Abstract 2088: Characterization of an inducible alcoholic liver fibrosis model for hepatocellular carcinoma investigation in a transgenic porcine platform
Authors: Schachtschneider Kyle M. , Mendoza-Elias Nasya , Regan Daniel P. , Garcia Kelly D. , Rund Lauretta A. , Schwind Regina M. , Schook Lawrence B. , Gaba Ron C. 
Published: August 2018

Hepatocellular carcinoma (HCC) is a deadly tumor that spans more than 780,000 new diagnoses and causes 750,000 annual deaths worldwide. While global cancer incidence and mortality are generally decreasing, HCC incidence is rising and projected to continually increase given the growing prevalence of chronic liver diseases. Alcoholic liver disease represents a common progressive chronic liver ailment that incites liver cirrhosis—a precancerous state of liver scarring—that increases the risk for HCC development. The health status of the liver can also affect HCC tumor biology and treatment responses. Therefore, a large animal model capable of exhibiting both HCC and alcohol induced liver cirrhosis would be a valuable resource for preclinical research investigating HCC in its native comorbid cirrhotic microenvironment. This study utilized the innovative Oncopig Cancer Model (OCM)—a transgenic swine model that recapitulates human cancer through development of site and cell specific tumors via induced expression of heterozygous KRASG12D and TP53R167H transgenes—to develop alcohol induced fibrosis in a porcine model capable of developing HCC tumors.

Liver injury was induced in Oncopigs (n=5) via transcatheter infusion of absolute ethanol and ethiodized oil (1:3 v/v dosed at 0.75 mL/kg) into the hepatic arterial circulation. Histological assessment of resected liver specimens collected 8 weeks post-induction revealed METAVIR stage F2-F4 fibrosis, stage A2-A3 inflammation, and a median percent fibrosis of 15.3% (range 5.0-22.9%). All METAVIR and inflammation scores were elevated compared to age matched controls (F0-F1, A0-A1, median percent fibrosis 8.7%, range 5.8-12.1%). Liver injury was then induced via the same protocol in a second OCM cohort (n=5) for a time course study in which post-induction disease surveillance via general health assessment, lab analysis, and serial liver biopsies was performed every 2 weeks for 20 weeks post-induction. Histology revealed METAVIR stage F1-F3 fibrosis as early as 2 weeks post-induction. However, as clinically observed for patients presenting with pre-cirrhotic alcohol induced liver damage, a lack of persistent alcohol exposure resulted in liver recovery as evidenced by METAVIR F1-F2 fibrosis levels at 20 weeks post-induction. No behavioral or biochemical abnormalities were observed during the monitoring period to suggest liver decompensation.

In conclusion, this study successfully validated a protocol to develop a pre-cirrhotic METAVIR F2-F3 model of alcoholic liver disease within 8 weeks using transarterial ethanol-ethiodized oil infusion. While these results support the OCM's capability to serve as a model for HCC in a cirrhotic liver background, the data indicate prolonged exposure to alcohol may be required to develop an irreversible METAVIR stage F4 porcine model of cirrhosis.

Citation Format: Kyle M. Schachtschneider, Nasya Mendoza-Elias, Daniel P. Regan, Kelly D. Garcia, Lauretta A. Rund, Regina M. Schwind, Lawrence B. Schook, Ron C. Gaba. Characterization of an inducible alcoholic liver fibrosis model for hepatocellular carcinoma investigation in a transgenic porcine platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2088.