br Transparency document br Acknowledgements Own research
Acknowledgements Own research included in this review article was funded by the University Hospital Frankfurt, Frankfurt am Main, Germany and grants of the German Research Foundation (DFG) (CH 806/1-1).
Introduction Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma. CCAs are epithelial tumors likely originating from the biliary tree and are classified into three subtypes based on their anatomic location . Intrahepatic cholangiocarcinoma (iCCA) originates above the second order bile ducts within the hepatic parenchyma . Perihilar CCA (pCCA) arises between the second-order bile ducts and the cystic duct; pCCA is the most common type of CCA, accounting for approximately 50–70% of CCAs in different series [3,4]. Distal CCA (dCCA), arises distal to the cystic duct . Each anatomic subtype has a distinct epidemiology, molecular pathogenesis, and management. Overall, CCA is a relatively rare malignancy, representing 3% of all gastrointestinal cancers . Although the incidence of CCA has increased over the past three decades, the prognosis remains poor with a 5-year overall survival of <10% [6,7]. Potentially curative options such as surgical resection and liver transplantation (for pCCA) are limited to the subset of patients with early stage disease. For patients with advanced disease not amenable to surgical options, the standard of care is systemic chemotherapy with gemcitabine and cisplatin. However, the median overall survival with this regimen is <1 year . Hence, there is a critical need for development of effective targeted molecular therapies for CCA. Such a precision medicine approach requires greater insight into the molecular pathogenesis of CCA. In cancer research, in vitro studies utilizing cell culture are generally used to investigate the biochemical processes of cancer AWD 131-138 . However, this approach is not sufficient to investigate the myriad of biologic process occurring in tumors including cell survival, inflammation, angiogenesis, and mutations. Although cell culture models have advantages including high reproducibility, homogeneity and highly controlled experimental conditions, cultured cells typically have uniform phenotypic and genetic characteristics; hence, it is challenging to study interactions between different cell types within a tumor or investigate the role of various biologic processes. Moreover, investigating novel therapeutic targets ultimately requires preclinical studies in animal models. Hence, the use of in vivo models is necessary in cancer research. The ideal animal model of CCA would originate from the biliary tract in an immunocompetent host with a species-matched microenvironment; have time-efficient tumor development; recapitulate the genetic, anatomic, and phenotypic features of human CCA (Table 1). Assessment of such a model would require anatomic, histopathologic, and genetic characterization as well as evaluation of liver injury or dysfunction (Table 2). Herein, we review the available animal models of cholangiocarcinoma, summarizing the strengths and weaknesses of the different models with a focus on carcinogen-based, xenograft, allograft, and genetic models. These animal models represent iCCA; we are still in need of pCCA and dCCA animal models of CCA.
Carcinogen-based CCA animal models In chemical models, CCA is induced by administration of a carcinogen such as dimethylnitrosamine (DMN), thioacetamide (TAA) or furan. These carcinogenic compounds can be used to either induce a genotoxic effect with deoxyribonucleotide acid (DNA) structural changes or to enhance tumor formation via expansion of preneoplastic cells. Other carcinogens include infectious agents such as the liver flukes Opisthorchis viverrini (O. viverrini) and Clonorchis sinensis, known risk factors for CCA in Southeast Asia .
Cholestatic models of CCA