title: Dkk-3 expression in the tumor endothelium: a novel prognostic marker of pancreatic adenocarcinomas.
abstract: Dkk-3 is proposed to be a new specific marker for tumor endothelial cells. Here we analyzed the clinical relevance of Dkk-3 expression in pancreas adenocarcinomas and determined its role on endothelial cell growth in vitro. Microvessel density in tumor samples was immunohistochemically determined using Dkk-3 and CD31 as endothelial cell markers, respectively. Based on the median microvessel density as a cut-off point, patients were categorized into high and low microvessel density groups and a correlation with survival and clinical parameters was assessed. Moreover, the role of Dkk-3 expression on chemosensitivity of endothelial cells was analyzed. In contrast to CD31 staining, Dkk-3-positive vessels were found only in tumor tissue and Dkk-3 microvessel density significantly correlated negative with tumor grading. In survival analysis the median survival time was 7 months for patients with Dkk-3 low, and 15 months for Dkk-3 high microvessel density (P = 0.0013). Subset analysis of patients receiving gemcitabine therapy showed that overall survival was significantly decreased in Dkk-3 low tumors than in high tumors (P = 0.009). In Cox regression Dkk-3 emerged as a significant independent parameter (P = 0.024). Dkk-3 overexpression in endothelial cells resulted in significantly enhanced growth inhibition after 5-fluorouracil or gemcitabine treatment compared to control endothelial cells and cancer cell lines. Dkk-3 low microvessel density was associated with tumor progression and worse clinical outcome. Overexpression of Dkk-3 enhanced endothelial cell growth inhibition to chemotherapeutic drugs. Therefore, we suggest that Dkk-3 high microvessel density may help to select patients who may benefit from chemotherapy.
authors.affiliation: Department of Haematology and Oncology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Dominic
authors.initials: D
authors.lastname: Fong
authors.forename: Martin
authors.initials: M
authors.lastname: Hermann
authors.forename: Gerold
authors.initials: G
authors.lastname: Untergasser
authors.forename: Daniela
authors.initials: D
authors.lastname: Pirkebner
authors.forename: Anna
authors.initials: A
authors.lastname: Draxl
authors.forename: Martin
authors.initials: M
authors.lastname: Heitz
authors.forename: Patrizia
authors.initials: P
authors.lastname: Moser
authors.forename: Raimund
authors.initials: R
authors.lastname: Margreiter
authors.forename: Paul
authors.initials: P
authors.lastname: Hengster
authors.forename: Albert
authors.initials: A
authors.lastname: Amberger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000256:Adenoviridae / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018925:Chemokines; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D013997:Time Factors; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins