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  • 1
    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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  • 2
    Keywords: ADHESION, ADHESION MOLECULE, BREAST, breast cancer, BREAST-CANCER, CANCER, CANCERS, carcinoma, CARCI
    Abstract: The L1 adhesion molecule (L1-CAM) is associated with impaired prognosis in many carcinomas. However, limited information about its expression in breast cancer tissue is available. Therefore, we carried out an analysis on L1 expression in primary breast cancers using a combination of Western blot, DNA-microarray analysis and immunohistochemistry. We observed L1 protein and mRNA overexpression in 14-15% of the carcinomas and this was confirmed by immunohistochemical staining. High L1 expression was associated with nodal involvement, high grading, human epidermal growth receptor 2 (Her-2), plasminogen activator inhibitor 1 (PAI-1) and vascular endothelial growth factor (VEGF) expression and a negative estrogen receptor (ER) status, but not with neuroendocrine markers. Moreover, patients with tumors showing high L1-CAM expression had a shorter disease-free and overall survival. Given the emerging functional role of L1 in promoting tumor cell migration, invasion, tumor growth and metastasis, our results suggest that L1 may have this function in breast cancer as well
    Type of Publication: Journal article published
    PubMed ID: 19787228
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  • 3
    Abstract: Endometrial carcinomas (ECs) are classified into type 1 (less aggressive) and type 2 (aggressive) tumours that differ in genetic alterations. So far reliable immunohistochemical markers that can identify patients with high risk for recurrence are rare. We have defined the expression of L1CAM, a biomarker previously identified for EC, and compared its expression to estrogen receptor (ER)/progesterone receptor (PR) and E-cadherin. We found that L1CAM was absent in normal endometrium and the vast majority of endometrioid ECs (type 1) but was strongly expressed in serous and clear-cell ECs considered as type 2. 78/272 cases were identified as L1CAM positive endometrioid ECs that were correlated with a poor prognosis. Strikingly, we observed an inverse relationship between L1CAM and ER/PR/E-cadherin expression in all ECs. In mixed ECs, composed of endometrioid (L1CAM- ER/PR+ ECadherin+) and clear-cell/serous (L1CAM+ ER/PR- E-Cadherin-), both phenotypes were coexpressed. In some of these cases L1CAM was upregulated at the leading edge of the tumour where ER/PR and E-cadherin expression was selectively lost. In EC cell lines treated with the epithelial-mesenchymal transition (EMT) inducer TGF-1, L1CAM and vimentin were strongly upregulated while E-cadherin expression was reduced. The treatment also resulted in an increased expression of the EMT transcription factor Slug and an enhanced cell invasion. Depletion of Slug by siRNA knockdown prevented both TGF-1-mediated effects. According to our analysis we suggest that L1CAM is a novel marker for EMT in ECs and that L1CAMtyping could identify endometrioid ECs that have type 2-like features and are at high risk for recurrence.
    Type of Publication: Journal article published
    PubMed ID: 20077528
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  • 4
    Keywords: antibodies ; PROGRESSION ; chemotherapy ; PROGNOSTIC-SIGNIFICANCE ; ADHESION MOLECULE ; SEROUS CARCINOMA ; FEATURES ; OVARIAN-CARCINOMA ; L1 EXPRESSION ; UTERINE
    Abstract: BACKGROUND: Despite the excellent prognosis of Federation Internationale de Gynecologie et d'Obstetrique (FIGO) stage I, type I endometrial cancers, a substantial number of patients experience recurrence and die from this disease. We analyzed the value of immunohistochemical L1CAM determination to predict clinical outcome. METHODS: We conducted a retrospective multicenter cohort study to determine expression of L1CAM by immunohistochemistry in 1021 endometrial cancer specimens. The Kaplan-Meier method and Cox proportional hazard model were applied for survival and multivariable analyses. A machine-learning approach was used to validate variables for predicting recurrence and death. RESULTS: Of 1021 included cancers, 17.7% were rated L1CAM-positive. Of these L1CAM-positive cancers, 51.4% recurred during follow-up compared with 2.9% L1CAM-negative cancers. Patients bearing L1CAM-positive cancers had poorer disease-free and overall survival (two-sided Log-rank P 〈 .001). Multivariable analyses revealed an increase in the likelihood of recurrence (hazard ratio [HR] = 16.33; 95% confidence interval [CI] = 10.55 to 25.28) and death (HR = 15.01; 95% CI = 9.28 to 24.26). In the L1CAM-negative cancers FIGO stage I subdivision, grading and risk assessment were irrelevant for predicting disease-free and overall survival. The prognostic relevance of these parameters was related strictly to L1CAM positivity. A classification and regression decision tree (CRT)identified L1CAM as the best variable for predicting recurrence (sensitivity = 0.74; specificity = 0.91) and death (sensitivity = 0.77; specificity = 0.89). CONCLUSIONS: To our knowledge, L1CAM has been shown to be the best-ever published prognostic factor in FIGO stage I, type I endometrial cancers and shows clear superiority over the standardly used multifactor risk score. L1CAM expression in type I cancers indicates the need for adjuvant treatment. This adhesion molecule might serve as a treatment target for the fully humanized anti-L1CAM antibody currently under development for clinical use.
    Type of Publication: Journal article published
    PubMed ID: 23781004
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  • 5
    Keywords: CANCER ; CELLS ; SURVIVAL ; carcinoma ; PROGRESSION ; adenocarcinoma ; ADHESION MOLECULE ; POOR-PROGNOSIS ; KAPPA-B ACTIVATION ; L1 EXPRESSION
    Abstract: The L1 cell adhesion molecule (L1CAM) is overexpressed in many human cancers and can serve as a biomarker for prognosis in most of these cancers (including type I endometrial carcinomas). Here we provide an optimized immunohistochemical staining procedure for a widely used automated platform (VENTANA(TM)), which has recourse to commercially available primary antibody and detection reagents. In parallel, we optimized the staining on a semi-automated BioGenix (i6000) immunostainer. These protocols yield good stainings and should represent the basis for a reliable and standardized immunohistochemical detection of L1CAM in a variety of malignancies in different laboratories.
    Type of Publication: Journal article published
    PubMed ID: 24242293
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  • 6
    Abstract: The majority of endometrial carcinomas are classified as Type I endometrioid endometrial carcinomas (EECs) and have a good prognosis. Type II non-endometrioid endometrial carcinomas (NEECs) have a significant worse outcome. Yet, 20 % of the EECs are associated with an unexplained poor outcome. The aim of this study was to determine if L1CAM expression, a recently reported biomarker for aggressive tumor behavior in endometrial carcinoma, was associated with clinicopathological features of EECs. A total of 103 patients diagnosed as EEC at the Radboud University Medical Centre, based on the pathology report were selected. L1CAM status of these tumors was determined, and histologic slides were reviewed by two expert pathologists. L1CAM-positivity was observed in 17 % (18/103). Review of the diagnostic slides revealed that 11 out of these 18 L1CAM-positive tumors (61 %) contained a serous- or mixed carcinoma component that was not initially mentioned in the pathology report. L1CAM-expression was associated with advanced age, poor tumor grade, and lymphovascular space invasion. A worse five year progression free survival rate was observed for patients with L1CAM-positive tumors (55.6 % for the L1CAM-positive group, compared to 83.3 % for the L1CAM-negative group P = 0.01). L1CAM expression carries prognostic value for histologically classified EEC and supports the identification of tumors with a NEEC component.
    Type of Publication: Journal article published
    PubMed ID: 26891628
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  • 7
    Keywords: EXPRESSION ; tumor ; carcinoma ; Germany ; human ; IN-VIVO ; LUNG ; THERAPY ; VIVO ; DIAGNOSIS ; SYSTEM ; MONOCLONAL-ANTIBODY ; TISSUE ; TUMORS ; LINES ; kidney ; MARKER ; colon ; TISSUES ; BINDING ; CELL-LINES ; BREAST ; antibodies ; antibody ; NERVOUS-SYSTEM ; PROGRESSION ; immunohistochemistry ; METASTASIS ; CERVIX ; CELL-LINE ; LINE ; MELANOMA ; ADHESION ; CELL-ADHESION ; MIGRATION ; MONOCLONAL-ANTIBODIES ; BENIGN ; INTEGRIN ; CARCINOMAS ; adenocarcinoma ; ADENOCARCINOMAS ; L1 ; MALIGNANT-MELANOMA ; ADHESION MOLECULE ; CELL-ADHESION MOLECULE ; cell lines ; LUNG-CARCINOMA ; DOMAINS ; ADULTS ; ENDOMETRIAL ; RE ; cell adhesion ; SUBTYPES ; CD171 ; lung carcinoma ; in vivo ; PREDICTOR ; RENAL-CARCINOMA ; OVARIAN ; molecular marker ; pediatric ; nongynecological tumors ; OVARIAN-CARCINOMA CELLS ; tumors of female genital tract
    Abstract: L1 cell adhesion molecule (CD171) represents a strongly unfavorable prognostic biomarker for ovarian and endometrial carcinomas. Here we carried out an immunohistochemical survey of L1 expression in normal adults and in a broad range of benign and malignant tumors using monoclonal antibody L1-11A and the novel monoclonal antibody L1-14.10. In normal tissues, L1 was expressed in the collecting tubules of adult tissues and pediatric kidney and in peripheral nerve bundles. In tumors of the female genital tract, L 1 was detected in adenocarcinomas of the cervix and fallopian tubes, in addition to ovarian and endometrial carcinomas. Nongynecological tumors expressing L1 comprised malignant melanoma, colon adenocarcinoma positive to chromogranin, clear-cell adenocarcinoma of the urinary bladder, pheochromocytoma, small cell lung carcinoma, and tumors of the nervous system. L1 was absent in breast carcinoma, gastrointestinal tract carcinomas, gastrointestinal carcinoids, renal clear-cell carcinomas, prostate adenocarcinomas, and mesotheliomas. Surprisingly, L1 expression in established breast and renal carcinoma cell lines was not a predictor for its presence in these human tumors in vivo. Our results suggest that L1 expression in tumors is not ubiquitous but restricted to certain subtypes and may be a helpful molecular marker for differential diagnosis and target for antibody-based therapy. (c) 2006 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16867862
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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
    Abstract: OBJECTIVE: Cancer cells in the body release soluble and membranous factors that manipulate the tumor environment to facilitate growth and survival. Recent years have provided evidence that small microvesicles that are termed exosomes may play a pivotal role in this process. Exosomes are membrane vesicles with a size of 40-100nm that are released by both tumor and normal cells and can be found in various body fluids. Tumor-derived exosomes carry functional proteins, mRNAs, and miRNAs and could serve as novel platform for tumor diagnosis and prognosis. However, marker proteins that allow enrichment of tumor-derived exosomes over normal exosomes are less well defined. METHODS: We used Western blot analysis and antibody coupled magnetic beads to characterize CD24 and EpCAM as markers for exosomes. We investigated ovarian carcinoma ascites, pleural effusions and serum of breast carcinoma patients. As non-tumor derived control we used exosomes from ascites of liver cirrhosis patients. RESULTS: Exosomes could be isolated from all body fluids and contained marker proteins as well as miRNAs. We observed that CD24 and EpCAM were selectively present on ascites exosomes of tumor patients and copurified together on anti-EpCAM or anti-CD24 magnetic beads. In breast cancer patients CD24 was present but EpCAM was absent from serum exosomes. Instead, the intact EpCAM ectodomain was recovered in a soluble form. We provide evidence that EpCAM can be cleaved from exosomes via serum metalloproteinase(s). CONCLUSION: Loss of EpCAM on serum exosomes may hamper enrichment by immune-affinity isolation. We suggest that CD24 could be an additional marker for the enrichment of tumor-derived exosomes from blood.
    Type of Publication: Journal article published
    PubMed ID: 21601258
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  • 10
    Keywords: ACTIVATION ; CARCINOMA-CELLS ; LIPID RAFTS ; PROTEIN-TYROSINE KINASES ; focal adhesion kinase ; OVARIAN-CARCINOMA ; BREAST-CANCER CELLS ; GENE CD24 ; BIOLOGICAL ASPECTS ; SRC
    Abstract: CD24 is a glycosyl-phosphatidylinositol-anchored membrane protein that is frequently over-expressed in a variety of human carcinomas and is correlated with poor prognosis. In cancer cell lines, changes of CD24 expression can alter several cellular properties in vitro and tumor growth in vivo. However, little is known about how CD24 mediates these effects. Here we have analyzed the functional consequences of CD24 knock-down or over-expression in human cancer cell lines. Depletion of CD24 reduced cell proliferation and adhesion, enhanced apoptosis, and regulated the expression of various genes some of which were identified as STAT3 target genes. Loss of CD24 reduced STAT3 and FAK phosphorylation. Diminished STAT3 activity was confirmed by specific reporter assays. We found that reduced STAT3 activity after CD24 knock-down was accompanied by altered Src phosphorylation. Silencing of Src, similar to CD24, targeted the expression of prototype STAT3-regulated genes. Likewise, the over-expression of CD24 augmented Src-Y416 phosphorylation, the recruitment of Src into lipid rafts and the expression of STAT3-dependent target genes. An antibody to CD24 was effective in reducing tumor growth of A549 lung cancer and BxPC3 pancreatic cancer xenografts in mice. Antibody treatment affected the level of Src-phosphorylation in the tumor and altered the expression of STAT3 target genes. Our results provide evidence that CD24 regulates STAT3 and FAK activity and suggest an important role of Src in this process. Finally, the targeting of CD24 by antibodies could represent a novel route for tumor therapy.
    Type of Publication: Journal article published
    PubMed ID: 22760497
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