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  • 1
    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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  • 2
    Keywords: TIME ; EXPERIENCE ; BONE-MARROW-TRANSPLANTATION ; HIGH-DOSE CHEMOTHERAPY ; PHYSICAL-ACTIVITY ; QUALITY-OF-LIFE ; RANDOMIZED CONTROLLED-TRIAL ; AEROBIC EXERCISE ; CANCER-RELATED FATIGUE ; SKELETAL-MUSCLE STRENGTH ; SOCIAL SUPPORT ; SYMPTOM DISTRESS
    Abstract: Before, during, and after allogeneic hematopoietic stem cell transplantation (allo-HSCT), patients experience considerable physical and psychologic distress. Besides graft-versus-host disease and infections, reduced physical performance and high levels of fatigue affect patients' quality of life. This multicenter randomized controlled trial examined the effects of a partly self-administered exercise intervention before, during, and after allo-HSCT on these side effects. After randomization to an exercise and a social contact control group 105 patients trained in a home-based setting before hospital admission, during inpatient treatment and a 6- to 8-week period after discharge. Fatigue, physical performance, quality of life, and physical/psychologic distress were measured by standardized instruments at baseline, admission to, and discharge from hospital and 6 to 8 weeks after discharge. The exercise group showed significantly improvement in fatigue scores (up to 15% improvement in exercise group vs up to 28% deterioration in control; P 〈 .01-.03), physical fitness/functioning (P = .02-.03) and global distress (P = .03). All effects were at least detectable at one assessment time point after hospitalization or repeatedly. Physical fitness correlated significantly with all reported symptoms/variables. In conclusion, this partly supervised exercise intervention is beneficial for patients undergoing allo-HSCT. Because of low personnel requirements, it might be valuable to integrate such a program into standard medical care.
    Type of Publication: Journal article published
    PubMed ID: 21190995
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  • 3
    Keywords: GENE-EXPRESSION ; BREAST-CANCER ; TUMOR PROGRESSION ; CARCINOMA-CELLS ; KAPPA-B ; CELL-ADHESION MOLECULE ; E-cadherin ; PANCREATIC-CANCER ; EPITHELIAL-MESENCHYMAL TRANSITION ; ENDOMETRIAL CARCINOMAS
    Abstract: Expression of L1 cell adhesion molecule (L1CAM) is associated with poor prognosis in a variety of human carcinomas including breast, ovarian and pancreatic ductal adenocarcinoma (PDAC). Recently we reported that L1CAM induces sustained nuclear factor kappa B (NF-kappaB) activation by augmenting the autocrine production of interleukin 1 beta (IL-1beta), a process dependent on interaction of L1CAM with integrins. In the present study, we demonstrate that transforming growth factor beta1 (TGF-beta1) treatment of breast carcinoma (MDA-MB231) and PDAC (BxPc3) cell lines induces an EMT (epithelial to mesenchymal transition)-like phenotype and leads to the expression of L1CAM. In MDA-MB231 cells, up-regulation of L1CAM augmented expression of IL-1beta and NF-kappaB activation, which was reversed by depletion of L1CAM, L1CAM-binding membrane cytoskeleton linker protein ezrin, beta1-integrin or focal adhesion kinase (FAK). Over-expression of L1CAM not only induced NF-kappaB activation but also mediated the phosphorylation of FAK and Src. Phosphorylation was not induced in cells expressing a mutant form of L1CAM (L1-RGE) devoid of the integrin-binding site. FAK- and Src-phosphorylation were inhibited by knock-down of various components of the integrin signalling pathway such as beta1- and alpha5-integrins, integrin-linked kinase (ILK), FAK and the phosphoinositide 3-kinase (PI3K) subunit p110beta. In summary, these results reveal that during EMT, L1CAM promotes IL-1beta expression through a process dependent on integrin signalling and supports a motile and invasive tumour cell phenotype. We also identify important novel downstream effector molecules of the L1CAM-integrin signalling crosstalk that help to understand the molecular mechanisms underlying L1CAM-promoted tumour progression.
    Type of Publication: Journal article published
    PubMed ID: 22764136
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  • 4
    Keywords: NF-KAPPA-B ; INTEGRIN ALPHA(V)BETA(3) ; NEURITE OUTGROWTH ; EPITHELIAL-MESENCHYMAL TRANSITIONS ; BIOCHEMICAL-CHARACTERIZATION ; ADHESION MOLECULE L1 ; OVARIAN-CARCINOMA CELLS ; NEURAL RECOGNITION MOLECULES ; PRESENILIN/GAMMA-SECRETASE ; IMMUNOGLOBULIN-LIKE DOMAIN
    Abstract: The L1 cell adhesion molecule (L1CAM) plays a major role in the development of the nervous system and in the malignancy of human tumors. In terms of biological function, L1CAM comes along in two different flavors: (1) a static function as a cell adhesion molecule that acts as a glue between cells; (2) a motility promoting function that drives cell migration during neural development and supports metastasis of human cancers. Important factors that contribute to the switch in the functional mode of L1CAM are: (1) the cleavage from the cell surface by membrane proximal proteolysis and (2) the ability to change binding partners and engage in L1CAM-integrin binding. Recent studies have shown that the cleavage of L1CAM by metalloproteinases and the binding of L1CAM to integrins via its RGD-motif in the sixth Ig-domain activate signaling pathways distinct from the ones elicited by homophilic binding. Here we highlight important features of L1CAM proteolysis and the signaling of L1CAM via integrin engagement. The novel insights into L1CAM downstream signaling and its regulation during tumor progression and epithelial-mesenchymal transition (EMT) will lead to a better understanding of the dualistic role of L1CAM as a cell adhesion and/or motility promoting cell surface molecule.
    Type of Publication: Journal article published
    PubMed ID: 22796939
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  • 5
    Keywords: THERAPY ; TRIAL ; GUIDELINES ; fludarabine ; rituximab ; TERM-FOLLOW-UP ; REGIMEN ; ALEMTUZUMAB ; 1ST COMPLETE REMISSION ; REFRACTORY CLL
    Abstract: BACKGROUND: In a single-center retrospective donor versus no-donor comparison, we investigated if allogeneic stem cell transplantation (alloSCT) can improve the dismal course of poor-risk chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: All patients with CLL who were referred for evaluation of alloSCT within a 7-year time frame and had a donor search indication according to the EBMT criteria or because of Richter's transformation were included. Patients for whom a matched donor could be found within 3 months (matches) were compared with patients without such a donor (controls). Primary end point was overall survival measured from the 3-month landmark after search initiation. RESULTS: Of 105 patients with donor search, 97 (matches 83; controls 14) were assessable at the 3-month landmark. Matches and controls were comparable for age, gender, time from diagnosis, number of previous regimens, and remission status. Disregarding if alloSCT was actually carried out or not, survival from the 3-month landmark was significantly better in matches versus controls [hazard ratio 0.38, 95% confidence interval (CI) 0.17-0.85; P = 0.014]. The survival benefit of matches remained significant on multivariate analysis. CONCLUSION: This study provides first comparative evidence that alloSCT may have the potential to improve the natural course of poor-risk CLL as defined by the EBMT criteria.
    Type of Publication: Journal article published
    PubMed ID: 24356631
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  • 6
    Keywords: QUANTIFICATION ; TRIAL ; INFECTIONS ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; MANAGEMENT ; MINIMAL RESIDUAL DISEASE ; rituximab ; TERM-FOLLOW-UP ; CONSENSUS ; HEMATOLOGICAL MALIGNANCIES
    Abstract: To elucidate factors contributing to the effectiveness of allogeneic hematopoietic stem cell transplantation (alloHCT) in high-risk CLL, immune interventions, GvHD and clinical outcome of 77 consecutive patients allografted for CLL were analyzed. Immune modulation (immunosuppression tapering, rituximab-augmented donor lymphocyte infusions) was guided by minimal residual disease (MRD) monitoring and commenced at a median of 91 (22-273) days after alloHCT, resulting in a probability of being event free and MRD-negative 1 year after transplant of 57% (84% in those encountering chronic GvHD). Patients who were event free and MRD-negative at the 12-month landmark had a 4-year PFS of 77% and largely remained durably MRD-negative if MRD clearance had occurred subsequent to immune modulation. Three-year overall survival, PFS, relapse incidence and non-relapse mortality of all 77 patients were 69, 57, 26 and 24%, respectively. Survival was not affected by EBMT risk category but by active disease at alloHCT, which could not be overcome by intensification of conditioning. Twenty-three patients who experienced relapse post alloHCT had a survival of 56% at 2 years after CLL recurrence. In conclusion, MRD-guided immune modulation after alloHCT for high-risk CLL can provide durable MRD clearance in more than half of the patients.
    Type of Publication: Journal article published
    PubMed ID: 26146810
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  • 7
    Abstract: L1 cell adhesion molecule (L1CAM) overexpression is often associated with bad prognosis in various human carcinomas. Recent studies also suggest a role of L1CAM in pancreatic ductal adenocarcinomas (PDAC). To further address its contribution, we expressed functional domains of L1CAM in PT45-P1 PDAC cells. We found that L1CAM that is full length (L1-FL), but neither the soluble ectodomain (L1ecto) nor the cytoplasmic part (L1cyt), could enhance cell proliferation or tumour growth in mice. Expression of L1-FL resulted in constitutive activation of NF-kappa B, which was abolished by L1CAM knockdown. We showed that the expression of IL-1 beta was selectively upregulated by L1-FL, and increased IL-1 beta levels were instrumental for sustained NF-kappa B activation. IL-1 beta production and NF-kappa B activation were abolished by knockdown of alpha 5-integrin and integrin-linked kinase, but insensitive to depletion of L1CAM cleavage proteinases. Supporting these data, PT45-P1 cells transduced with an L1CAM mutant deficient in integrin binding (L1-RGE) did not support the described L1-FL functions. Our results suggest that membranous L1CAM interacts with RGD-binding integrins, leading to sustained NF-kappa B activation by IL-1 beta production and autocrine/paracrine signalling. The unravelling of this novel mechanism sheds new light on the important role of L1CAM expression in PDAC cells. Oncogene (2010) 29, 4766-4778; doi:10.1038/onc.2010.230; published online 14 June 2010
    Type of Publication: Journal article published
    PubMed ID: 20543863
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  • 8
    Keywords: CANCER CELLS ; GROWTH-FACTOR ; TRANSCRIPTION FACTOR ; CELL-ADHESION MOLECULE ; AMYLOID PRECURSOR PROTEIN ; EXTRACELLULAR-MATRIX PROTEINS ; OVARIAN-CARCINOMA CELLS ; NEURONAL MIGRATION ; PANCREATIC ADENOCARCINOMA CELLS ; PRESENILIN/GAMMA-SECRETASE
    Abstract: The cell adhesion molecule L1 (L1CAM) was originally identified as a neural adhesion molecule essential for neurite outgrowth and axon guidance. Many studies have now shown that L1CAM is overexpressed in human carcinomas and associated with poor prognosis. So far, L1CAM-mediated cellular signaling has been largely attributed to an association with growth factor receptors, referred to as L1CAM-'assisted' signaling. New data demonstrate that L1CAM can signal via two additional mechanisms: 'forward' signaling via regulated intra-membrane proteolysis and 'reverse' signaling via the activation of the transcription factor nuclear factor (NF)-kappa B. Taken together, these findings lead to a new understanding of L1CAM downstream signaling that is fundamental for the development of anti-L1CAM antibody-mediated therapeutics in human tumor cells
    Type of Publication: Journal article published
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  • 9
    Keywords: CANCER ; prognosis ; polymorphism ; single nucleotide polymorphism ; BREAST-CANCER ; PROGRESSION ; resistance ; ovarian cancer ; SNP ; SQUAMOUS-CELL CARCINOMA ; HEAD ; PREDICTION ; ARG(388) ALLELE ; ARG388 ALLELE ; FGFR4 ; GLY388ARG POLYMORPHISM ; OVCAD
    Abstract: BACKGROUND: FGFR4 has been shown to play an important role in the etiology and progression of solid tumors. A single nucleotide polymorphism (SNP) within the FGFR4 gene has previously been linked to prognosis and response to chemotherapy in breast cancer and other malignancies. This study evaluates the relevance of this SNP in advanced ovarian cancer. PATIENTS AND METHODS: FGFR4-genotype was analyzed in 236 patients recruited as part of the OVCAD project. Genotyping was performed on germ-line DNA using a TaqMan based genotyping assay. Results were correlated with clinicopathological variables and survival. RESULTS: The FGFR4 388Arg genotype was significantly associated with prolonged progression-free and overall survival (univariate: HR 0.68, p=0.017; HR 0.49, p=0.005; multivariate: HR 0.69, p=0.025; HR 0.49, p=0.006) though the positive prognostic value was restricted to patients without post-operative residual tumor. Indeed, there was a significant interaction between FGFR4 genotype and residual tumor for overall survival. Furthermore, the FGFR4 388Arg genotype significantly correlated with platinum sensitivity in the same subgroup (multivariate OR 3.81 p=0.004). CONCLUSION: FGFR4 Arg388Gly genotype is an independent and strong context specific prognostic factor in patients with advanced ovarian cancer and could be used to predict platinum-sensitivity.
    Type of Publication: Journal article published
    PubMed ID: 22034009
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  • 10
    Keywords: GENE-EXPRESSION ; CARCINOMA CELLS ; MIGRATION ; CELL-ADHESION MOLECULE ; inflammation ; IMMUNOGLOBULIN SUPERFAMILY ; HUMAN TUMORS ; SOLUBLE FORM ; L1 CD171 ; NEURAL RECOGNITION MOLECULES
    Abstract: BACKGROUND: Overexpression of L1-cell adhesion molecule (L1CAM) has been observed for various carcinomas and correlates with poor prognosis and late-stage disease. In vitro, L1CAM enhances proliferation, cell migration, adhesion and chemoresistance. We tested L1CAM and interleukin-1 beta (IL-1beta) expression in tumor samples and ascitic fluid from ovarian carcinoma patients to examine its role as a prognostic marker. PATIENTS AND METHODS: We investigated tumor samples and ascitic fluid from 232 serous ovarian carcinoma patients for L1CAM by enzyme-linked immunosorbent assay. L1CAM expression was correlated with pathoclinical parameters and patients' outcome. IL-1beta levels were measured in tumor cell lysates. Ovarian cancer cell lines were analyzed for the contribution of L1CAM to IL-1beta production and nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-kappaB) activation. RESULTS: We observed that L1CAM-expressing tumors show a highly invasive phenotype associated with restricted tumor resectability at primary debulking surgery and increased lymphogenic spread. Soluble L1CAM proved to be a marker for poor progression-free survival and chemoresistance. In ovarian carcinoma cell lines, the specific knock-down of L1CAM reduces IL-1beta expression and NF-kappaB activity. CONCLUSIONS: L1CAM expression contributes to the invasive and metastatic phenotype of serous ovarian carcinoma. L1CAM expression and shedding in the tumor microenvironment could contribute to enhanced invasion and tumor progression through increased IL-1beta production and NF-kappaB activation.
    Type of Publication: Journal article published
    PubMed ID: 22228447
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