title: Prognostic significance of Zinc finger E-box binding homeobox 1 (ZEB1) expression in cancer cells and cancer-associated fibroblasts in pancreatic head cancer.
abstract: BACKGROUND
  Pancreatic ductal adenocarcinoma (PDAC) is characterized by an aggressive biology and poor prognosis. Experimental evidence has suggested a role for the transcriptional repressor Zinc finger E-box binding homeobox 1 (ZEB1) in epithelial-mesenchymal transition, invasion, and metastasis in PDAC. ZEB1 expression has been observed in cancer cells as well as stromal fibroblasts. Our study aimed to evaluate the prognostic value of ZEB1 expression in PDAC tissue.
  
  
  METHODS
  Patient baseline and follow-up data were extracted from a prospectively maintained database. After clinicopathologic re-review, serial sliced tissue slides were immunostained for ZEB1, E-cadherin, vimentin, and pan-cytokeratin. ZEB1 expression in cancer cells and adjacent stromal fibroblasts was graded separately and correlated to routine histopathologic parameters and survival after resection.
  
  
  RESULTS
  A total of 117 cases of PDAC were included in the study. High ZEB1 expression in cancer cells and in stromal cancer-associated fibroblasts was associated with poor prognosis. There was also a trend for poor prognosis with a lymph node ratio of greater than 0.10. In line with its role as an inducer of epithelial-mesenchymal transition, ZEB1 expression in cancer cells was positively correlated with Vimentin expression and negatively with E-Cadherin expression. In multivariate analysis, stromal ZEB1 expression grade was the only independent factor of survival after resection.
  
  
  CONCLUSIONS
  Our data suggest that ZEB1 expression in cancer cells as well as in stromal fibroblasts are strong prognostic factors in PDAC. Stromal ZEB1 expression is identified for the first time as an independent predictor of survival after resection of PDAC. This observation suggests that therapies targeting ZEB1 and its downstream pathways could hit both cancer cells and supporting cancer-associated fibroblasts.
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany; Comprehensive Cancer Center, Freiburg, Germany. Electronic address: peter.bronsert@uniklinik-freiburg.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Bronsert
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kohler
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Timme
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Selina
authors.initials: S
authors.lastname: Kiefer
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany; Comprehensive Cancer Center, Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Werner
authors.affiliation: Institute for Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schilling
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Vashist
authors.affiliation: Comprehensive Cancer Center, Freiburg, Germany; Clinic for General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Makowiec
authors.affiliation: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Clinic for General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brabletz
authors.affiliation: Clinic for General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Ulrich T
authors.initials: UT
authors.lastname: Hopt
authors.affiliation: Clinic for General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany; Clinic for Surgery, University Clinic Schleswig-Holstein Campus, Lübeck, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bausch
authors.affiliation: Clinic for General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Kulemann
authors.affiliation: Clinic for General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany; Clinic for Surgery, University Clinic Schleswig-Holstein Campus, Lübeck, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Keck
authors.affiliation: Clinic for General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany; Clinic for Surgery, University Clinic Schleswig-Holstein Campus, Lübeck, Germany.
authors.forename: Ulrich F
authors.initials: UF
authors.lastname: Wellner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D016577:Pancreaticoduodenectomy; D011379:Prognosis; D012372:ROC Curve; D012189:Retrospective Studies; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism*; D016896:Treatment Outcome; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1