Improved, Shorter-Latency Carcinogen-Induced Hepatocellular Carcinoma Model in Pigs

Abstract

Large animal models are important tools for hepatocellular carcinoma (HCC) research, especially in studies of hepatic vasculature, interventional techniques, and radiofrequency or microwave hyperthermia. Currently, diethylnitrosamine (DENA)-induced HCC in pigs is the only large animal model for in situ HCC with a tumor latency of 10–26 months. While phenobarbital (PB) is often used to accelerate DENA-induced HCC in rodents, it has not been previously studied in the porcine model. Therefore, we hypothesize that the addition of PB in the DENA-induced HCC porcine model will accelerate tumor latency compared to DENA alone. HCC and benign lesions were seen on serial MRI and confirmed on histopathology. Liver and tumors were further characterized by CT angiography, vascular corrosion casting, and permittivity measurements.

Induction of Hepatocellular Carcinoma in Conventional Domestic Swine Using N-Diethylnitrosamine and Phenobarbital

“…16 This method was also conducted in other studies using Yucatan miniature pigs, with the addition of PB as an accelerator of carcinogenesis. 6,17 DENA is an established hepatocarcinogen naturally present in a variety of foods. It induces hepatocarcinogenesis by forming alkyl DNA adducts, DNA structure alteration, chromosomal aberrations, micronuclei induction, and oxidative stress.…”

“…According to a previous study by Ho et al, who used minipigs as the model, tumor nodules were expected to develop within 5-11 months post-DENA and PB induction. 6 Animal body weight measurements and laboratory and imaging tests were conducted regularly to monitor tumor growth.…”

“…7 However, Ho et al were the first to utilize PB as an accelerator for HCC induction in large animal models, using miniature pigs. 6 PB was demonstrated to activate CAR via an indirect mechanism. It is revealed that PB induces HCC carcinogenesis by increasing the CAR-Gadd45B complex that suppresses anti-tumor p38 MAPK activity.…”

“…In a miniature pig model, PB shortened the time of tumor latency period from 10-26 months to 5-11 months. 6 PB is a non-genotoxic promoter and a well-known inducer of drug-metabolizing enzymes that have been used in various rodent hepatocarcinogenesis model studies since it was first initiated by Weisburger et al in 1975. 7 However, Ho et al were the first to utilize PB as an accelerator for HCC induction in large animal models, using miniature pigs.…”

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“…While the Oncopig HCC model is not the only porcine HCC model reported to date, it does provide significant advantages over previously published models. Autochthonous HCC has been developed in chemically induced porcine models [29][30][31]; however, such models take 1-2 years to develop clinically relevant tumors and do not allow for control of tumor number, location, underlying genetics, or comorbidities, rendering them potentially less suitable for preclinical and co-clinical trials. On the other hand, the Oncopig HCC model presented allows for development of genetically defined intrahepatic HCC tumors of clinically relevant size in animals as young as 4-5 months of age.…”