Cholangiocarcinomas can originate from hepatocytes in mice

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Significance The precise roles of E-cadherin in the liver and liver carcinogenesis are still unknown. Here we show that mice lacking E-cadherin in the liver develop spontaneous periportal inflammation via an impaired intrahepatic biliary network, as well as periductal fibrosis, which resembles primary sclerosing cholangitis. Inducible gene knockout studies identified E-cadherin loss in biliary epithelial cells as a causal factor of cholangitis induction, and dysregulated E-cadherin expression was also seen in patients with primary sclerosing cholangitis. E-cadherin loss also significantly accelerates genetically and chemically engineered liver cancer through epithelial–mesenchymal transition, up-regulation of stem cell markers, and ERK activation. Thus, E-cadherin plays critical roles in maintaining homeostasis and suppressing carcinogenesis in the liver.

Section: Discussionmentioning

confidence: 99%

Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis

Nakagawa

Hikiba

Hirata

et al. 2014

105

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confidence: 99%

“…Although CC is considered to originate from biliary epithelial cells (BECs), recent studies have suggested that multiple cell types could develop into CC (6)(7)(8). For example, hepatocytes can transdifferentiate into biliary cells through activation of Notch signaling and eventually give rise to ICC (6,7). With regard to the EHBD, recent anatomical and immunohistochemical (IHC) analyses revealed that peribiliary glands (PBGs), clusters of epithelial cells residing in the submucosal compartment of the EHBD, form epithelial networks within the walls of EHBDs and might function as BEC stem-cell niches.…”

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confidence: 99%

Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

Nakagawa

Suzuki

Hirata

et al. 2017

The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras-and TGFβ/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell-specific Kras activation and a TGFβ receptor type 2 (TGFβR2) deletion were first generated by crossing LSL-Kras G12D , Tgfbr2 flox/flox , and K19 CreERT mice (KT-K19 CreERT ). However, KT-K19 CreERT mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas. Next, to analyze the additional effect of E-cadherin loss, KT-K19 CreERT mice were crossed with CDH1 flox/flox mice (KTC-K19 CreERT ). Surprisingly, KTC-K19 CreERT mice exhibited a markedly thickened EHBD wall accompanied by a swollen gallbladder within 4 wk after tamoxifen administration. Histologically, invasive periductal infiltrating-type ECC with lymphatic metastasis was observed. Time-course analysis of EHBD revealed that recombined BECs lining the bile duct lumen detached due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs), which are considered a BEC stem-cell niche. Detached dying BECs released high levels of IL-33, as determined by microarray analysis using biliary organoids, and stimulated inflammation and a regenerative response by PBGs, leading eventually to ECC development. Cell lineage tracing suggested PBGs as the cellular origin of ECC. IL-33 cooperated with Kras and TGFβR2 mutations in the development of ECC, and anti-IL-33 treatment suppressed ECC development significantly. Thus, this mouse model provided insight into the carcinogenic mechanisms, cellular origin, and potential therapeutic targets of ECC.extrahepatic cholangiocarcinoma | IL-33 | organoid | ILC2 | amphiregulin

“…Mouse models have proven a powerful tool for understanding the relationship between cancer genetics and tumor behavior, but only a few genetically engineered mouse models (GEMMs) of ICC exist and many display a mixed ICC/hepatocellular carcinoma (HCC) histology (10)(11)(12)(13). A histopathologically accurate ICC model has been produced by liver-specific expression of endogenous Kras G12D mutant in combination with Tp53 tumor suppressor gene deletion (14).…”

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confidence: 99%

Mouse model of intrahepatic cholangiocarcinoma validates FIG–ROS as a potent fusion oncogene and therapeutic target

Saborowski

Davare

et al. 2013

Cholangiocarcinoma is the second most common primary liver cancer and responds poorly to existing therapies. Intrahepatic cholangiocarcinoma (ICC) likely originates from the biliary tree and develops within the hepatic parenchyma. We have generated a flexible orthotopic allograft mouse model of ICC that incorporates common genetic alterations identified in human ICC and histologically resembles the human disease. We examined the utility of this model to validate driver alterations in ICC and tested their suitability as therapeutic targets. Specifically, we showed that the fused-in-glioblastoma-c-ros-oncogene1 (FIG-ROS1(S); FIG-ROS) fusion gene dramatically accelerates ICC development and that its inactivation in established tumors has a potent antitumor effect. Our studies establish a versatile model of ICC that will be a useful preclinical tool and validate ROS1 fusions as potent oncoproteins and therapeutic targets in ICC and potentially other tumor types.C holangiocarcinoma, the second most common primary liver cancer, has a dismal prognosis due to its poor responsiveness to existing therapies. It represents 10-25% of primary liver cancers worldwide (1), but is more frequent in Asia, due to a higher prevalence of risk factors such as parasitic infections, biliary-duct cysts, hepatolithiasis, and primary sclerosing cholangitis (2). Intrahepatic cholangiocarcinoma (ICC) develops within the liver parenchyma, shows markers of cholangiocyte differentiation, including positivity for cytokeratin 19, and leads to abundant stromal desmoplasia. Whereas surgical resection can be curative, most patients are not eligible for this procedure due to advanced disease, and no effective systemic therapy has been developed to date (3, 4).Sequencing efforts are beginning to generate in-depth information about the somatic alterations that occur in cholangiocarcinoma. Among the most frequently mutated genes are the tumor suppressor tumor protein p53 (TP53) (37-44%) (5, 6) and the kirsten rat sarcoma viral oncogene homolog (KRAS) (17-54%) (6-8), although mutations in MLL3 and SMAD4 are also common (15% and 17% of cases, respectively) (6). Despite their high mutational frequency, none of these signature genes is amenable to targeted therapy.Recently, the mutational spectrum of cholangiocarcinoma has been extended by the identification of ROS1 fusions in nearly 9% of cholangiocarcinoma patients (9). Oncogenic fusion kinases involving the orphan receptor tyrosine kinase ROS1 have been previously reported at low frequency in lung adenocarcinoma and glioblastoma and result from chromosomal rearrangements that lead to constitutive activation of the ROS1 kinase activity. Consequently, ROS1 presents a potential drug target for a subset of patients with ICC.Mouse models have proven a powerful tool for understanding the relationship between cancer genetics and tumor behavior, but only a few genetically engineered mouse models (GEMMs) of ICC exist and many display a mixed ICC/hepatocellular carcinoma (HCC) histology (10-13). A histopathologica...