Abstract
Angiogenesis plays a fundamental role in tumor growth and progression. It is regulated by several growth factors, including vascular endothelial growth factor protein family (VEGF) and its receptors, which are probably the most important factors responsible for the development of new vessels. The VEGF family includes several members: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, placental growth factor (PlGF), and their receptors VEGFR-1, VEGFR-2 and VEGFR-3. Other relevant factors are represented by angiopoietins, thrombospondin-1, and endothelins. However, since the therapeutic benefit associated with VEGF-targeted therapy is really complex, a better understanding of these pathways will lead to future advances in the use of these agents for clinic management of tumors. Here we present a review regarding the role of angiogenic factors in cholangiocarcinoma, which arise from cholangiocytes, the epithelial cells of bile ducts. They are rare and aggressive neoplasms with a poor prognosis and limited treatment options, classified as intrahepatic, perihilar, and distal cholangiocarcinoma based on their anatomical location. Therefore, the identification of specific signaling pathways or new tumor biomarkers is crucial in order to develop more effective anti-angiogenic therapies.
Highlights
The Biliary Epithelium in Normal and Pathological ConditionsThe human biliary epithelium, which is formed by cholangiocytes, originates at the level of the biliary pole
Union for International Cancer Control (UICC) in two major categories, according to their anatomical origin in the biliary tree: Intrahepatic cholangiocarcinoma, which accounts for about 20% of tumors developing within the liver, from the bile duct of the second order and from the most proximal intrahepatic bile duct, and extrahepatic bile duct carcinoma, which represents 80% of CCAs and it can be classified into perihilar (60–70%) and distal (20–30%). pCCA spreads between the second-order bile ducts and the attachment of the cystic duct into the common bile duct, whereas dCCA grows in areas between the cystic duct and the ampulla of Vater [22,23] (Figure 1)
CCA is characterized by desmoplastic stroma with α-SMA positive cancer-associated fibroblasts (CAFs)
Summary
The human biliary epithelium, which is formed by cholangiocytes, originates at the level of the biliary pole. 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 complexity of the intrahepatic biliary tree represents nowadays an open challenge for liver tissue engineering Progress in both bioengineered scaffolds and in vitro cholangiocytes culture has led to the employment of cellular constructs to replace or repair the biliary tree [16,17,18]. 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
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