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  • 1
    Call number: YY Diss Stoe/Mag
    Keywords: DKFZ-publications / academic dissertations
    Pages: v, 83 p.
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  • 2
    ISSN: 0075-4617
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 3
    Keywords: CELLS ; GROWTH-FACTOR ; IRRADIATION ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; KINASE ; DENSITY ; LINES ; RELEASE ; PATIENT ; prognosis ; CELL-LINES ; PHOSPHORYLATION ; MOLECULE ; CLEAVAGE ; DESIGN ; CARCINOMA CELLS ; MEMBRANE ; NECROSIS-FACTOR-ALPHA ; LINE ; ADHESION ; MIGRATION ; CARCINOMAS ; L1 ; MALIGNANT-MELANOMA ; ADHESION MOLECULE ; ECTODOMAIN ; MEDIATED RELEASE ; ovarian carcinoma ; cell lines ; CELL-MIGRATION ; SERUM ; ELISA ; FEATURES ; RE ; CONVERTING-ENZYME ; cell migration ; ADHESION MOLECULE L1 ; CD171 ; CELLULAR CHOLESTEROL ; PROHB-EGF
    Abstract: Purpose: The L1 adhesion molecule (CD171) is overexpressed in human ovarian and endometrial carcinomas and is associated with bad prognosis. Although expressed as a transmembrane molecule, L1 is released from carcinoma cells in a soluble form. Soluble L1 is present in serum and ascites of ovarian carcinoma patients. We investigated the mode of L1 cleavage and the function of soluble L1. Experimental Design: We used ovarian carcinoma cell lines and ascites from ovarian carcinoma patients to analyze soluble L1 and L1 cleavage by Western blot analysis and ELISA. Results: We find that in ovarian carcinoma cells the constitutive cleavage of L1 proceeds in secretory vesicles. We show that apoptotic stimuli like C-2-ceramide, staurosporine, UV irradiation, and hypoxic conditions enhance L1-vesicle release resulting in elevated levels of soluble L1. Constitutive cleavage of L1 is mediated by a disintegrin and metalloproteinase 10, but under apoptotic conditions multiple metalloproteinases are involved. L1 cleavage occurs in two types of vesicles with distinct density features: constitutively released vesicles with similarity to exosomes and apoptotic vesicles. Both types of L1-containing vesicles are present in the ascites fluids of ovarian carcinoma patients. Soluble L1 from ascites is a potent inducer of cell migration and can trigger extracellular signal-regulated kinase phosphorylation. Conclusions: We suggest that tumor-derived vesicles may be an important source for soluble L1 that could regulate tumor cell function in an autocrine/paracrine fashion
    Type of Publication: Journal article published
    PubMed ID: 15814625
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; carcinoma ; MODEL ; MODELS ; VITRO ; DEATH ; PROTEIN ; TISSUE ; LINES ; MESSENGER-RNA EXPRESSION ; TISSUES ; CELL-LINES ; ALPHA ; MOUSE ; PATTERNS ; PLASMA ; ovarian cancer ; COUNTRIES ; CELL-LINE ; LINE ; PLASMA-MEMBRANE ; CARCINOMAS ; RT-PCR ; specificity ; ovarian carcinoma ; cell lines ; MOLECULAR-CLONING ; VESICLES ; PRODUCTS ; LEVEL ; ENZYME ; EXPRESSION PATTERNS ; CANCERS ; OVARIAN ; ALPHA-1,3/4-FUCOSYL-TRANSFERASES ; carbohydrate ; fucosyltransferase ; HUMAN ADENOCARCINOMA ; HUMAN ALPHA(1,3)FUCOSYLTRANSFERASE GENE ; Lewis determinant ; TYPE-2 CHAIN
    Abstract: Ovarian carcinoma is the leading cause of death from gynecological cancers in many countries. Fucosylated glycoconjugates have been associated with various carcinomas. In the present study, we have characterized the expression of alpha 3/4 fucosyltransferases transcripts and their products, the Lewis carbohydrate determinants, and their in vitro specificity towards synthetic acceptors using ovarian carcinoma cell lines OVM, m130, GG and SKOV3. We found different expression patterns: GG cells expressed mostly Lewis(x) (Le(x)), Lewis(y) (Le(y)), sLe(a) and Le(b), and m130 cells expressed mostly Le(x) and Le(y). The detection was on the plasma membrane and in intracellular vesicles. OVM and SKOV3 cells had very low amounts of staining. From RT-PCR studies, enzyme specificity of cellular extracts towards a panel of synthetic carbohydrate acceptors and Western blot analysis we concluded that Le(a), sLe(a) and Le(b) were synthesised by FUT3, whereas Le(x) and Le(y) were synthesized by FUT4 and FUT9 in both cell lines. The GG and m130 cell lines are adequate models to investigate the role of Le(x), Le(y), sLe(a) and Le(b) in ovarian carcinoma development
    Type of Publication: Journal article published
    PubMed ID: 16865271
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  • 5
    Keywords: CELLS ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; RELEASE ; MECHANISM ; CLEAVAGE ; PRECURSOR PROTEIN ; L1 ; ADHESION MOLECULE ; ovarian carcinoma ; CD44 ; RE ; VESICLES ; OVARIAN CARCINOMAS ; CELLULAR CHOLESTEROL ; exosome ; METALLOPROTEINASE ; ectodomain shedding ; CALCIUM INFLUX ; ALPHA-CONVERTING-ENZYME ; ADAM (a disintegrin and metalloproteinase) ; DEPENDENT MECHANISM
    Abstract: Ectodomain shedding is a proteolytic mechanism by which transmembrane molecules are converted into a soluble form. Cleavage is mediated by metalloproteases and proceeds in a constitutive or inducible fashion. Although believed to be a cell-surface event, there is increasing evidence that cleavage can take place in intracellular compartments. However, it is unknown how cleaved soluble molecules get access to the extracellular space. By analysing L1 (CD171) and CD44 in ovarian carcinoma cells, we show in the present paper that the cleavage induced by ionomycin, APMA (4-aminophenylmercuric acetate) or MCD (methyl-beta-cyclodextrin) is initiated in an endosomal compartment that is subsequently released in the form of exosomes. Calcium influx augmented the release of exosomes containing functionally active forms of ADAM10 (a disintegrin and metalloprotease 10) and ADAM 17 [TACE (tumour necrosis factor alpha-converting enzyme)] as well as CD44 and L1 cytoplasmic cleavage fragments. Cleavage could also proceed in released exosomes, but only depletion of ADAM 10 by small interfering RNA blocked cleavage under constitutive and induced conditions. In contrast, cleavage of L1 in response to PMA occurred at the cell surface and was mediated by ADAM17. We conclude that different ADAMs are involved in distinct cellular compartments and that ADAM10 is responsible for shedding in vesicles. Our findings open up the possibility that exosomes serve as a platform for ectodomain shedding and as a vehicle for the cellular export of soluble molecules
    Type of Publication: Journal article published
    PubMed ID: 16229685
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  • 6
    Keywords: RECEPTOR ; ANGIOGENESIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; tumor ; TUMOR-CELLS ; carcinoma ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; human ; PATHWAY ; SYSTEM ; PROTEIN ; TISSUE ; TUMORS ; LINES ; PATIENT ; COMPLEX ; COMPLEXES ; MARKER ; prognosis ; TISSUES ; BINDING ; CELL-LINES ; SIGNAL ; NERVOUS-SYSTEM ; PROGRESSION ; ovarian cancer ; OVARIAN-CANCER ; CELL-LINE ; FUSION ; LINE ; CANCER-CELLS ; ADHESION ; INTEGRIN ; CARCINOMAS ; RT-PCR ; L1 ; NEURITE OUTGROWTH ; ADHESION MOLECULE ; L1 adhesion molecule ; ovarian carcinoma ; OVEREXPRESSION ; cell lines ; TUMOR CELLS ; PERMEABILITY ; RE ; TUMOR-GROWTH ; cell adhesion ; LEVEL ; TUMOR-CELL ; ADHESION MOLECULE L1 ; OVARIAN CARCINOMAS ; function ; SIGNALS ; OVARIAN ; VARIETIES ; VASCULAR-PERMEABILITY ; heterophilic binding ; mesothelial cells ; MOUSE LEUKOCYTES ; neuropilin-1 ; SEMAPHORIN-III
    Abstract: The progression of ovarian cancer is driven by a variety of cellular factors that are incompletely understood. Binding of tumor cells to normal cells and to soluble factors influence tumor growth, angiogenesis and the stimulation of vascular permeability leading to ascites production. L1 adhesion molecule is overexpressed in ovarian carcinoma and is associated with bad prognosis. One receptor for L1 is Neuropilin-1 (NRP-1) that is also known as a receptor for VEGF(165). In the nervous system a complex of NRP-1 and L1 transmits signals by the neurorepellant Sem3A that is critical for the control of neurite outgrowth. NRP-1 has also been detected in human carcinomas but its function remains unknown. Here, we have examined NRP-1 expression in ovarian carcinoma cell lines and tissue. We report that little NRP-1 protein was detected in primary ovarian carcinoma tissues or established cell lines although mRNA for soluble and transmembrane NRP-1 were detected by RT-PCR. Instead, we observed strong expression of NRP-1 in mesothelial cells, which form the lining of the peritoneum. NRP-1 could serve as an isolation marker for primary mesothelial cells present in ascites fluid. We demonstrate that ovarian cancer cells expressing L1 can bind to NRP-1 overexpressing cells and mesothelial cells. Likewise, soluble L1 isolated from ascites of patients or produced as a fusion protein could bind to NRP-1 overexpressing cells and a direct interaction was demonstrated at the protein level. These findings suggest that L1 can support the binding of ovarian carcinoma cells to mesothelial cells via NRP-1. The L1-NRP-1 binding pathway could contribute to the growth of ovarian carcinomas and to reciprocal signalling between mesothelial cells and tumors. (c) 2005 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16377081
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  • 7
    Keywords: brain ; EXPRESSION ; IN-VITRO ; CELL ; IN-VIVO ; PATHWAY ; PATHWAYS ; VITRO ; GENERATION ; NEW-YORK ; MICE ; RESPONSES ; DOMAIN ; BINDING ; MOLECULE ; DELETION ; MOUSE ; NERVOUS-SYSTEM ; LINE ; ADHESION ; CELL-ADHESION ; INTEGRIN ; TRACT ; NEURITE OUTGROWTH ; PROJECT ; MICE LACKING ; adhesion,hydrocephalus,L1cam,corticospinal tract,integrin ; CELL-CELL ADHESION ; COLLAPSING ACTIVITY ; L1 KNOCKOUT MICE ; MOLECULE L1 ; NR-CAM ; SEMAPHORIN 3A
    Abstract: A new mouse line has been produced in which the A sixth 1g domain of the L1 cell adhesion molecule has been deleted. Despite the rather large deletion, L1 expression is preserved at normal levels. in vitro experiments showed that L1-L1 homophilic binding was lost, along with L1-alpha5beta1 integrin binding. However, L1-neurocan and L1-neuropilin binding were preserved and sema3a responses were intact. Surprisingly, many of the axon guidance defects present in the L1 knockout mice, such as abnormal corticospinal tract and corpus callosum, were not observed. Nonetheless, when backcrossed on the C57BL/6 strain, a severe hydrocephalus was observed and after several generations, became an embryonic lethal. These results imply that L1 binding to L1, TAG-1, or F3, and L1-alpha5beta1 integrin binding are not essential for normal development of a variety of axon pathways, and suggest that L1-L1 homophilic binding is important in the production of X-linked hydrocephalus
    Type of Publication: Journal article published
    PubMed ID: 15067019
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  • 8
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; BLOOD ; CELL ; Germany ; NEW-YORK ; PROTEIN ; MICE ; RELEASE ; kidney ; MARKER ; ANTIGEN ; T-CELLS ; treatment ; CLEAVAGE ; knockout ; MEMBRANE ; WOMEN ; SURFACE ; INDIVIDUALS ; L1 ; CALCIUM ; BODY ; ADHESION MOLECULE ; membrane vesicles ; MEMBRANE-VESICLES ; CD24 ; URINE ; AGENT ; BODIES ; RE ; VESICLES ; secretion ; interaction ; KNOCKOUT MICE ; USA ; BIOGENESIS ; PODOCYTES ; exosome ; OVARIAN-CARCINOMA CELLS ; exosomes ; amniotic fluid ; INFANT
    Abstract: Exosomes are small membrane vesicles that are secreted from a variety of cell types into various body fluids including the blood and urine. These vesicles are thought to play a role in cell-cell interactions. CD24 is a small but extensively glycosylated protein linked to the cell surface by means of a glycosyl-phosphatidylinositol anchor. In this study we found that CD24 is present in membrane vesicles characterized as exosomes that were isolated from the urine of normal individuals. CD24 was expressed by both tubule cells and podocytes and treatment of the latter with a cholesterol-extracting agent, but not with a calcium ionophore, caused the release of CD24-containing exosomes. Using CD24 as a marker, we found exosomes in the urine of newborn infants and in the amniotic fluid of pregnant women with similar findings made in mice. Interestingly, studies with CD24 knockout mice showed that the exosomes are released from the fetus but not from the mother; however, exosome release was similar from both the knockout and the wild-type mice. This indicates that CD24 is not essential for exosome formation or release but may be a convenient exosome marker. Our studies suggest that exosomal secretion from the embryonic kidney could play a biological role at the fetal-maternal interphase
    Type of Publication: Journal article published
    PubMed ID: 17700640
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  • 9
    Keywords: EXPRESSION ; SURVIVAL ; tumor ; carcinoma ; Germany ; PROTEINS ; PATIENT ; FAMILY ; PROGRESSION ; METASTASIS ; INTEGRIN ; L1 ; MALIGNANT-MELANOMA ; ECTODOMAIN ; MEDIATED RELEASE ; CELL-ADHESION MOLECULE ; METALLOPROTEASE ; ovarian carcinoma ; SEROUS CARCINOMA
    Abstract: Background Ovarian and uterine carcinomas are the most common cause of cancer-related deaths in gynecological malignant diseases. We aimed to assess whether the L1 adhesion molecule, an important mediator for cell migration for neural and tumour cells, is expressed in these carcinomas, Methods We investigated L1 expression by immunohistochemistry, RT-PCR, and Western blot analysis of tumour samples. Soluble L1 in the serum was detected by ELISA and immunoprecipitation. Findings We detected the L1 adhesion molecule in ovarian and uterine tumours in a stage-dependent manner. In a retrospective study L1 was found in 46 of 58 ovarian carcinomas and 20 of 72 uterine adenocarcinomas. L1 expression was an excellent predictor of poor outlook (p〈0.00001). Patients with L1 positive uterine tumours were at high risk for progression even in the endometrioid-type tumours, which usually have a favourable prognosis. In uterine tumours, expression of L1 in curettage samples enabled us to identify aggressive tumours before the operation. Soluble L1 was specifically detected in serum samples from patients with ovarian and uterine tumours. ADAM10, which was implicated in previous studies as L1 sheddase, was expressed in tumours in which soluble L1 was present in the serum. Interpretation L1 is overexpressed in ovarian and uterine carcinomas and is associated with short survival. L1 can serve as a new marker for prediction of clinical outcome and could be helpful to identify patients with uterine tumours who are at high risk for recurrent disease. L1 expression and cleavage could promote dissemination of tumours by facilitating cell migration.
    Type of Publication: Journal article published
    PubMed ID: 13678974
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  • 10
    Keywords: CELLS ; IN-VITRO ; tumor ; TUMOR-CELLS ; CELL ; Germany ; PATHWAY ; PATHWAYS ; COMPONENTS ; RELEASE ; TRIGGER ; treatment ; SIGNAL ; MOLECULE ; CLEAVAGE ; FORM ; MEMBRANE ; COMPONENT ; endocytosis ; SIGNALING PATHWAY ; SURFACE ; LOCALIZATION ; ADHESION ; INTRACELLULAR DOMAIN ; MIGRATION ; Golgi apparatus ; GOLGI-APPARATUS ; cholesterol ; L1 ; LIPID RAFTS ; ADHESION MOLECULE ; ECTODOMAIN ; L1 adhesion molecule ; MEDIATED RELEASE ; CELL-SURFACE ; AMYLOID PRECURSOR PROTEIN ; BETA-SECRETASE ; CELL-MIGRATION ; CHOLESTEROL DEPLETION ; GOLGI ; HUMAN TUMOR-CELLS ; membrane vesicles ; MEMBRANE-VESICLES ; methyl-beta-cyclodextrin ; PHORBOL ESTER ; PHORBOL-ESTER ; protease ; shedding ; TUMOR CELLS
    Abstract: Cells can release membrane components in a soluble form and as membrane vesicles. L1, an important molecule for cell migration of neural and tumor cells, is released by membrane-proximal cleavage, and soluble L1 promotes cell migration. Release of L1 is enhanced by shedding inducers such as phorbol ester and pervanadate, but it is also enhanced by depletion of cellular cholesterol with methyl-beta-cyclodextrin (MCD). How such different compounds can induce shedding is presently unknown. We show here that ADAM10 is involved in L1 cleavage, which occurs at the cell surface and in the Golgi apparatus. MCD and pervanadate treatment induced the release of microvesicles containing full-length L1 and the active form of ADAM10. L1 cleavage occurred in isolated vesicles. L1-containing microvesicles could trigger haptotactic cell migration. Only the neural L1 form carrying the RSLE signal for clathrin- dependent endocytosis was recruited and cleaved in vesicles. Phorbol ester treatment activated L1 cleavage predominantly at the cell surface. Our results provide evidence for two pathways of L1 cleavage, based on ADAM10 localization, that can be activated differentially: 1) direct cleavage at the cell surface, and 2) release and cleavage in secretory vesicles most likely derived from the Golgi apparatus. The findings establish a novel role for ADAM10 as a vesicle-based protease
    Type of Publication: Journal article published
    PubMed ID: 12475894
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