A validated, transitional and translational porcine model of hepatocellular carcinoma

// Kyle M. Schachtschneider 1, 2, 3 , Regina M. Schwind 3 , Kwame A. Darfour-Oduro 1 , Arun K. De 1 , Lauretta A. Rund 1 , Kuldeep Singh 4 , Daniel R. Principe 5 , Grace Guzman 6 , Charles E. Ray Jr. 3, 7 , Howard Ozer 7 , Ron C. Gaba 3 and Lawrence B. Schook 1, 3 1 Department of Animal Sciences, University of Illinois, Urbana, IL, USA 2 Animal Breeding and Genomics Centre, Wageningen University, Wageningen, The Netherlands 3 Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA 4 Veterinary Diagnostic Laboratory, University of Illinois, Urbana, IL, USA 5 College of Medicine, University of Illinois at Chicago, Chicago, IL, USA 6 Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA 7 Department of Medicine, Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, IL, USA Correspondence to: Lawrence B. Schook, email: schook@illinois.edu Keywords: hepatocellular carcinoma, human, porcine model, gene expression, interventional radiology Received: October 21, 2016     Accepted: June 05, 2017     Published: June 29, 2017 ABSTRACT Difficult questions are confronting clinicians attempting to improve hepatocellular carcinoma (HCC) outcomes. A large animal model with genetic, anatomical, and physiological similarities to humans is required to transition from mouse models to human clinical trials to address unmet clinical needs. To validate our previously reported inducible porcine cancer model (Oncopig) as a transitional HCC model, Oncopig hepatocyte cultures were transformed using Cre recombinase. The resulting porcine HCC cells (pHCC) expressed oncogenic TP53 R167H and KRAS G12D , and displayed nuclear pleomorphisms with pale to granular cytoplasm arranged in expanded plates similar to human HCC histopathology. Human HCC transcriptional hallmarks were detected in pHCC cells using RNA-seq, including TERT reactivation, apoptosis evasion, angiogenesis activation, and Wnt signaling activation. Master regulators of gene expression were conserved across Oncopig and 18 human HCC cell lines. pHCC injection into SCID mice resulted in tumors recapitulating human HCC characteristics, including thick trabeculae formation, pseudoacini patterning, and sheets of well-vascularized stroma. Finally, autologous injection of pHCC cells subcutaneously yielded a tumor histologically characterized as Edmondson Steiner (HCC nuclear grade assessment system) grade 2 HCC with trabecular patterning and T-lymphocyte infiltration. These data demonstrate the Oncopig HCC model’s utility for improving detection, treatment, and biomarker discovery relevant to human HCC.