In Vivo Models for Cholangiocarcinoma—What Can We Learn for Human Disease?

Abstract

Cholangiocarcinoma (CCA) comprises a heterogeneous group of primary liver tumors. They emerge from different hepatic (progenitor) cell populations, typically via sporadic mutations. Chronic biliary inflammation, as seen in primary sclerosing cholangitis (PSC), may trigger CCA development. Although several efforts were made in the last decade to better understand the complex processes of biliary carcinogenesis, it was only recently that new therapeutic advances have been achieved. Animal models are a crucial bridge between in vitro findings on molecular or genetic alterations, pathophysiological understanding, and new therapeutic strategies for the clinic. Nevertheless, it is inherently difficult to recapitulate simultaneously the stromal microenvironment (e.g., immune-competent cells, cholestasis, inflammation, PSC-like changes, fibrosis) and the tumor biology (e.g., mutational burden, local growth, and metastatic spread) in an animal model, so that it would reflect the full clinical reality of CCA. In this review, we highlight available data on animal models for CCA. We discuss if and how these models reflect human disease and whether they can serve as a tool for understanding the pathogenesis, or for predicting a treatment response in patients. In addition, open issues for future developments will be discussed.

Developing models of cholangiocarcinoma to close the translational gap in cancer research

“…Organoids from other tissues have been shown to reflect the biology of the primary tumour more closely than 2D cell lines and improve therapeutic selection. While Mohr et al rightfully argue that organoid cultures are limited by the absence of an intact immune system [110], we believe advancements will be made for CCA PDOs, as we have seen for other cancers [64], that allow for multi-cell-type cultures that represent patient tumours in their entirety in vitro, which will prove valuable for high-throughput drug screening and develop our understanding of the stromal response to therapeutics.. Over the coming years, it will be exciting to watch the expansion of CCA organoid banks that represent the genetic and phenotypic diversity of human CCA. Furthermore, expanding this platform to incorporate an extracellular matrix that more closely resembles that found in CCA, as well as the fibrogenic and immune cells that we know are important in CCA development and in drug responsiveness, will set these complex organoid systems at the front of therapeutic screening and development -not just for small molecules, but for biological agents too.…”

Development of extrahepatic bile ducts and mechanisms of tumorigenesis: Lessons from mouse models

“…GEMMs can create not only genetic alterations that are found in humans in the biliary epithelium, but also assess changes in the surrounding microenvironment due to inflammation or chemical exposure, for example, inflammatory cell infiltration, fibrosis, and so on. 18,21 For example, in human diagnostic pathology, papillomatosis, which generates papillary and cystic dilated ducts, was classified as a benign lesion (currently, it is classified as IPNB with low-grade dysplasia 23 ). iFGF10 mice develop this papillomatosis-like lesion, which then progresses to a malignant lesion with more dysplasia resulting from the continuous severe inflammation present.…”

Unmet needs in basic and translational research in Cholangiocarcinoma

“…This calls into question whether the generation of experimental models is able indeed to recapitulate this protean disease condition and to reproduce the consistency of management of CCA. In fact, despite the availability of several animal models with different approaches, including chemically induced, implantation, genetically‐engineered mouse models (GEMM) or hydrodynamic gene delivery, 106‐110 it is still uncertain whether and to what extent they may reproduce the various features of CCA, as essentially they are all models of iCCA, which is the less frequent type among clinical CCAs 108,109 . A further gap in our knowledge of these models is the lack of characterization of the pathophysiological sequence that leads from biliary inflammation and fibrosis to dysplasia and cancer.…”

“…or hydrodynamic gene delivery, [106][107][108][109][110] it is still uncertain whether and to what extent they may reproduce the various features of CCA, as essentially they are all models of iCCA, which is the less frequent type among clinical CCAs. 108,109 A further gap in our knowledge of these models is the lack of characterization of the pathophysiological sequence that leads from biliary inflammation and fibrosis to dysplasia and cancer.…”