The Role of the Hedgehog Pathway in Cholangiocarcinoma

Cholangiocarcinoma (CCA) is one of the most refractory malignancies with a high mortality rate. Among all the pathways involved in CCA development, emerging evidence highlights Hedgehog (HH) signaling as a substantial player in CCA-genesis and development. The pro-tumoral function of HH provides potential therapeutic implications, and recently the use of HH inhibitors has paved the way for clinical application in various solid tumors. Targeting HH members, namely Hedgehog ligands, SMO transmembrane protein and GLI transcription factors may thus confer therapeutic options for the improvement of CCA treatment outcome. Cholangiocarcinoma (CCA) is a poorly treatable type of cancer and, along with hepatocellular carcinoma (HCC), is the predominant type of primitive liver cancer in adults. The lack of understanding of CCA biology has slowed down the identification of novel targets and the development of effective treatments. While tumors share some general characteristics, detailed knowledge of specific features is essential for the development of effectively tailored therapeutic approaches. The Hedgehog (HH) signaling cascade regulates stemness biology, embryonal development, tissue homeostasis, and cell proliferation and differentiation. Its aberrant activation has been associated with a variety of solid and hematological human malignancies. Several HH-inhibiting compounds have been indeed developed as potential anticancer agents in different types of tumors, with Smoothened and GLI inhibitors showing the most promising results. Beside its well-established function in other tumors, findings regarding the HH signaling in CCA are still controversial. Here we will give an overview of the most important clinical and molecular features of cholangiocarcinoma, and we will discuss the available evidence of the crosstalk between the HH signaling pathway and the cholangiocarcinoma cell biology.