Review articlePigs as models of human cancers
Introduction
Recent decades have seen revolutionary advances in our understanding of cancer, with the molecular mechanisms underlying many human cancers now reasonably well understood. Nevertheless, effective means of early diagnosis and therapies are often lacking. This rich body of knowledge should be exploited to fulfill unmet clinical needs, and preclinical studies with animal models can play an important role translating basic research into benefit for patients. Most cancer models are in rodents, particularly genetically engineered mice. Although mice and humans share many fundamental similarities as mammals, there are clear differences in cancer biology. For example, murine cells are more easily transformed in vitro than human cells [1], [2], and the set of genetic events required for mouse tumorigenesis differs from humans [3]. Differences in protein interactions, physiology, and anatomy can thus lead to significantly different disease phenotypes from similar genetic lesions. Metastatic human cancers are particularly difficult to reproduce in mice. As a consequence, basic studies in murine models often do not translate into success in clinical trials. Only 5% of anticancer agents developed in preclinical studies on the basis of traditional mouse models demonstrate sufficient efficacy in phase-III trials [4].
Evidence of the limitations and shortcomings of mouse models is also accumulating in other disease areas. Three independent research groups recently published phase-III studies of new anti-tuberculosis drug regimens showing that despite positive results in mouse studies, the new drugs completely failed in humans [5], [6], [7]. Similar discrepancy between mouse and human trials has been shown for amyotrophic lateral sclerosis treatment [8]. The drawbacks of mouse models are also evident in some basic research, e.g., drug metabolism [9], cystic fibrosis [10], breast cancer [11], and colorectal cancer [12]. A systematic study into inflammatory disease highlighted the lack of correlation between results in mice and human conditions [13], and provoked critical commentary in the popular press.
Although the mouse is an invaluable tool for basic disease research, other animals are clearly required as complementary resources. No single species is likely to provide the best model for all human disease, each has advantages and disadvantages. Interspecific studies provide broad insight into the genetic bases of disease and disease predisposition. Comparative analysis of gene expression data can identify evolutionarily conserved networks of expression and gene regulatory regions and unravel the complex interactions between genetic, environmental, and lifestyle factors that influence disease pathology. Canine oncology is already providing a useful complementary perspective. Dogs develop spontaneous tumors with histopathological and biological feature similar to human cancers (reviewed by [14]). This has allowed veterinary oncologists to develop substantial repositories, biobanks, of canine cancer samples, and findings show direct relevance to human treatments [15].
Although, pigs have not so far played a major role in experimental oncology, their usefulness is evident in a wide range of preclinical research. Pigs are very similar to humans in terms of body size, anatomy, and their physiological and pathophysiological responses. As such, they are used to study newly designed human-sized equipment and instruments and to develop procedures such as endoscopic and laparoscopic surgery [16]. Pigs are also relatively long-lived, enabling longitudinal studies of disease initiation and progression in individual animals under conditions that mimic the human patient.
As in humans, spontaneous cancer caused by natural mutations is rare in pigs, the most common forms being lymphomasarcoma in young animals [17], [18] and melanoma in adult pigs [19]. For many years, only two spontaneous pig tumor models on the basis of germline mutations were available for biomedical research. These are the Libechov and Sinclair minipigs, both predisposed to melanoma. These however, differ from humans because the melanomas spontaneously regress at high frequency (reviewed by [14]). Unfortunately the causative genetic lesions are undefined, making it difficult to draw parallels with human melanoma.
In the absence of genetically based pig tumors, a variety of strategies have been adopted to aid development of tumor therapies in pigs. Adam et al., [20] reported a porcine cancer model based on autologous transplantation of primary porcine cells transduced with retroviral vectors carrying oncogenic complementary DNAs. These studies revealed important similarities in tumorigenesis between pig and human. However, this model falls somewhat short as a representation of human cancer. The use of viral complementary DNA constructs does not reliably reflect the expression and regulation of endogenous genes. Tumors arising from grafted cells also differ in important respects from autochthonous tumors. Tumors arising from grafted cell lines also tend to be poor predictors of clinical efficacy, e.g., anti-cancer drugs found to be effective on such grafts can be ineffective on real tumors [21].
However livestock genetic engineering holds the real key to produce representative pig cancer models. The key techniques for generating genetically modified large animals, nuclear transfer [22], and gene targeting [23], were developed some time ago but it has taken time to refine and improve these sufficiently to produce genetically modified pigs “to order”. The rate of advance is now increasing rapidly with the development of highly specific synthetic endonucleases, transcription activator-like effector nucleases [24], [25], zinc finger nucleases [26], and RNA-guided endonucleases [27], together with the availability of the porcine genomic sequence [28]. Generating genetically modified pigs does take more time and effort than mice, but the potential benefits for preclinical research and human welfare are substantial.
The number of pigs genetically modified to replicate human diseases has increased dramatically [29]. Valuable models such as cystic fibrosis and diabetes are established [30], [31]. Work is also proceeding toward genetically defined porcine cancer models [32]. Here we provide a brief review of the genetically modified porcine cancer models described in the scientific literature (Table 1).
Section snippets
Genetically modified porcine cancer models
The first transgenic pigs designed to model cancer carried the v-Ha-ras oncogene directed by the mouse mammary tumor virus long terminal repeat promoter, but no phenotype was observed [39]. Constitutive expression of the Gli2 transcriptional activator in keratinocytes resulted in basal cell carcinoma-like lesions in young pigs, but these were euthanized because of bacterial infection before fuller investigation could be carried out [38]. The first gene-targeted pigs for cancer were generated by
Future directions
Fortunately, the genetic basis of several serious human cancers is well enough understood to make them suitable targets for replication in pigs. The results outlined previously are thus only the first steps, more mutant cancer–related genes are being generated and combinations generated by breeding. Pigs are unlikely to supplant mice as subjects for basic research, but they are already providing powerful complementary resources for translational studies. Pigs are increasingly being recognized
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