TY - JOUR
T1 - A validated, transitional and translational porcine model of hepatocellular carcinoma
AU - Schachtschneider, Kyle M.
AU - Schwind, Regina M.
AU - Darfour-Oduro, Kwame A.
AU - De, Arun K.
AU - Rund, Lauretta A.
AU - Singh, Kuldeep
AU - Principe, Daniel R.
AU - Guzman, Grace
AU - Ray, Charles E.
AU - Ozer, Howard
AU - Gaba, Ron C.
AU - Schook, Lawrence B.
N1 - Funding Information:
The authors also wish to express their gratitude to Dr Laura Selmic (UIUC Department of Veterinary Clinical Medicine) for performing the liver resections, and Dr Patrick Roady (UIUC Veterinary Diagnostic Lab) for reviewing histopathology. This research was supported by grants from the USDA/ARS (AG 58-5438-2-3070), the NIH (RFAGM-09-008), the DOD (CA150590), and by grants from the Cooperative Research Program for Agriculture Science & Technology Development (PJ009103) of the Rural Development Administration, Republic of Korea.
Publisher Copyright:
© Schachtschneider et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Gene expression
KW - Hepatocellular carcinoma
KW - Human
KW - Interventional radiology
KW - Porcine model
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U2 - 10.18632/oncotarget.18872
DO - 10.18632/oncotarget.18872
M3 - Article
C2 - 28969016
AN - SCOPUS:85027965245
SN - 1949-2553
VL - 8
SP - 63620
EP - 63634
JO - Oncotarget
JF - Oncotarget
IS - 38
ER -