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  • Cholestasis the retention of bile acids normally excreted

    2019-07-08

    Cholestasis, the retention of bile acids normally excreted into bile within the liver, elicits a toxic response leading to liver injury [41]. Cholestasis is a prominent component of several chronic biliary tract diseases such as primary sclerosing cholangitis, primary biliary cirrhosis, and biliary atresia [41]. Chronic cholestasis promotes CCA carcinogenesis by inducing genetic aberrations and pro-survival signaling pathways. Cholestasis alone or in combination with chemical carcinogens serves as the basis for several animal models of liver injury or CCA. One of the earlier cholestatic CCA models was reported by Thamavit et al. [18]. In this model, cholestasis was achieved via left and medial bile duct ligation (LMBDL). The combination of DMN and LMBDL resulted in CCA formation in approximately 40% of the mice after 40 weeks of treatment [18]. A more recent model utilized the combination of DEN and cholestasis [42]. Following two weekly DEN intraperitoneal injections, chronic cholestasis was induced by LMBDL. One week after LMBDL mice received DEN in corn oil via oral gavage. This combination resulted in CCA formation in 50% (5/10) of the animals by week 28, whereas none of the animals undergoing LMBDL alone or DEN administration alone developed CCA [42]. The advantages of this model include a higher tumor incidence and shorter duration to tumor development compared to prior similar models. However, it does require significant technical skill.
    CCA xenograft and allograft models Tumor graft models are commonly used in cancer studies. They permit investigation of novel therapeutic compounds, while remaining easy to use and cost effective. There are multiple types of graft models, the most common being the xenograft model, but many models implore the allograft as well [43].
    Genetic models of CCA Genetically engineered models (GEMs) of CCA include transgenic models and transduction models. Genetic models are an important tool in cancer investigation for elucidating complex biologic pathways, molecular processes, as well as for studying the role of oncogenes and tumor suppressor genes. Indeed, the possibility to generate animal models which have the potential to recapitulate specific genetic AUY922 (NVP-AUY922) as well as the biochemical, proteomic and phenotypic features observed in human CCA has enabled important progress in the understanding of CCA cancer. In these models, tumors develop spontaneously in situ in an immunocompetent organism with the appropriate tumor microenvironment. Before the development of Crispr/Cas9 system [90], the most commonly used systems to develop these models were Cre-Lox, tetracycline-dependent promoter regulation and FLP-mediated site-specific and spontaneous recombination methods [[91], [92], [93]]. Although genetic models can be quite informative in terms of elucidating mechanisms, they are not very time efficient and can be technically challenging and expensive. Moreover, these models may have uncontrolled pattern expression of the transgenes and their random integration can induce unexpected results [94].
    Conclusion and future directions Animal models are essential tools in cancer research that permit the study of cancer biology and novel therapeutic agents. Historically, animal models of CCA were carcinogen based or xenograft models. Carcinogen based models are not specific for CCA development as various carcinogens can give rise to other tumor types. Xenograft models with xenotransplantation of CCA cell lines develop in a species mismatched immunodeficient host. A syngeneic orthotopic transplantation model in rats overcame these shortcomings. However, the primary limitation of this model was that there are fewer reagents for rats than there are for mice. There are several transgenic mouse models which can be quite informative in terms of elucidating mechanisms. However, these models are not very time efficient, can be technically challenging and expensive. In a recently developed transduction model in which oncogenes (AKT/YAP) are instilled directly into the biliary tree [89], tumors arise from the biliary tract in immunocompetent hosts with species-matched tumor microenvironment. This model is time efficient and closely mimics features of human CCA. Malignant cell lines derived from these tumors can in turn be implanted into mice resulting in a unique syngeneic orthotopic mouse model of CCA that overcomes the shortcomings of the orthotopic rat model. The vast majority of available CCA models are those of iCCA. PDX models can allow the study of pCCA/dCCA, however, there remains the issue of species mismatch as these are xenografts. As the majority of CCAs are pCCA/dCCA there is a need to develop specific animal models for these subtypes.