title: E-Cadherin fragments as potential mediators for peritoneal metastasis in advanced epithelial ovarian cancer.
abstract: BACKGROUND
  Peritoneal dissemination and retroperitoneal lymph node involvement are main routes for tumour spread of epithelial ovarian cancer (EOC), possibly determined by the intercellular connecting protein E-Cadherin (E-Cad) and its fragments.
  
  
  METHODS
  Tumour tissue of 105 advanced EOC patients was evaluated for protein expression of E-Cad, β-Catenin and Calpain by western blotting and immunohistochemistry. Expression patterns were compared between tumours with solely intraperitoneal (pT3c, pN0; n=41) and tumours with retroperitoneal metastases (pT1a-3c, pN1; n=64). Lysates of the EOC cell line SKOV3 and tumour tissue from the intraperitoneal group were tested for E-Cad expression following Calpain treatment.
  
  
  RESULTS
  E-Cad full-length (E-Cad-FL, 120 kDa) and two major fragments at 85 kDa (E-Cad-85) and 23 kDa (E-Cad-23) were detected by western blotting. E-Cad-85 expression was significantly higher in tumours with solely intraperitoneal metastases and correlated strongly with E-Cad-23 and the protease Calpain. Calpain-mediated cleavage was identified as a potential mechanism to generate E-Cad-85 from E-Cad-FL by treating lysates from SKOV3 cells and tumour tissue with this enzyme. Increased cytoplasmic localisation of β-Catenin in tumours with high E-Cad-85 expression corroborates that E-Cad-85 loses the binding site for β-Catenin after fragmentation, enabling tumour cluster formation and peritoneal dissemination.
  
  
  CONCLUSIONS
  Calpain-mediated E-Cad fragmentation appears to promote intraperitoneal EOC progression. Understanding these mechanisms might eventually lead to new tailored subtype-specific diagnostic and therapeutic interventions.
authors.affiliation: Department of Gynaecology and Gynaecologic Oncology, University Medical Centre Hamburg-Eppendorf, Martinistr 52, Hamburg 20246, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Trillsch
authors.affiliation: Department of Gynaecology and Gynaecologic Oncology, University Medical Centre Hamburg-Eppendorf, Martinistr 52, Hamburg 20246, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Kuerti
authors.affiliation: Department of Medical Biometry and Epidemiology, University Medical Centre Hamburg-Eppendorf, Martinistr 52, Hamburg 20246, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Eulenburg
authors.affiliation: Institute of Pathology, University Medical Centre Hamburg-Eppendorf, Martinistr 52, Hamburg 20246, Germany.
authors.forename: Eike
authors.initials: E
authors.lastname: Burandt
authors.affiliation: Department of Gynaecology and Gynaecologic Oncology, University Medical Centre Hamburg-Eppendorf, Martinistr 52, Hamburg 20246, Germany.
authors.forename: Linn
authors.initials: L
authors.lastname: Woelber
authors.affiliation: Department of Gynaecology and Gynaecologic Oncology, University Medical Centre Hamburg-Eppendorf, Martinistr 52, Hamburg 20246, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Prieske
authors.affiliation: Department of Gynaecology and Gynaecologic Oncology, University Medical Centre Hamburg-Eppendorf, Martinistr 52, Hamburg 20246, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Eylmann
authors.affiliation: Department of Gynaecology and Gynaecologic Oncology, University Medical Centre Hamburg-Eppendorf, Martinistr 52, Hamburg 20246, Germany.
authors.forename: Leticia
authors.initials: L
authors.lastname: Oliveira-Ferrer
authors.affiliation: Department of Gynaecology and Gynaecologic Oncology, University Medical Centre Hamburg-Eppendorf, Martinistr 52, Hamburg 20246, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Milde-Langosch
authors.affiliation: Department of Gynaecology and Gynaecologic Oncology, University Medical Centre Hamburg-Eppendorf, Martinistr 52, Hamburg 20246, Germany.|Department of Obstetrics and Gynaecology, University of Munich, Marchioninistr 15, Munich 81377, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Mahner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008198:Lymph Nodes / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000556:secondary; D012186:Retroperitoneal Neoplasms / Q000378:metabolism* / Q000556:secondary; D012187:Retroperitoneal Space; D012189:Retrospective Studies; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015820:Cadherins; D010446:Peptide Fragments; D051176:beta Catenin; D002154:Calpain