A Genetic Porcine Model of Cancer

Abstract

The large size of the pig and its similarity in anatomy, physiology, metabolism, and genetics to humans make it an ideal platform to develop a genetically defined, large animal model of cancer. To this end, we created a transgenic “oncopig” line encoding Cre recombinase inducible porcine transgenes encoding KRASG12D and TP53R167H, which represent a commonly mutated oncogene and tumor suppressor in human cancers, respectively. Treatment of cells derived from these oncopigs with the adenovirus encoding Cre (AdCre) led to KRASG12D and TP53R167H expression, which rendered the cells transformed in culture and tumorigenic when engrafted into immunocompromised mice. Finally, injection of AdCre directly into these oncopigs led to the rapid and reproducible tumor development of mesenchymal origin. Transgenic animals receiving AdGFP (green fluorescent protein) did not have any tumor mass formation or altered histopathology. This oncopig line could thus serve as a genetically malleable model for potentially a wide spectrum of cancers, while controlling for temporal or spatial genesis, which should prove invaluable to studies previously hampered by the lack of a large animal model of cancer.

Improved, Shorter-Latency Carcinogen-Induced Hepatocellular Carcinoma Model in Pigs

“…A relevant porcine HCC model is that of the transgenic "oncopig" cancer model with Cre recombinase inducible TP53R167H and KRASG12D genes [40,41]. A primary hepatocyte cell line from an oncopig was exposed to a Cre-encoding adenovirus in vitro resulting in primary porcine HCC with similar histopathologic characteristics as human HCC [42].…”

Trimodal Therapy: Combining Hyperthermia with Repurposed Bexarotene and Ultrasound for Treating Liver Cancer

“…To this end, in a preliminary experiment, we tested the combination of PBNB and US ablation in a transgenic “oncopig” line encoding Cre recombinase inducible porcine transgenes encoding KRASG12D and TP53R167H. 49 These genes are known to represent a commonly mutated oncogene and tumor suppressor in human cancers. Due to the study limitation and unavailability of a tumor model grown in swine liver, an improvised approached was taken.…”

“…Hepatocytes were isolated from this transgenic oncopig and transfected with Cre plasmid which delegates the PolyA “STOP” sequence and allows transgene expression. 49 Histopathology of these cells revealed that they were of hepatocellular carcinoma cells (HCC) nature. The transformed hepatocytes cells were able to successfully generate hepatocellular carcinoma in mouse liver.…”

Untitled

“…[8] The recently developed oncopig cancer model (OCM) is a unique transgenic pig model that develops the inducible site and cell-specific tumors after Cre recombinase exposure. [46] The OCM was designed to innately harbor mutations found in more than 50% of human cancers, KRAS G12D and TP53…”

“…[46] In the OCM, the innate KRAS G12D and TP53 R167H germline mutations are heterozygous in nature, closely modeling human disease. [46] OCM cohorts are developed through crossbreeding a transgene/major histocompatibility complex homozygous oncopig minnesota-mini composite sire with any number of domestic, mini-pig, or transgenic dams, allowing for the development of tumor-bearing pigs with a range of genetic backgrounds. This, coupled with the use of a maintenance diet, ensures manageable and clinically relevant animal subject sizes within study time periods.…”