    Keywords: CANCER ; CANCER CELLS ; CELLS ; tumor ; CELL ; CLINICAL-TRIAL ; Germany ; THERAPY ; imaging ; METABOLISM ; NUCLEAR-MEDICINE ; radiation ; PATIENT ; ACTIVATION ; MECHANISM ; IMPACT ; mechanisms ; MRI ; MAGNETIC-RESONANCE-SPECTROSCOPY ; molecular imaging ; ACID ; TRIAL ; TRIALS ; CLINICAL-TRIALS ; CANCER-CELLS ; ONCOGENE ; POSITRON-EMISSION-TOMOGRAPHY ; GLUCOSE ; treatment planning ; PET ; nuclear medicine ; MANAGEMENT ; PROTON MR SPECTROSCOPY ; MAMMARY EPITHELIAL-CELLS ; radiology ; molecular ; review ; ADVANCED BREAST-CANCER ; THERAPIES ; monitoring ; ALPHA-METHYL TYROSINE ; MOLECULAR-MECHANISMS ; NUCLEAR ; HIGH-GRADE GLIOMAS ; technique ; optical imaging ; USA ; MEDICINE ; clinical trial ; FATTY-ACID SYNTHASE ; VA ; glucose metabolism ; amino acid metabolism ; CHOLINE KINASE-ALPHA ; lipid metabolism ; RECURRENT PROSTATE-CANCER
    Abstract: Molecular imaging of tumor metabolism has gained considerable interest, since preclinical studies have indicated a close relationship between the activation of various oncogenes and alterations of cellular metabolism. Furthermore, several clinical trials have shown that metabolic imaging can significantly impact patient management by improving tumor staging, restaging, radiation treatment planning, and monitoring of tumor response to therapy. In this review, we summarize recent data on the molecular mechanisms underlying the increased metabolic activity of cancer cells and discuss imaging techniques for studies of tumor glucose, lipid, and amino acid metabolism
    Type of Publication: Journal article published
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  • 9
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; IONIZING-RADIATION ; IRRADIATION ; proliferation ; radiotherapy ; SURVIVAL ; tumor ; AGENTS ; CELL ; CELL-PROLIFERATION ; COMBINATION ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; PROSTATE ; THERAPY ; tumor growth ; VITRO ; DENSITY ; DRUG ; TUMORS ; MICE ; radiation ; PATIENT ; MECHANISM ; INDEX ; TYROSINE KINASE INHIBITOR ; DESIGN ; UP-REGULATION ; prostate cancer ; PROSTATE-CANCER ; DAMAGE ; MUSCLE ; MIGRATION ; experimental design ; CELL-MIGRATION ; TUMOR ANGIOGENESIS ; VEGF ; signaling ; AGENT ; ONCOLOGY ; RE ; antiangiogenesis ; SU5416 ; TUMOR-GROWTH ; THERAPIES ; INCREASE ; cell proliferation ; cell migration ; USA ; vascular endothelial growth factor ; cancer research ; GLIOBLASTOMA ; GROWTH-FACTOR-RECEPTOR ; SMOOTH-MUSCLE-CELLS ; ENDOTHELIAL GROWTH ; MUSCLE-CELLS ; tumor therapy ; radiation dose ; FRACTIONATED-IRRADIATION ; SU6668
    Abstract: Purpose: Investigations on the combination of radiotherapy with vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) antiangiogenic agents, which has the potential to improve the clinical outcome in cancer patients. Experimental Design: Here, we analyze the combined VEGF (SU5416) and PDGF (SU6668) receptor tyrosine kinase inhibition with irradiation in human endothelium (HUVEC), prostate cancer (PC3), and glioblastoma (U87) in vitro and in vivo. Results: Combined inhibition of VEGF and PDGF signaling resulted in enhanced apoptosis, reduced cell proliferation, and clonogenic survival as well as reduced endothelial cell migration and tube formation compared with single pathway inhibition. These effects were further enhanced by additional irradiation. Likewise, in PC3 and U87 tumors growing s.c. on BALB/c nu/nu mice, dual inhibition of VEGF and PDGF signaling significantly increased tumor growth delay versus each monotherapy. Interestingly, radiation at similar to 20% of the dose necessary to induce local tumor control exerts similar tumor growth-inhibitory effects as the antiangiogenic drugs given at their maximum effective dose. Addition of radiotherapy to both mono- as well as dual-antiangiogenic treatment markedly increased tumor growth delay. With respect to tumor angiogenesis, radiation further decreased microvessel density (CD31 count) and tumor cell proliferation (Ki-67 index) in all drug-treated groups. Of note, the slowly growing PC3 tumor responded better to the antiangiogenic drug treatments than the faster-growing U87 tumor. In addition to the beneficial effect of abrogating VEGF survival signaling when combined with radiation, we identified here a novel mechanism for the tumor escape from radiation damage. We found that radiation induced up-regulation of all four isoforms of PDGF (A-D) in endothelial cells supporting adjacent smooth muscle cells resulting in a prosurvival effect of radiation. The addition of SU6668 attenuated this undesirable paracrine radiation effect, which may rationalize the combined application of radiation with PDGF signaling inhibition to increase antitumor effects. Conclusion: A relative low radiation dose markedly enhances local antitumor effects of combined VEGF and PDGF signaling inhibition, suggesting a promising combination regimen for local tumor treatment with radiotherapy remaining an essential element
    Type of Publication: Journal article published
    PubMed ID: 18381963
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  • 10
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; proliferation ; SURVIVAL ; tumor ; carcinoma ; CELL ; Germany ; IN-VIVO ; PATHWAY ; VIVO ; DEATH ; DISEASE ; HEPATOCELLULAR-CARCINOMA ; liver ; PROTEIN ; TUMORS ; MICE ; MECHANISM ; FAMILY ; MARKER ; CARCINOGENESIS ; DELETION ; hepatocellular carcinoma ; CELL-DEATH ; AGE ; DAMAGE ; REGULATOR ; MITOSIS ; Bcl-2 ; INJURY ; HUMAN CANCER ; SURVIVIN ; cell death ; CANCERS ; HOMEOSTASIS ; HUMAN HEPATOCELLULAR-CARCINOMA ; MCL-1 ; LIVER-REGENERATION
    Abstract: Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes toward apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and nonresponsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the antiapoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1(Delta hep)), spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in 〉50% of Mcl-1(Delta hep) mice already by the age of 8 months, whereas 12-month-old wild-type (wt) and heterozygous Mcl-1(flox/wt) mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1(Delta hep) mice was paralleled by markedly increased levels of Survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers. Conclusion: This study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases. (HEPATOLOGY 2010;51:1226-1236.)
    Type of Publication: Journal article published
    PubMed ID: 20099303
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