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  • 1
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    German Medical Science; Düsseldorf, Köln
    In:  56. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 3èmes journées françaises de Neurochirurgie (SFNC); 20050507-20050511; Strasbourg; DOCP168 /20050504/
    Publication Date: 2005-05-05
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; tumor ; PATHWAY ; THERAPY ; GENE ; GENE-EXPRESSION ; TUMORS ; ACTIVATION ; DOMAIN ; colon ; SUPPRESSION ; MOLECULE ; IDENTIFICATION ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; CANCER-CELLS ; COLON-CANCER ; MUTATIONS ; LOCALIZATION ; ADHESION ; TRANSFORMATION ; COLORECTAL CARCINOMAS ; L1 ; beta-catenin ; ADHESION MOLECULE ; INITIATION ; CYCLIN D1 ; signaling ; SERUM ; colon cancer ; COLON CANCERS ; cancer therapy ; TUMORIGENESIS ; cell adhesion ; TARGET GENE ; ADHESION MOLECULE L1 ; OVARIAN CARCINOMAS ; TUMOR ENVIRONMENT
    Abstract: Aberrant beta-catenin-TCF target gene activation plays a key role in colorectal cancer, both in the initiation stage and during invasion and metastasis. We identified the neuronal cell adhesion molecule L1, as a target gene of beta-catenin-TCF signaling in colorectal cancer cells. L1 expression was high in sparse cultures and coregulated with ADAM10, a metalloprotease involved in cleaving and shedding L1's extracellular domain. L1 expression conferred increased cell motility, growth in low serum, transformation and tumorigenesis, whereas its suppression in colon cancer cells decreased motility. L1 was exclusively localized in the invasive front of human colorectal tumors together with ADAM10. The transmembrane localization and shedding of L1 by metalloproteases could be useful for detection and as target for colon cancer therapy
    Type of Publication: Journal article published
    PubMed ID: 15716380
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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 ; CELLS ; EXPRESSION ; GROWTH ; tumor ; carcinoma ; CELL ; Germany ; human ; tumor growth ; SYSTEM ; SITE ; GENE ; GENE-EXPRESSION ; GENES ; TUMORS ; LINES ; MICE ; LIGAND ; prognosis ; DOMAIN ; BINDING ; BIOLOGY ; CELL-LINES ; MOLECULE ; ALPHA ; antibodies ; antibody ; MUTANT ; NERVOUS-SYSTEM ; METASTASIS ; NUDE-MICE ; CELL-LINE ; BETA ; ADHESION ; MIGRATION ; INTEGRIN ; CARCINOMAS ; HOMOPHILIC BINDING ; L1 ; MALIGNANT-MELANOMA ; NEURITE OUTGROWTH ; ADHESION MOLECULE ; CELL-ADHESION MOLECULE ; signaling ; ONCOLOGY ; RE ; TUMOR-GROWTH ; cell adhesion ; gene regulation ; INTEGRINS ; cell migration ; RGD ; NUCLEAR ; USA ; MOTILITY ; OVARIAN-CARCINOMA CELLS ; L1CAM ; CELL MOTILITY ; CELL BIOLOGY ; CELL ADHESION MOLECULE
    Abstract: L1 cell adhesion molecule (L1-CAM) is a transmembrane cell adhesion molecule initially defined as a promigratory molecule in the developing nervous system. L1 is also overexpressed in a variety of human carcinomas and is associated with bad prognosis. In carcinoma cell lines L1 augments cell motility and metastasis, tumor growth in nude mice and induces expression of L1-dependent genes. It is not known whether L1-signaling requires ligand binding. The RGD motif in the sixth Ig domain of L1 is a binding site for integrins. In the present study we analyzed the role of RGDs in L1-signaling using site-directed mutagenesis combined with antibody blocking studies. We observed that L1-RGE expressing HEK293 cells showed reduced cell-cell binding, cell motility, invasiveness and tumor growth in NOD/SCID mice. The RGE-mutation impaired L1-dependent gene regulation and antibodies to alpha v beta 5 integrin had similar effects. Mutant L1 was unable to translocate to the nucleus. our findings highlight the importance of the RGD site in L1 for human tumors and suggest that nuclear signaling of L1 is dependent on integrins. (c) 2008 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18555990
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  • 5
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; carcinoma ; CELL ; Germany ; DISEASE ; PROTEIN ; SAMPLE ; SAMPLES ; PATIENT ; prognosis ; BIOLOGY ; MOLECULE ; culture ; immunohistochemistry ; ASSAY ; CARCINOMA CELLS ; OVARIAN-CANCER ; WOMEN ; ADHESION ; INTEGRIN ALPHA(V)BETA(3) ; NEURITE OUTGROWTH ; PREVALENCE ; ADHESION MOLECULE ; MEDIATED RELEASE ; HUMAN TUMOR-CELLS ; quantitative RT-PCR ; cell adhesion ; LEVEL ; analysis ; methods ; ENGLAND ; SHORT-TERM ; L1CAM ; quantitative ; MEDIA ; RAT MODEL ; atypical endometriosis ; endometriosis ; OVARIAN ENDOMETRIOSIS ; PERITONEAL-FLUID
    Abstract: BACKGROUND: Endometriosis is a benign and progressive disease with a high prevalence. Women with endometriosis, especially with atypical endometriosis, have a higher probability for developing ovarian cancer compared with women without endometriosis. The L1 cell adhesion molecule (L1CAM) is over expressed in ovarian and endometrial carcinomas and is associated with a bad prognosis. Here, we have analysed L1CAM expression in endometriosis. METHODS AND RESULTS: In our study with the samples from 79 patients with, and 37 patients without, endometriosis, we found that endometriosis cell lines and short-term cultures of endometrium from women with endometriosis expressed L1CAM at the mRNA and protein level. Quantitative RT-PCR analysis showed that L1CAM was expressed at significantly higher level in the epithelial compartment from patients with endometriosis compared with healthy controls (P= 0.0126). By immunohistochemical staining, 15 of 31 ovarian endometriotic lesions (48%) were shown to have L1CAM-positive staining. Of these 15 L1CAM-positive samples, 13 were atypical endometriotic lesions. Soluble L1 present in the conditioned medium of epithelial endometrium cultures from women with endometriosis was able to stimulate neurite outgrowth as measured in a chicken ganglion assay. CONCLUSIONS: We propose that L1CAM could promote endometriosis development by increasing enervation and aggravation. L1CAM expression is higher in atypical endometriosis compared with normal endometriosis
    Type of Publication: Journal article published
    PubMed ID: 18332088
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  • 6
    Keywords: CANCER CELLS ; CELLS ; EXPRESSION ; TUMOR-CELLS ; CELL ; INHIBITION ; DRUG ; ACTIVATION ; MECHANISM ; mechanisms ; BINDING ; CELL-LINES ; MIGRATION ; INTEGRIN ; chemoresistance ; TUMOR-GROWTH ; pancreatic adenocarcinoma ; ADHESION MOLECULE L1 ; caspases ; OVARIAN-CARCINOMA CELLS ; neuropilin-1 ; L1CAM
    Abstract: We recently showed that the adhesion molecule LICAM (CD171) is overexpressed in pancreatic adenocarcinoma (PDAC) essentially contributing to chemoresistance of PDAC cells. In search of the mechanisms of this effect we now identified alpha 5-integrin as the LICAM ligand being essential for LICAM-mediated chemoresistance of these highly malignant tumor cells. Thus, blockade or knock-down of alpha 5-integrin in the LICAM expressing PDAC cell lines PT45-P1res, Colo357 and Panel increased anti-cancer drug sensitivity. In line with the previously reported NO-dependent caspase inhibition resulting from LICAM induced iNOS expression, the loss of chemoresistance upon alpha 5-integrin inhibition was preceded by decreased iNOS expression and enhanced caspase-3/-7 activation. Accordingly, the loss of anti-cancer drug protection by alpha 5-integrin inhibition Could anti be overcome by administration of the NO-donor SNAP. Moreover, the gain of chemoresistance of parental PT45-P1 cells when transfected with LICAM was abrogated by alpha 5-integrin inhibition, whereas transfection of PT45-P1 cells with an integrin binding-deficient LICAM mutant (L1mutRGE) (lid neither induce chemoresistance or iNOS expression nor conferred sensitivity to alpha 5-integrin inhibition as seen upon transfection with wild-type LICAM. Thus, mutational loss of the integrin binding site in the LICAM molecule or the
    Type of Publication: Journal article published
    PubMed ID: 19082495
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  • 7
    Keywords: CELLS ; GROWTH ; INHIBITOR ; INVASION ; carcinoma ; CELL ; Germany ; human ; INHIBITION ; MODEL ; GENE ; GENE-EXPRESSION ; ACCUMULATION ; LINES ; MICE ; RELEASE ; TIME ; MECHANISM ; DOMAIN ; BINDING ; BIOLOGY ; CELL-LINES ; MOLECULE ; CLEAVAGE ; PROGRESSION ; CARCINOMA CELLS ; METASTASIS ; COLORECTAL-CANCER ; NUDE-MICE ; CELL-LINE ; CARCINOMA-CELLS ; LOCALIZATION ; CELL-ADHESION ; INTRACELLULAR DOMAIN ; MIGRATION ; L1 ; LIPID RAFTS ; TRANSLOCATION ; L1 adhesion molecule ; OVEREXPRESSION ; cell lines ; AMYLOID PRECURSOR PROTEIN ; DOMAINS ; molecular biology ; regulation ; NUCLEAR TRANSLOCATION ; cell adhesion ; raft ; signalling ; MOTILITY ; PROMOTES ; L1CAM ; lipid ; nuclear localization ; ADAM10 ; DISINTEGRIN ; 3 ; a disintegrin and metalloprotease 10 (ADAM10) ; GAMMA-SECRETASE ; L1 cell-adhesion molecule (L1-CAM) ; presenilin (PS)/gamma-secretase activity
    Abstract: L1-CAM (L1 cell-adhesion molecule), or more simply L1, plays an important role ill the progression of human carcinoma. Overexpression promotes tumour-cell invasion and motility, growth in nude mice and tumour metastasis. It is feasible that L1-dependent signalling contributes to these effects, However, little is known about its mechanism in tumour cells. We reported previously that L1 is cleaved by ADAM (a disintegrin and metalloprotease) and that the cytoplasmic part is essential for L1 function. Here we analysed more closely the role of proteolytic cleavage in L1-mediated nuclear signalling. Using OVMz carcinoma cells and L1-transfected cells as a model, we found that ADAM 10-mediated cleavage of L1 proceeds in lipid raft and non-raft domains. The cleavage product, L1-32, is further processed by PS (presenilin)/gamma-secretase to release L1-ICD, an L1 intracellular domain of 28 kDa. Overexpression of dominant-negative PSI or use of a specific gamma-secretase inhibitor leads to all accumulation of L1-32. Fluorescence and biochemical analysis revealed a nuclear localization for L1-ICD. Moreover, inhibition of ADAM10 and/or gamma-secretase blocks nuclear translocation of L1-ICD and L1-dependent gene regulation. Overexpression of recombinant L1-ICD mediates gene regulation in a similar manner to full-length L1. Our results establish for the first time that regulated proteolytic processing by ADAM10 and PS/gamma-secretase is essential for the nuclear signalling of L1 in human carcinoma cell lines
    Type of Publication: Journal article published
    PubMed ID: 19260824
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  • 8
    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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  • 9
    Keywords: CELLS ; EXPRESSION ; GROWTH ; tumor ; carcinoma ; Germany ; KINASE ; PATHWAY ; GENE ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; TISSUE ; TUMORS ; LINES ; MICE ; gene transfer ; GENE-TRANSFER ; ACTIVATION ; prognosis ; CELL-LINES ; VARIANTS ; MOLECULE ; PROGRESSION ; gene expression ; TUMOR PROGRESSION ; METASTASIS ; LINE ; EXTRACELLULAR-MATRIX ; BETA ; ADHESION ; MIGRATION ; INTEGRIN ; CARCINOMAS ; L1 ; ADHESION MOLECULE ; ovarian carcinoma ; OVEREXPRESSION ; cell lines ; CELL-MIGRATION ; MORPHOGENESIS ; MATRIX ; RE ; TUMOR-GROWTH ; extracellular matrix ; cell adhesion ; cell migration ; CANCER PROGRESSION ; PROFILES ; ERK ; EPITHELIUM ; ADHESION MOLECULE L1 ; CD171 ; CUTANEOUS MALIGNANT-MELANOMA ; VITRONECTIN
    Abstract: L1 is a neural cell adhesion molecule involved in cell migration, axon growth and guidance. Recent data have shown that L1 is overexpressed in ovarian and endometrial tumors and is associated with bad prognosis. How L1 promotes tumor progression is presently unknown. Here we show that L1 expression is predominantly confined to the invasive front of ovarian carcinomas. Overexpression of L1 in carcinoma cell lines by adenovirus-mediated gene transfer enhanced the haptotactic cell migration on extracellular matrix proteins. Expression of L1 augmented tumor growth of carcinomas xenografted in nonobese diabetic/severe combined immunodeficient mice (NOD/SCID). A recent report has demonstrated L1-dependent upregulation of P3 integrin involving activation of the extracellular signal-regulated kinase (erk) pathway. We find that L1 and P3 integrin are not coexpressed in ovarian carcinoma tissues. Overexpression of L1 did not upregulate P3 integrin in ovarian carcinoma cell lines but could do so in HEK293 cells. Our results suggest that L1 could drive progression by enhancing cell migration and tumor growth but that L1 dependent and erk-regulated gene expression requires cell-type specific elements. © 2005 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 15704102
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  • 10
    Keywords: CELLS ; EXPRESSION ; GROWTH ; INVASION ; AGENTS ; carcinoma ; Germany ; human ; KINASE ; PATHWAY ; GENE ; ACTIVATION ; CONTRAST ; KERATINOCYTES ; SKIN ; ALPHA ; culture ; STAGE ; PROGRESSION ; metastases ; MELANOMA ; ADHESION ; MIGRATION ; INTEGRIN ; CARCINOMAS ; L1 ; MALIGNANT-MELANOMA ; ADHESION MOLECULE ; CUTANEOUS MELANOMA ; L1 adhesion molecule ; OVEREXPRESSION ; CELL-MIGRATION ; HUMAN SKIN ; GENE-PRODUCT ; PRODUCTS ; TUMOR-GROWTH ; HUMAN-MELANOMA ; PHASE ; ERK ; CD171 ; function ; HUMAN-SKIN ; ANTICANCER AGENTS ; BETA-3 INTEGRIN
    Abstract: The adhesion molecule L1 is expressed in primary melanomas and cutaneous metastases in contrast to melanocytic nevi and melanocytes, and is significantly associated with metastatic spread. Recent studies have demonstrated that in carcinomas L1 expression is associated with sustained activation of the extracellular signal-regulated kinase (ERK) pathway and upregulation of ERK-dependent, motility- and invasion-associated gene products including alpha v beta 3 integrin. The objective of this study was to further investigate the role of the adhesion molecule L1 in melanoma progression, and to evaluate whether targeting the L1 adhesion molecule would have therapeutic effects against invasive melanoma growth. Using human melanoma cells from different stages of progression in monolayer and organotypic human skin culture mimicking the pathophysiological environment of cutaneous melanoma, we found that (1) L1 expression mostly correlates with melanoma progression and alpha v beta 3 integrin expression, (2) overexpression of L1 in early radial growth phase melanoma cells promotes conversion from radial to vertical growth phase melanoma without upregulation of alpha v beta 3 integrin expression, and (3) suppression of L1 function significantly reduces migration and invasion of melanoma cells, but does not completely block invasive melanoma growth. Altogether, L1 plays a critical role in melanoma invasion and progression and offers therapeutic potential in combination with conventional anticancer agents. (c) 2006 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16506207
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