Dkk‐3 expression in the tumor endothelium: A novel prognostic marker of pancreatic adenocarcinomas

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. ( Cancer Sci 2009)