Table 1.

Animal models of cholangiocarcinoma.

Mice with xenograft tumors
Experimental Approach	Key Features	Study
Injection of 3 × 106 Mz-ChA-1 cells	Tumor development in 3 weeks	Fava et al. 112
Injection of 5 × 106 Sk-ChA-1 cells +/− intratumoral tamoxifen injections	Significantly decreased CCA development with intratumoral tamoxifen injections	Pawar et al. 113
Injection of 2 × 106 QBC939 cells +/− magnetic nanoparticle injections via tail vein	CCA tumor growth inhibition with magnetic nanoparticles	Tang et al. 114
Injection of IL6 overexpressed Mz- ChA-1 stable cell line (Mz-ChA-IL6) vs. control vector Mz-ChA-1 cell line	Overexpression of IL6 increased growth of xenograft tumors	Meng et al. 43
Injection of miR26a overexpressed CCLP1 cell line vs. scramble control CCLP1 cell line	Overexpression of miR26a increased growth of xenograft tumors	Zhang et al. 115
Injection of miR494 overexpressed stable HuCCT1 cell line vs. control vector HuCCT1 cell line	Overexpression of miR494 increased growth of xenograft tumors	Olaru et al. 116
Injection of stable QBC939 cell line transfected with Slug siRNA vs. control vector QBC939 cell line	Slug silencing suppressed growth of xenograft tumors	Zhang et al. 117
Injection of CypA silenced stable M139 cell line vs. control vector M139 cell line	CypA silencing decreased growth of xenograft tumors	Obchoei et al. 118
Injection of stable QBC939 cell line transfected with Beclin-1 siRNA vs. control vector QBC939 cell line	Beclin-1 silencing decreased growth of xenograft tumors	Hou et al. 119
Genetically Engineered Mouse Models
Experimental Approach	Key Features	Study
Liver specific inactivation of SMAD4 and PTEN.	Tumor formation in all animals at 4–7 months of age	Xu et al. 120
Chronic carbon tetrachloride exposure in TP53-deficient mice.	Development of tumors with dense peritumoral fibrosis and other histologic and genetic features of human iCCA.	Farazi et al. 121
Liver-specific inactivation of macrophage stimulating factor 1 and 2	Tumor development (HCC or CCA) in all mice by 6 months of age	Song et al. 122
Liver-specific ablation of WW45, a homolog of Drosophila Salvador and adaptor for the Hippo kinase	Development of tumors with mixed histological features of HCC and CCA	Lee et al. 123
Liver-specific activation of KRAS and deletion of TP53.	Development of stroma-rich tumors. Shortened time to tumor development and increased metastasis with the combination of KRAS activation and TP53 deletion	O’Dell et al. 124
Overexpression of intracellular domain of Notch1 in livers of transgenic mice	Formation of tumors with features characteristic of iCCA	Zender et al. 86
Orthotopic Rat Models
Experimental Approach	Key Features	Study
Inoculation of BDEneu cells into bile duct of isogenic rats	Rapid (21–26 d) development of cholangiocarcinoma characterized by biliary obstruction and gross peritoneal metastasis; origin of tumor stroma and tumor tissue from same species (rat)	Sirica et al. 125
Three-dimensional organotypic culture model of CCA in rats	Stromal microenvironment, gene expression profile, and pathophysiological characteristics which mimic desmoplastic iCCA in vivo	Campell et al. 126
Carcinogen-induced Models
Experimental Approach	Key Features	Study
Furan induced cholangiocarcinogenesis in rat liver.	Formation of mucin-producing CCA tumors; overexpression of C-NEU and MET	Radaeva et al. 55
Chronic administration of thioacetamide in lean rats and rats with faulty leptin receptors	Increased development and growth of CCA tumors in lean rats treated with thioacetamide	Fava et al. 127
Administration of diethylnitrosamine (DEN) +/− left and median bile duct ligation (LMBDL) to induce chronic cholestasis and CCA development	Increased CCA progression in mice with LMBDL given DEN compared to mice without LMBDL given DEN	Yang et al. 128
Inoculation with Opisthorchis viverrini and administration of dimethynitrosaminein hamsters	Development of pus and tumor in liver starting at 20 weeks after O. viverrini infection/DEN administration; all hamsters in experimental group were dead by 28 weeks	Plengsuriyakarn et al. 129

BDEneu, highly malignant cholangiocarcinoma cell line; CCA, cholangiocarcinoma; CCLP1, cholangiocarcinoma cell line; C-NEU, rat homologue of human ERBB2; CypA, cyclophilin A; HCC, hepatocellular carcinoma; HuCCT1, cholangiocarcinoma cell line; IL6, interleukin-6; KRAS, Kirsten rat sarcoma viral oncogene homolog; MET, met proto-oncogene; M139, cholangiocarcinoma cell line; miR, microRNA; Mz-ChA-1, cholangiocarcinoma cell line; O. viverrini, Opisthorchis viverrini; PTEN, phosphatase and tensin homolog deleted on chromosome ten; QBC939, human hilar bile duct carcinoma cell line; Sk-ChA-1, cholangiocarcinoma cell line; siRNA, SMAD4, SMAD family member 4; small interfering RNA; TP53, tumor protein 53.