Human Xenografts Are Not Rejected in a Naturally Occurring Immunodeficient Porcine Line: A Human Tumor Model in Pigs

Abstract

Animal models for cancer therapy are invaluable for preclinical testing of potential cancer treatments; however, therapies tested in such models often fail to translate into clinical settings. Therefore, a better preclinical model for cancer treatment testing is needed. Here we demonstrate that an immunodeficient line of pigs can host and support the growth of xenografted human tumors and has the potential to be an effective animal model for cancer therapy. Wild-type and immunodeficient pigs were injected subcutaneously in the left ear with human melanoma cells (A375SM cells) and in the right ear with human pancreatic carcinoma cells (PANC-1). All immunodeficient pigs developed tumors that were verified by histology and immunohistochemistry. Nonaffected littermates did not develop tumors. Immunodeficient pigs, which do not reject xenografted human tumors, have the potential to become an extremely useful animal model for cancer therapy because of their similarity in size, anatomy, and physiology to humans.

Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency

“…The ability of RAG2 Δ140,S141H/Δ140-527 pigs to support the rapid growth of well-developed human teratomas representing a wide range of tissue types, and to permit the growth of tumors from an allogeneic porcine trophoblast cell line, suggests that such mutant animals could have considerable value in regenerative medicine. Large animals with a SCID phenotype have arisen occasionally in breeding programs (13,14,35), and IL2RG knock-out pigs have also been genetically engineered (15,16). At least some of these animals appear to permit limited engraftment of both porcine and human cells.…”

“…This response to immune challenge may be particularly true for diseases associated with the immune system. For example, there are two brief descriptions of a group of SCID-like pigs that arose spontaneously in a standard breeding program (13,14). These animals were unable to produce antibodies, had atrophied lymph nodes, and lacked a thymus and B and T cells, and were also able to accept s.c. grafts of human melanoma and pancreatic carcinoma cells.…”

Development and translational imaging of a TP53 porcine tumorigenesis model

“…It is important to note that a model can also be too large. For example, domestic pig breeds, such as those being used in other cancer models (8)(9)(10), are 2-3 times bigger. This would exclude domestic pigs from most longitudinal monitoring/treatment studies with clinical imaging technologies, as they would quickly outgrow the size capacity of a typical clinical imaging scanner with a bore diameter of 60-70 cm.…”

“…Furthermore, many cancer types are heterogeneous in content, composed not only of cancerous cells, but also of inflammatory mediators (41), fibrotic stroma (42), necrotic tissue, and complex vascularity (43). Our porcine model does not rely on an immunocompromised host for tumor development, unlike xenograft models (8). The mutant TP53 pig opens new lines of investigation to explore the interplay between a functional immune response and the tumor microenvironment as it relates to tumor progression, diagnosis, treatment, and monitoring (44).…”

“…Efforts have begun to move cancer-modeling technology previously developed in mice to new species. For example, xenograft models are being tested in immunodeficient pigs (8), and several groups, including our own in the present study, are using gene engineering technology to introduce cancer-related mutations to the porcine genome (9,10).…”