However, CA 19-9 remains unspecific as it is also increased in benign biliary disorders such as cholestasis or cholangitis. In addition, the diagnostic accuracy of CA 19-9 in patients with PSC remains limited. Consequently, there is a need for new diagnostic approachesto improve the ability of an early detection and subsequently the clinical management of patients with CC. The angiopoietin /Tie2 system consists of the transmembrane Ganoderic-acid-F endothelial tyrosine kinase Tie2 and its antagonistic circulating ligands Angpt-1, and Angpt-2. The balance between the canonical agonist Angpt-1 and its competitive inhibitor, Angpt-2, regulates basal endothelial quiescence. Angpt-2 is strongly expressed in the vasculature of many tumors and it has been suggested that Angpt-2 may act synergistically with other cytokines to promote tumor-associated angiogenesis and tumor progression. It has been proposed that Angpt-2 might play a proangiogenic role in CC. We therefore hypothesized that circulating levels of Angpt-2 might serve as a biomarker for the detection of CC. As the action of CC takes place at the biliary epithelium, we performed Angpt-2 analysis not only in serum, but also in bile in patients with CC, PSC, CC complicating PSC or bile duct stones and investigated Angpt-2 expression in human biopsies by immunohistochemistry. The detection of CC and differentiation from benign biliary strictures is challenging in clinical practice. Consequently, new diagnostic approaches are needed in order to improve the clinical management of patients with CC and tumorpredisposing conditions such as PSC. Proteomic analysis of bile and urine is a new promising technique as it analyzes a complete protein pattern in contrast to classical biochemical methods. However, these studies are complex, time-consuming and expensive and therefore supporting diagnostic tests are of special interest. As the malignant transformation in CC takes place at the biliary epithelium analysis of bile might detect tumor-derived proteins in higher concentrations compared to serum specimens. To date, none of the single markers studied in bile has been implemented in clinical routine so far. Carcinogenesis in patients with CC includes a complex interaction between cancer-associated fibroblasts, remodeling of the extracellular matrix, immune cell migration and stimulation of proangiogenic factors. Particularly, formation of new blood vessels is crucial for tumor maintenance, growth and metastasis as it supplies the neoplasia with essential nutrients and oxygen. Danshensu Vascular endothelial growth factor, VEGF receptors and nerve growth factor-bare crucial mediators of pathological neoangiogenesis in the tumor environment and are also overexpressed in human CC samples favoring neoangiogenesis. Tang et. al analyzed surgically resected human CC samples and reported an association between tissue expression of VEGF, Angpt-2 and tumor microvessel density. The role of the Angpt/Tie2 system, a second class of tyrosine kinase receptors, has not been fully evaluated in CC, but may play a role in tumor angiogenesis of other malignancies. Therefore, we hypothesized that Angpt-2 might also be involved in CC and may serve as a putative novel biomarker. This hypothesis is of high translational relevance as recently function-blocking antibodies against the Tie2 antagonist Angpt-2 have been developed and are currently investigated in ongoing clinical trials.