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Development and translational imaging of a TP53 porcine tumorigenesis model
Jessica C. Sieren, … , Dawn E. Quelle, Christopher S. Rogers
Jessica C. Sieren, … , Dawn E. Quelle, Christopher S. Rogers
Published August 8, 2014
Citation Information: J Clin Invest. 2014;124(9):4052-4066. https://doi.org/10.1172/JCI75447.
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Technical Advance Oncology

Development and translational imaging of a TP53 porcine tumorigenesis model

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Abstract

Cancer is the second deadliest disease in the United States, necessitating improvements in tumor diagnosis and treatment. Current model systems of cancer are informative, but translating promising imaging approaches and therapies to clinical practice has been challenging. In particular, the lack of a large-animal model that accurately mimics human cancer has been a major barrier to the development of effective diagnostic tools along with surgical and therapeutic interventions. Here, we developed a genetically modified porcine model of cancer in which animals express a mutation in TP53 (which encodes p53) that is orthologous to one commonly found in humans (R175H in people, R167H in pigs). TP53R167H/R167H mutant pigs primarily developed lymphomas and osteogenic tumors, recapitulating the tumor types observed in mice and humans expressing orthologous TP53 mutant alleles. CT and MRI imaging data effectively detected developing tumors, which were validated by histopathological evaluation after necropsy. Molecular genetic analyses confirmed that these animals expressed the R167H mutant p53, and evaluation of tumors revealed characteristic chromosomal instability. Together, these results demonstrated that TP53R167H/R167H pigs represent a large-animal tumor model that replicates the human condition. Our data further suggest that this model will be uniquely suited for developing clinically relevant, noninvasive imaging approaches to facilitate earlier detection, diagnosis, and treatment of human cancers.

Authors

Jessica C. Sieren, David K. Meyerholz, Xiao-Jun Wang, Bryan T. Davis, John D. Newell Jr., Emily Hammond, Judy A. Rohret, Frank A. Rohret, Jason T. Struzynski, J. Adam Goeken, Paul W. Naumann, Mariah R. Leidinger, Agshin Taghiyev, Richard Van Rheeden, Jussara Hagen, Benjamin W. Darbro, Dawn E. Quelle, Christopher S. Rogers

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Figure 8

Renal tumor in a TP53R167H/R167H pig.

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Renal tumor in a TP53R167H/R167H pig.
In case 6, the change in renal tum...
In case 6, the change in renal tumor size over time was assessed with iodinated contrast-enhanced CT at time points 1 (A) and 2 (B); sagittal views are shown. (C) The renal tumor (arrow) was elevated from the cortex at the cranial pole of the right kidney. (D) Cut surface of the tumor (T) showed an encapsulated (arrow) mass that was well-demarcated from normal kidney (K). (E) The tumor was composed of necrosis and hemorrhages (red patches) that were distinct from the unaffected kidney. (F) The necrotic tumor tissue had irregular tubules separated by cords of connective tissue (asterisks). (G) At the edges of the tumor, invading through the tumor capsule were small nests (see E, arrows) of poorly differentiated tubules with a high mitotic rate (arrows). Original magnification, ×20 (E); ×100 (F); ×600 (G).
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