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      L1CAM expression in endometrial carcinomas: an ENITEC collaboration study

      research-article
      1 , * , 2 , 3 , 4 , 5 , 2 , 6 , 7 , 8 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 20 , 21 , 22 , 23 , 4 , 13 , 17 , 1 , 24
      British Journal of Cancer
      Nature Publishing Group
      endometrial cancer, endometrioid, non-endometrioid, L1CAM, immunohistochemistry

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          Abstract

          Background:

          Identification of aggressive endometrioid endometrial carcinomas (EECs) and non-endometrioid carcinomas (NEECs) is essential to improve outcome. L1 cell adhesion molecule (L1CAM) expression is a strong prognostic marker in stage I EECs, but less is known about L1CAM expression in advanced-stage EECs and NEECs. This study analyses L1CAM expression in a clinically representative cohort of endometrial carcinomas.

          Methods:

          The expression of L1CAM was immunohistochemically determined in 1199 endometrial carcinomas, treated at one of the European Network for Individualized Treatment of Endometrial Cancer (ENITEC) centres. Staining was considered positive when >10% of the tumour cells expressed L1CAM. The association between L1CAM expression and several clincopathological characteristics and disease outcome was calculated.

          Results:

          In all, L1CAM was expressed in 10% of the 935 stage I EECs, 18% of the 160 advanced stage EECs, and 75% of the 104 NEECs. The expression of L1CAM was associated with advanced stage, nodal involvement, high tumour grade, non-endometrioid histology, lymphovascular space invasion, and distant recurrences in all cases, and with reduced survival in the EECs, but not in the NEECs.

          Conclusions:

          The expression of L1CAM is a strong predictor of poor outcome in EECs, but not NEECs. It is strongly associated with non-endometrioid histology and distant spread, and could improve the postoperative selection of high-risk endometrial carcinomas. The value of L1CAM expression in the preoperative selection of high-risk endometrial carcinomas should be studied.

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          Most cited references26

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          L1 cell adhesion molecule is a strong predictor for distant recurrence and overall survival in early stage endometrial cancer: pooled PORTEC trial results.

          L1 cell adhesion molecule (L1CAM) expression has been implicated as risk factor for disease recurrence in endometrial cancer (EC), most likely due to its role in promoting tumour cell motility. We tested the performance of L1CAM expression in predicting the risk of recurrence in the randomised post operative radiation therapy in endometrial carcinoma (PORTEC)-1 and -2 trials.
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            L1 expression as a predictor of progression and survival in patients with uterine and ovarian carcinomas.

            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. 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. 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. 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.
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              Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins

              The L1 adhesion molecule plays an important role in axon guidance and cell migration in the nervous system. L1 is also expressed by many human carcinomas. In addition to cell surface expression, the L1 ectodomain can be released by a metalloproteinase, but the biological function of this process is unknown. Here we demonstrate that membrane-proximal cleavage of L1 can be detected in tumors and in the developing mouse brain. The shedding of L1 involved a disintegrin and metalloproteinase (ADAM)10, as transfection with dominant-negative ADAM10 completely abolishes L1 release. L1-transfected CHO cells (L1-CHO) showed enhanced haptotactic migration on fibronectin and laminin, which was blocked by antibodies to αvβ5 and L1. Migration of L1-CHO cells, but not the basal migration of CHO cells, was blocked by a metalloproteinase inhibitor, indicating a role for L1 shedding in the migration process. CHO and metalloproteinase-inhibited L1-CHO cells were stimulated to migrate by soluble L1-Fc protein. The induction of migration was blocked by αvβ5-specific antibodies and required Arg-Gly-Asp sites in L1. A 150-kD L1 fragment released by plasmin could also stimulate CHO cell migration. We propose that ectodomain-released L1 promotes migration by autocrine/paracrine stimulation via αvβ5. This regulatory loop could be relevant for migratory processes under physiological and pathophysiological conditions.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                06 September 2016
                09 August 2016
                : 115
                : 6
                : 716-724
                Affiliations
                [1 ]Department of Obstetrics and Gynaecology, Radboud University Medical Center , Geert Grooteplein 10, Nijmegen 6525GA, The Netherlands
                [2 ]Department of Pathology, Radboud University Medical Center , Geert Grooteplein 10, Nijmegen 6525GA, The Netherlands
                [3 ]Department of Pathology, Anthoni van Leeuwenhoek Hospital , Plesmanlaan 121, Amsterdam 1066CX, The Netherlands
                [4 ]Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA , Avenida Alcalde Rovira Roure, 80, Lleida 25198, Spain
                [5 ]Institute of Pathology, University Medical Center Freiburg , Hugstetter Strasse 55, Freiburg 79106, Germany
                [6 ]Department of Obstetrics and Gynecology, University Medical Center Freiburg , Hugstetter Strasse 55, Freiburg 79106, Germany
                [7 ]German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) , Im Neuenheimer Feld 280, Heidelberg D-69120, Germany
                [8 ]Biomedical Research Group in Gynecology, Vall Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona , Passeig de la Vall d'Hebron, 119-129, Barcelona 08035, Spain
                [9 ]Gynecological Department, Vall Hebron University Hospital , Passeig de la Vall d'Hebron, 119-129, Barcelona 08035, Spain
                [10 ]Department of Pathology, Vall Hebron University Hospital , Passeig de la Vall d'Hebron, 119-129, Barcelona 08035, Spain
                [11 ]Department of Obstetrics and Gynecology, Hospital del Mar , Passeig Marítim, 25-29, Barcelona 08003, Spain
                [12 ]Department of Pathology, Hospital del Mar , Passeig Marítim, 25-29, Barcelona 08003, Spain
                [13 ]Department of Obstetrics and Gynecology, Haukeland University Hospital , Jonas Lies vei 65, Bergen 5021, Norway
                [14 ]Department of Clinical Science, University of Bergen , PO Box 7800, Bergen 5020, Norway
                [15 ]Center for Cancer Biomarkers (CCBIO), University of Bergen , PO Box 7800, Bergen 5020, Norway
                [16 ]Department of Pathology, University of Turku , PO Box 7245, Laskut, Turku 01051, Finland
                [17 ]Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospital Gasthuisberg , Herestraat 49, Leuven 3000, Belgium
                [18 ]Department of Obstetrics and Gynecology, Bichat-Claude Bernard Hospital , 46 Rue Henri Huchard, Paris 75018, France
                [19 ]Department of Pathology, Bichat-Claude Bernard Hospital , 46 Rue Henri Huchard, Paris 75018, France
                [20 ]Department of Gynecology and Obstetrics, Faculty of Medicine, Masaryk University , Kamenice 5, Brno 625 00, Czech Republic
                [21 ]Institute of Pathology, Faculty of Medicine, Masaryk University , Kamenice 5, Brno 625 00, Czech Republic
                [22 ]Department of Obstetrics and Gynaecology, Canisius-Wilhelmina Hospital , Weg door Jonkerbos 100, Nijmegen 6532SZ, The Netherlands
                [23 ]Department of Pathology, Canisius-Wilhelmina Hospital , Weg door Jonkerbos 100, Nijmegen 6532SZ, The Netherlands
                [24 ]Department of Obstetrics and Gynaecology, TweeSteden Hospital , Doctor Deelenlaan 5, Tilburg 5042AD, The Netherlands
                Author notes
                Article
                bjc2016235
                10.1038/bjc.2016.235
                5023774
                27505134
                7c343264-4fc6-4d9a-9acb-bae0822e5c05
                Copyright © 2016 Cancer Research UK

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                : 26 April 2016
                : 08 July 2016
                : 12 July 2016
                Categories
                Molecular Diagnostics

                Oncology & Radiotherapy
                endometrial cancer,endometrioid,non-endometrioid,l1cam,immunohistochemistry

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