Abstract
Simple SummaryCholangiocarcinoma (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.
Highlights
Primary liver cancer (PLC) is one of the most common cancers worldwide and is the second leading cause of cancer-related mortality [1,2]
Even though the function and the mechanisms of action of the HH pathway in CCA biology are still poorly explored and not completely understood, available data suggest a prominent role for HH in supporting cholangiocarcinoma malignant properties
The expression of Hedgehog signaling members has been analyzed in a cohort of 50 human CCA tissues, where GLI1 and Patched 1 (PTCH1) have been found overexpressed in approximately 50% and 30% of cases, respectively, together with SHH, detecting a significant activation of Hedgehog in almost 50% of cases [56]
Summary
Primary liver cancer (PLC) is one of the most common cancers worldwide and is the second leading cause of cancer-related mortality [1,2]. Primary liver tumors are grossly classified in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Diagnosis is based on a combination of modalities, but, so far, no specific markers have been identified [1,2]. Another aspect contributing to the very poor survival rate of this tumor is its unresponsiveness to conventional therapies [3,4]. CCAs are generally asymptomatic in early stages and are usually diagnosed at an advanced unresectable stage and, chemotherapy improves the quality of life of these patients, it remains only a palliative treatment [1,2]. The goal of this review is to highlight the importance of the Hedgehog signaling pathway in the cholangio-carcinogenesis as a novel druggable candidate for this disease
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