title: Loss of membranous Ep-CAM in budding colorectal carcinoma cells.
abstract: Tumor budding is a histological feature that reflects loss of adhesion of tumor cells and is associated with locoregional metastasis of colorectal carcinoma. Although nuclear localization of beta-catenin is associated with tumor budding, the molecular mechanism remains largely elusive. In this study, we hypothesize that the epithelial cell adhesion molecule (Ep-CAM) is involved in tumor budding. In order to address this question, we performed immunohistochemistry on Ep-CAM using three different antibodies (monoclonal antibodies Ber-ep4 and 311-1K1 and a polyclonal antibody) and a double staining on beta-catenin and Ep-CAM. In addition, Ep-CAM mRNA was monitored with mRNA in situ hybridization. Subsequently, we determined the effect of Ep-CAM staining patterns on tumor spread in rectal cancer. In contrast to the tumor mass, budding cells of colorectal carcinoma displayed lack of membranous but highly increased cytoplasmic Ep-CAM staining and nuclear translocation of beta-catenin. mRNA in situ hybridization suggested no differences in Ep-CAM expression between the invasive front and the tumor mass. Importantly, reduced Ep-CAM staining at the invasive margin of rectal tumor specimens (n=133) correlated significantly with tumor budding, tumor grade and an increased risk of local recurrence (P=0.001, P=0.04 and P=0.03, respectively). These data demonstrate abnormal processing of Ep-CAM at the invasive margin of colorectal carcinomas. Our observations indicate that loss of membranous Ep-CAM is associated with nuclear beta-catenin localization and suggest that this contributes to reduced cell-cell adhesions, increased migratory potential and tumor budding.
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.gosens@pathol.umcn.nl
authors.forename: Marleen J E M
authors.initials: MJ
authors.lastname: Gosens
authors.forename: Léon C L
authors.initials: LC
authors.lastname: van Kempen
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: J Han J M
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Iris D
authors.initials: ID
authors.lastname: Nagtegaal
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D000071858:Epithelial Cell Adhesion Molecule; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009367:Neoplasm Staging; D009426:Netherlands / Q000453:epidemiology; D012333:RNA, Messenger / Q000378:metabolism; D015996:Survival Rate; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D008565:Membrane Proteins; D012333:RNA, Messenger; D051176:beta Catenin