Swine as an Animal Model for Wound Healing & Melanoma - part 3

Swine skin is remarkably similar to human skin and as such has become a standard model for reconstructive and plastic surgery and wound healing. Anatomically, swine skin is largely hairless, has a thick epidermal layer, a fixed subcutaneous layer, and a human-like pattern of cutaneous blood supply. Physiologically, swine skin responds as human skin does to various growth factors and cytokines and displays a wound healing process, similar to that documented in humans, in which re-epithelialization rather than contraction occurs. Swine skin has been used in the development of skin surgical techniques, laser therapy, and burn care and the study of dermatological conditions including vitiligo, dry skin, aseptic necrosis, hypertrophic scarring, melanoma, and others. [1,6]

Burn injury results in hypertrophic scarring (HS), which produces permanent hard, red, raised scars that are painful, disfiguring, and often debilitating. Despite decades of research, there is still very little known about the pathophysiology of HS and no treatments are available. Experimental models have been attempted using mice, rats, rabbits, dogs, and cats, but have been abandoned due to their failure to mimic human HS. By contrast, swine appear to produce scarring most similar to human HS as measured by clinical and histological appearance, biomarker presence, and nerve fiber, mast cell, and myofibroblast populations. The swine model of human HS is not perfect, but currently presents the best overall approximate for studies of burn wound healing and scarring available. [6]

Cutaneous malignant melanoma is very aggressive and infamously resistant to chemotherapy, radiotherapy, and immunotherapy strategies. Partial spontaneous regression is observed in some forms of human melanoma, but only rarely does complete regression occur. By contrast, swine spontaneously develop melanoma analogous to that observed in humans that very frequently regresses completely. The Sinclair swine cutaneous melanoma (SSCM) model and the melanoma-bearing Libechov minipig (MeLiM) model have been developed and characterized in the hope of discovering genes that can be identified as susceptibility loci for heritable melanoma or associated with the cellular and molecular mechanisms involved in melanoma regression. [3,7,8] Genetic variability in four genes are already known to account for 50% of human familial malignant melanoma (FMM) cases. Further work on this issue is being performed using computer-assisted mathematical modeling using the SSCM model in the hope of identifying these and other candidate loci involved in the initiation, progression, and aggressiveness of FMM in swine. In this case the SSCM model provides advantages over similar familial studies in humans because of the short gestation times and high progeny numbers achievable with swine. [7] In the MeLiM swine model, tumors naturally regress with a frequency of 96% and are observed to become more flat, dry, depigmented, and infiltrated with leukocytes as they regress. Analysis of the swine transcriptome during tumor regression has identified a pool of approximately 1,400 genes that are differentially expressed during this process. Though obviously further review of each of these genes will be required, some interesting general trends are apparent. For example, genes involved in cell cycle and DNA replication and repair are down-regulated early in regression suggesting retardation of melanoma cell proliferation. Additionally, genes associated with monocytes/macrophages are up-regulated at intermediate time points during regression suggesting that tumors do not evade immune attack in swine. [8]

References
6. Zhu, K.Q. et al. (2007) Review of the female Duroc/Yorkshire pig model of human fibroproliferative scarring. Wound Repair Regen. 15(Suppl. 1):S32-S39.

7. Gomez-Raya, L. et al. (2007) Modeling inheritance of malignant melanoma with DNA markers in Sinclair swine. Genetics 176(1):585-597.

8. Rambow, F. et al. (2008) Gene expression signature for spontaneous cancer regression in melanoma pigs. Neoplasia 10(7):714-726.