title: Glucocorticoid-induced TNFR family-related receptor (GITR)-expression in tumor infiltrating leucocytes (TILs) is associated with the pathogenesis of esophageal adenocarcinomas with and without Barrett's mucosa.
abstract: BACKGROUND
  Esophageal adenocarcinomas (EACs) arise due to gastroesophageal reflux, with Barrett's esophagus (BE) regarded as precancerous lesion. Glucocorticoid-induced TNFR family-related Receptor (GITR)-mediated inflammation of tumor infiltrating leucocytes (TILs) in the tumor microenvironment might play a role during the multistep carcinogenetic process as either tumor promoting factor according to an inflammatory microenvironment or as a feature of anti-tumor activity.
  
  
  METHODS
  Immunohistochemical analysis of GITR expression was analyzed in esophageal cancer (n=70: 41 EAC with BE, 19 EAC without BE, and n=10 esophageal squamous-cell carcinomas, ESCC), the adenocarcinoma cell line OE-33, and peripheral blood leucocytes (PBLs) of EAC patients, furthermore in biopsies of BE without intraepithelial neoplasia (IN) (n=18). Results were correlated with clinicopathological parameters and five-year survival rates. Immunohistochemical GITR expression results were confirmed on mRNA level (RT-PCR).
  
  
  RESULTS
  Quantification showed a significant increase of 25% GITR positive TILs in EAC with BE (p< 0.05) compared to 13% in adjacent BE, 24% in EAC without BE, 14% in ESCC, and 1% in BE without IN. High GITR levels were not significantly associated with clinicopathologic features which may predict worse clinical outcome and had no impact on survival (p= 0.7878). Increased GITR expression of peripheral blood leucocytes (PBLs) in EAC patients was shown on protein level (32%) and confirmed by RT-PCR (3.7-fold difference compared to normal tissue).
  
  
  CONCLUSIONS
  This study provides for the first time evidence that GITR expression of TILs is associated in the pathogenesis of Barrett's esophagus. Our findings suggest that GITR-expression of TILs is associated with cancer progression. Its role as either tumor promoting factor %according to an in the inflammatory microenvironment or as a feature of anti-tumor activity and promising target for molecular therapies needs to be substantiated in further investigations.
authors.affiliation: Department of General-, Visceral-, Vascular and Pediatric Surgery, University of Wuerzburg Hospital, Germany. Rahden_B@chirurgie.uni-wuerzburg.de
authors.forename: Burkhard H A
authors.initials: BH
authors.lastname: von Rahden
authors.forename: S
authors.initials: S
authors.lastname: Kircher
authors.forename: M
authors.initials: M
authors.lastname: Kafka
authors.forename: L
authors.initials: L
authors.lastname: Stuermer
authors.forename: C
authors.initials: C
authors.lastname: Reiber
authors.forename: S
authors.initials: S
authors.lastname: Gattenlöhner
authors.forename: C T
authors.initials: CT
authors.lastname: Germer
authors.forename: M
authors.initials: M
authors.lastname: Grimm
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein