## 1 Introduction: The Biliary Epithelium in Normal and Pathological Conditions  
The human biliary epithelium, which is formed by cholangiocarcinoma, originates at the level of the biliary pole. Cholangiocytes represent the second cellular hepatic population after hepatocytes, corresponding to 3-5% of the total epithelial cells, whose morphology depends on their position in the biliary tree [1]. Cholangiocytes play an active role in both homeostatic and pathologic conditions and they modify the composition of canalicular bile through their several secretory activities [2; 3; 4]. These cells are able to activate a number of intracellular cascades: they respond to inflammatory insults through a large variety of proinflammatory mediators that, via autocrine or paracrine mechanisms, determine cell proliferation, and mediate interaction with other liver cells, like hepatocytes, stem/progenitor cells, hepatic stellate cells (HCS), and endothelial and inflammatory cells [5].  
The biliary network consists of intra- and extrahepatic bile ducts: IIBDs and EHBDs. IHBDs includes, progressively, ductular-canalicular junctions, Hering's canals, bile ductules, interlobular, septal, and zonal and segmental ducts, whereas EHBDs consists of hepatic ducts. The ductular-canalicular junction is characterized by the resident progenitor cells compartment of the liver. Hering's canals and ductules are lined by cubic cholangiocarcinomaytes. Interlobular, septal, and bile ductules are considered small bile ducts, while zonal and segmental ducts are considered large bile ducts. In fact, within small and progressively larger bile ducts, cholangiocarcinomaytes increase their height and width, showing a morphological, as well as a functional, heterogeneity [6; 7]. Cholangiopathies are diseases in which the biliary epithelium represents the main target and they are characterized by an alteration of the correct balance between proliferation and loss of cholangiocarcinomaytes that is physiologically/normally regulated by several factors such as somatostatin, secretin, gastrin, serotonin, and melatonin [8; 9; 10; 11; 12]. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are diffused cholangopathies. In PBC patients there is no substantial increase in the risk of liver cancer development [13]. In contrast, PSC is strongly associated with liver cancer development risk: classical PSC of large ducts is the most important risk factor for biliary cancer in developed countries [14; 15]. Therefore, in response to different injury, cholangiocarcinomaytes adapt their phenotype, reacting, and secreting proinflammatory mediators and contributing actively to disease progression or resolution [3]. Moreover, the complexity of the intrahepatic biliary tree represents nowadays an open challenge for liver tissue engineering. Progress in both bioengineered scaffolds and in vitro cholangiocarcinomaytes culture has led to the employment of cellular constructs to replace or repair the biliary tree [16; 17; 18]. Several studies support the concept that biliary development and homeostasis is coordinately regulated by different autocrine factors, including angiogenic factors. In fact, angiogenesis represents the biological process that leads to the formation of new vessels from pre-existing blood and lymphatic vessels through a well-planned cascade of events. In malignant tumors and in the carcinogenesis of biliary tumors, it is dysregulated and neoplastic cells secrete or induce the microenvironment to produce pro-angiogenic signals which are able to expand endothelial cells and to sustain tumor growth. In biliary cancers, many angiogenic factors, such as the vascular endothelial growth factor (VEGF)-A is expressed in more than half of patients and it is correlated with stage, metastasis, and survival rate [19; 20]. Therefore, it is important to focus on the link between angiogenic factors and biliary tumor to better detect the possible therapeutic strategies in the prevention of tumor progression, metastasis, and invasion.