Animal models of cholangiocarcinoma

Loeuillard, Emilien; Fischbach, Samantha R.; Gores, Gregory J.; Rizvi, Sumera

doi:10.1016/j.bbadis.2018.03.026

Cited by 59 publications

(70 citation statements)

References 120 publications

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“…Several genetic mouse models of cholangiocarcinoma have been generated by Cre recombinase-mediated gene alterations. [35][36][37] These models often induce genetic modifications at prenatal stages, or simultaneously in multiple liver cell types. For these reasons, they are not optimally suited for analysis of tumor progression starting from a well-identified adult liver cell type.…”

Section: Discussionmentioning

confidence: 99%

“…[32][33][34] Animal models are invaluable for investigating intra-and extrahepatic CCA development, and several models were designed based on induction of cholestasis, administration of tumor-promoting agents, injection of tumor cells, and generation of genomic alterations. [35][36][37] However, limited attention was paid to tumor initiation and progression, and in several instances genetic alterations were induced at the prenatal stage or simultaneously in hepatocytes and cholangiocytes, unlike in humans. Here, we generated an original mouse model of iCCA tumorigenesis in which expression of the oncogenic mutant Kras G12D is specifically induced in cholangiocytes and is combined with diet-induced inflammation that mimics chronic cholangitis.…”

Section: Introductionmentioning

confidence: 99%

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A novel mouse model of cholangiocarcinoma uncovers a role for a SOX17-Tensin 4 pathway in tumor progression

Di-Luoffo

Pirenne

Saandi

et al. 2019

Preprint

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Background & AimsAlthough earlier diagnosis and treatment of intrahepatic cholangiocarcinoma (iCCA) is necessary to improve therapy, there is still limited information available about initiation and evolution of iCCA precursor lesions. Therefore, there is a need to identify mechanisms driving formation of precancerous lesions and their progression towards invasive tumor using experimental models that faithfully recapitulate human tumorigenesis.MethodsWe generated a new mouse model which combines cholangiocyte-specific expression of KrasG12D with 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-induced inflammation to mimic iCCA development in patients with cholangitis. Histological and transcriptomic analyses of the mouse precursor lesions and iCCA were performed and compared with human analyses. The function of genes overexpressed during tumorigenesis was investigated in human cell lines.ResultsMice expressing KrasG12D in cholangiocytes and fed a DDC diet developed cholangitis, ductular proliferations, intraductal papillary neoplasms of bile ducts (IPNBs) and eventually iCCAs. The histology of mouse and human IPNBs were highly similar, and mouse iCCAs displayed histological characteristics of human mucin-producing large duct type iCCA. Signaling pathways activated in human iCCA were activated in mice. The identification of transition zones between IPNB and iCCA on tissue sections, combined with RNA-sequencing analyses of the lesions supported that iCCAs derive from IPNBs. We provide evidence that a gene cascade which comprises KRASG12D, SRY-related HMG box transcription factor 17 (SOX17) and Tensin 4 (TNS4), and which is activated by epidermal growth factor, promotes tumor progression.ConclusionsWe developed a novel mouse model that faithfully recapitulates human iCCA tumorigenesis and identified a gene cascade promoting tumor progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel mouse model of cholangiocarcinoma uncovers a role for a SOX17-Tensin 4 pathway in tumor progression

Di-Luoffo

Pirenne

Saandi

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Proper chemically induced mouse models should better reflect the clinical background of CCA patients, such as the presence of chronic cholestasis, which has an active role in CCA onset due to the induction of genetic aberrations and pro-survival signaling pathways [146]. For this purpose, a recent model showed the tumorigenicity of intraperitoneal administration of DEN for 2 weeks prior to the left and median bile duct ligation (LMBDL), responsible for cholestasis, and DEN gavage once a week, 7 days after LDMB [150].…”

Section: Chemically Induced Rodent Modelsmentioning

confidence: 99%

Evolution of the Experimental Models of Cholangiocarcinoma

Massa

Varamo

Vita

et al. 2020

Cancers

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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.

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“…Functions of estrogen receptors may differ between ER-α and ER-β. Thioacetamide (TAA) is a carcinogen which induces liver fibrosis, cirrhosis, and CCA [53,54]. Administration of KB9520, a selective ER-β agonist, decreased cell proliferation and increased apoptosis in HuH-28 cells in vitro [55].…”

Section: Estrogenmentioning

confidence: 99%

Neuroendocrine Changes in Cholangiocarcinoma Growth

Sato

Francis

Zhou

et al. 2020

Cells

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Cholangiocarcinoma (CCA) is a highly aggressive malignancy that emerges from the biliary tree. There are three major classes of CCA—intrahepatic, hilar (perihilar), or distal (extrahepatic)—according to the location of tumor development. Although CCA tumors are mainly derived from biliary epithelia (i.e., cholangiocytes), CCA can be originated from other cells, such as hepatic progenitor cells and hepatocytes. This heterogeneity of CCA may be responsible for poor survival rates of patients, limited effects of chemotherapy and radiotherapy, and the lack of treatment options and novel therapies. Previous studies have identified a number of neuroendocrine mediators, such as hormones, neuropeptides, and neurotransmitters, as well as corresponding receptors. The mediator/receptor signaling pathways play a vital role in cholangiocyte proliferation, as well as CCA progression and metastases. Agonists or antagonists for candidate pathways may lead to the development of novel therapies for CCA patients. However, effects of mediators may differ between healthy or cancerous cholangiocytes, or between different subtypes of receptors. This review summarizes current understandings of neuroendocrine mediators and their functional roles in CCA.

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Animal models of cholangiocarcinoma

Cited by 59 publications

References 120 publications

A novel mouse model of cholangiocarcinoma uncovers a role for a SOX17-Tensin 4 pathway in tumor progression

A novel mouse model of cholangiocarcinoma uncovers a role for a SOX17-Tensin 4 pathway in tumor progression

Evolution of the Experimental Models of Cholangiocarcinoma

Neuroendocrine Changes in Cholangiocarcinoma Growth

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