A validated, transitional and translational porcine model of hepatocellular carcinoma

Kyle M. Schachtschneider, Regina M. Schwind, Kwame A. Darfour-Oduro, Arun K. De, Lauretta A. Rund, Kuldeep Singh, Daniel R. Principe, Grace Guzman, Charles E. Ray, Howard Ozer, Ron C. Gaba, Lawrence B. Schook*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Scopus)

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 TP53R167H and KRASG12D, 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 wellvascularized 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.

Original languageEnglish
Pages (from-to)63620-63634
JournalOncotarget
Volume8
Issue number38
DOIs
Publication statusPublished - 2017

Keywords

  • Gene expression
  • Hepatocellular carcinoma
  • Human
  • Interventional radiology
  • Porcine model

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    Schachtschneider, K. M., Schwind, R. M., Darfour-Oduro, K. A., De, A. K., Rund, L. A., Singh, K., ... Schook, L. B. (2017). A validated, transitional and translational porcine model of hepatocellular carcinoma. Oncotarget, 8(38), 63620-63634. https://doi.org/10.18632/oncotarget.18872