title: Context-dependent adaption of EpCAM expression in early systemic esophageal cancer.
abstract: The role of the epithelial cell adhesion molecule EpCAM in cancer progression remains largely unclear. High expression of EpCAM in primary tumors is often associated with more aggressive phenotypes and EpCAM is the prime epithelial antigen in use to isolate circulating tumor cells (CTCs) and characterize disseminated tumor cells (DTCs). However, reduced expression of EpCAM was associated with epithelial-to-mesenchymal transition (EMT) and reports on a lack of EpCAM on CTCs emerged. These contradictory observations might reflect a context-dependent adaption of EpCAM expression during metastatic progression. To test this, EpCAM expression was monitored in esophageal cancer at different sites of early systemic disease. Although most of the primary esophageal tumors expressed high levels of EpCAM, the majority of DTCs in bone marrow lacked EpCAM. In vitro, downregulation of EpCAM expression at the plasma membrane was observed in migrating and invading cells, and was associated with a partial loss of the epithelial phenotype and with significantly decreased proliferation. Accordingly, induction of EMT through the action of TGFβ resulted in substantial loss of EpCAM cell surface expression on esophageal cancer cells. Knock-down or natural loss of EpCAM recapitulated these effects as it reduced proliferation while enhancing migration and invasion of cancer cells. Importantly, expression of EpCAM on DTCs was significantly associated with the occurrence of lymph node metastases and with significantly decreased overall survival of esophageal cancer patients. We validated this observation by showing that high expression of EpCAM promoted tumor outgrowth after xenotransplantation of esophageal carcinoma cells. The present data disclose a dynamic expression of EpCAM throughout tumor progression, where EpCAM(high) phenotypes correlate with proliferative stages, whereas EpCAM(low/negative) phenotypes associated with migration, invasion and dissemination. Thus, differing expression levels of EpCAM must be taken into consideration for therapeutic approaches and during clinical retrieval of disseminated tumor cells.
authors.affiliation: Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Driemel
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians University of Munich, Munich, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kremling
authors.affiliation: Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schumacher
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians University of Munich, Munich, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Will
authors.affiliation: Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wolters
authors.affiliation: Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Lindenlauf
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians University of Munich, Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Mack
authors.affiliation: Institute for Pathology, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: S A
authors.initials: SA
authors.lastname: Baldus
authors.affiliation: Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Hoya
authors.affiliation: Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Pietsch
authors.affiliation: Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Panagiotidou
authors.affiliation: Institute for Transplantation Diagnostics and Cellular Therapy, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Raba
authors.affiliation: Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Vay
authors.affiliation: Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Vallböhmer
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians University of Munich, Munich, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Harréus
authors.affiliation: Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: W T
authors.initials: WT
authors.lastname: Knoefel
authors.affiliation: Department for General, Visceral und Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: N H
authors.initials: NH
authors.lastname: Stoecklein
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians University of Munich, Munich, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Gires
mesh_terms: D000368:Aged; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D000071858:Epithelial Cell Adhesion Molecule; D058750:Epithelial-Mesenchymal Transition; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D016212:Transforming Growth Factor beta