Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. New animal models that faithfully recapitulate human HCC phenotypes are required to address unmet clinical needs and advance standard-of-care therapeutics. This study utilized the Oncopig Cancer Model to develop a translational porcine HCC model which can serve as a bridge between murine studies and human clinical practice. Reliable development of Oncopig HCC cell lines was demonstrated through hepatocyte isolation and Cre recombinase exposure across 15 Oncopigs. Oncopig and human HCC cell lines displayed similar cell cycle lengths, alpha-fetoprotein production, arginase-1 staining, chemosusceptibility, and drug metabolizing enzyme expression. The ability of Oncopig HCC cells to consistently produce tumors in vivo was confirmed via subcutaneous (SQ) injection into immunodeficient mice and Oncopigs. Reproducible development of intrahepatic tumors in an alcohol-induced fibrotic microenvironment was achieved via engraftment of SQ tumors into fibrotic Oncopig livers. Whole-genome sequencing demontrated intrahepatic tumor tissue resembled human HCC at the genomic level. Finally, Oncopig HCC cells are amenable to gene editing for development of personalized HCC tumors. This study provides a novel, clinically-relevant porcine HCC model which holds great promise for improving HCC outcomes through testing of novel therapeutic approaches to accelerate and enhance clinical trials.
Highlights
Hepatocellular carcinoma (HCC)—the most common type of primary liver cancer—is an aggressive cancer that spans more than 850,000 new yearly diagnoses and causes 800,000 annual deaths, representing the fifth most common cancer globally and the second most common cause of cancer-related death worldwide [1].The incidence of HCC in the United States has tripled over the past three decades, and is projected to increase for the foreseeable future given the growing prevalence of HCC risk factors, including hepatitis B or C virus infection, obesity, diabetes mellitus, and excessive alcohol consumption [2]
While Oncopig HCC cells correctly predicted www.oncotarget.com resistance of human HCC to 5-FU treatment, murine HCC cells displayed markedly increased susceptibility to 5-FU (Supplementary Figure 2C). These results demonstrate similar expression of key genes involved in drug metabolism and transport between Oncopig and human HCC, and the ability of Oncopig HCC cells to predict human HCC chemotherapeutic susceptibility in vitro, providing a rationale for utilization of the Oncopig HCC model as a translational model to bridge the gap between murine and human studies
This study presents a genetically adjustable, reproducible Oncopig HCC model that closely predicts human HCC chemotherapeutic responses
Summary
Hepatocellular carcinoma (HCC)—the most common type of primary liver cancer—is an aggressive cancer that spans more than 850,000 new yearly diagnoses and causes 800,000 annual deaths, representing the fifth most common cancer globally and the second most common cause of cancer-related death worldwide [1].The incidence of HCC in the United States has tripled over the past three decades, and is projected to increase for the foreseeable future given the growing prevalence of HCC risk factors, including hepatitis B or C virus infection, obesity, diabetes mellitus, and excessive alcohol consumption [2]. A large number of rodent HCC models have been developed and utilized for preclinical research [6] Despite their benefits, current HCC animal models have significant disadvantages that limit the testing of novel therapies and their translation to clinical practice. Rodents are poor preclinical models of drug toxicity, sensitivity, and efficacy due to significant differences in xenobiotic receptors and drug metabolism [7] This factor is of immense importance as less than 8% of drugs translate successfully from animal testing into Phase 1 clinical cancer trials [8]. The small size of rodents prohibits the testing of devicebased tools and techniques widely employed in clinical practice This is of significant consequence given the central role of locoregional therapies (LRTs) in HCC clinical management.
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