Evolution of the Experimental Models of Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a rare, aggressive disease with poor overall survival. In advanced cases, surgery is often not possible or fails; in addition, there is a lack of effective and specific therapies. Multidisciplinary approaches and advanced technologies have improved the knowledge of CCA molecular pathogenesis, highlighting its extreme heterogeneity and high frequency of genetic and molecular aberrations. Effective preclinical models, therefore, should be based on a comparable level of complexity. In the past years, there has been a consistent increase in the number of available CCA models. The exploitation of even more complex CCA models is rising. Examples are the use of CRISPR/Cas9 or stabilized organoids for in vitro studies, as well as patient-derived xenografts or transgenic mouse models for in vivo applications. Here, we examine the available preclinical CCA models exploited to investigate: (i) carcinogenesis processes from initiation to progression; and (ii) tools for personalized therapy and innovative therapeutic approaches, including chemotherapy and immune/targeted therapies. For each model, we describe the potential applications, highlighting both its advantages and limits.

PD-L1, TMB, MSI, and Other Predictors of Response to Immune Checkpoint Inhibitors in Biliary Tract Cancer

“…The last decade has registered important advances in the understanding of the tumor biology of BTCs, as witnessed by the parallel development of novel treatment options and genomic sequencing, which has paved the way toward the identification of several possible therapeutic targets [ 13 , 14 , 15 ]. In fact, molecularly targeted therapies have been tested in BTC patients harboring specific druggable alterations, especially in iCCAs where agents targeting isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor (FGFR) aberrations have entered into clinical practice [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ]; in addition, following the results observed in several hematological and solid malignancies, immune checkpoint inhibitors (ICIs) have been explored and are currently being investigated in BTC ( Table 1 ) [ 23 , 24 , 25 ].…”

Independent Risk Factors of Early Recurrence After Curative Resection for Perihilar Cholangiocarcinoma: Adjuvant Chemotherapy May Be Beneficial in Early Recurrence Subgroup

“…In recent years, immunotherapy has shown encouraging results in some tumors and has become increasingly popular. 3 In our opinion, the creation of a suitable immunocompetent scheme for CCA could play a prominent role in the next 5 years. Immunotherapy combined with chemotherapy (camrelizumab plus GEMOX [a gemcitabine and oxaliplatin regimen]) has been investigated and shown promising antitumor efficacy in biliary tract cancer.…”

“…Cholangiocarcinoma (CCA) is a challenging biliary tract tumor that is often difficult to diagnose and treat. [1][2][3] According to different tumor characteristics, CCA can be divided into 3 groups: intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), and distal cholangiocarcinoma (dCCA). 4 pCCA represents the most common type of biliary tract cancer and is often characterized in terms of pathology by aggressive biological behavior.…”

Severe Salmonella spp. or Campylobacter spp. Infection and the Risk of Biliary Tract Cancer: A Population-Based Study

“…Although the genomic landscape of BTC is incredibly diverse, multiple preclinical and clinical models show that BTC development may be associated with the alteration of several actionable genes. A particular example is the overexpression of cyclophilin-A in patients with liver-fluke-associated cholangiocarcinoma [ 32 , 33 ]. Identification of inflammation-associated driving mutations is an important topic as it has implications for both risk profiling and potential personalized treatment.…”