Germline gene polymorphisms predisposing domestic mammals to carcinogenesis

Flisikowski, Krzysztof; Flisikowska, Tatiana; Sikorska, Agata; Perkowska, Anna; Kind, Alexander; Schnieke, Angelika; Świtoński, M.

doi:10.1111/vco.12186

Cited by 15 publications

(7 citation statements)

References 77 publications

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“…Naturally occurring large animal models provide an unprecedented opportunity to better understand genetic diseases due to their heterogeneous genetic backgrounds, long life span, large size, and more similar immune system to humans [17]. Indeed, many genetic diseases in domestic animals are currently being investigated as potential models for the human counterpart [18]. PNSTs, including schwannomas, neurofibromas, and MPNSTs have been reported in many large animal species, and NF-like syndromes are referred to in the literature, particularly in cattle and dogs [19,20].…”

Section: Introductionmentioning

confidence: 99%

Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1

Osum

Watson

Largaespada

2021

IJMS

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Animal models are crucial to understanding human disease biology and developing new therapies. By far the most common animal used to investigate prevailing questions about human disease is the mouse. Mouse models are powerful tools for research as their small size, limited lifespan, and defined genetic background allow researchers to easily manipulate their genome and maintain large numbers of animals in general laboratory spaces. However, it is precisely these attributes that make them so different from humans and explains, in part, why these models do not accurately predict drug responses in human patients. This is particularly true of the neurofibromatoses (NFs), a group of genetic diseases that predispose individuals to tumors of the nervous system, the most common of which is Neurofibromatosis type 1 (NF1). Despite years of research, there are still many unanswered questions and few effective treatments for NF1. Genetically engineered mice have drastically improved our understanding of many aspects of NF1, but they do not exemplify the overall complexity of the disease and some findings do not translate well to humans due to differences in body size and physiology. Moreover, NF1 mouse models are heavily reliant on the Cre-Lox system, which does not accurately reflect the molecular mechanism of spontaneous loss of heterozygosity that accompanies human tumor development. Spontaneous and genetically engineered large animal models may provide a valuable supplement to rodent studies for NF1. Naturally occurring comparative models of disease are an attractive prospect because they occur on heterogeneous genetic backgrounds and are due to spontaneous rather than engineered mutations. The use of animals with naturally occurring disease has been effective for studying osteosarcoma, lymphoma, and diabetes. Spontaneous NF-like symptoms including neurofibromas and malignant peripheral nerve sheath tumors (MPNST) have been documented in several large animal species and share biological and clinical similarities with human NF1. These animals could provide additional insight into the complex biology of NF1 and potentially provide a platform for pre-clinical trials. Additionally, genetically engineered porcine models of NF1 have recently been developed and display a variety of clinical features similar to those seen in NF1 patients. Their large size and relatively long lifespan allow for longitudinal imaging studies and evaluation of innovative surgical techniques using human equipment. Greater genetic, anatomic, and physiologic similarities to humans enable the engineering of precise disease alleles found in human patients and make them ideal for preclinical pharmacokinetic and pharmacodynamic studies of small molecule, cellular, and gene therapies prior to clinical trials in patients. Comparative genomic studies between humans and animals with naturally occurring disease, as well as preclinical studies in large animal disease models, may help identify new targets for therapeutic intervention and expedite the translation of new therapies. In this review, we discuss new genetically engineered large animal models of NF1 and cases of spontaneous NF-like manifestations in large animals, with a special emphasis on how these comparative models could act as a crucial translational intermediary between specialized murine models and NF1 patients.

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Section: Introductionmentioning

confidence: 99%

Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1

Osum

Watson

Largaespada

2021

IJMS

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“…In contrast to osteosarcoma, which affects large dog breeds, mammary tumors ( Figure 15) tend to occur in the achondroplastic Dachshund and a number of small breeds including the Poodle, Maltese Terrier, Cocker Spaniel, Yorkshire Terrier and the Beagle. Conserved tumorigenesis orthologs implicated in this tumor type include CTNNB1 and PTEN [59] while least conserved orthologs associated with canine mammary tumors include BRCA1 [4] AND [60], BRCA2 [61], MUC1 [62], and KLF4 [63]. Interestingly, tumor associated macrophages (TAMs) have been implicated in modulating tumor invasion and metastasis in this cancer type [64].…”

Section: Discussionmentioning

confidence: 99%

Leveraging Naked Mole Rat (Heterocephalus glaber) Comparative Genomics to Identify Canine Genes Modulating Susceptibility to Tumorigenesis and Cancer Phenotypes

Irizarry¹,

Punt²

2015

J Veterinar Sci Technol

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We utilized a comparative genomics approach to analyze a core set of tumorigenesis orthologs among human, mouse, dog and naked mole rat. The analysis identified cancer orthologs that are both conserved and divergent between dog and the cancer resistant species naked mole rat. These tumorigenesis orthologous are associated with phenotypes that modulate cancer susceptibility, cardiac development, craniofacial development, brain development, skeletal development, and immune function, to name a few. This bioinformatics approach employed a variety of literature mining tools to further uncover relationships between the tumorigenesis orthologs. Together, these results shed light on the relationship between breed formations, breed associated morphological traits and breed associated susceptibility to tumorigenesis. These findings support the use of a comparative genomic analysis between species with dramatically different disease phenotypes as a gene discovery tool. A total of 146 proteins coding SNPs were identified in these tumorigenesis orthologs representing missense variations, frame shift variations and nonsense variations. The genes identified in this study can serve as a list of candidates for subsequent laboratory and clinical study. Furthermore, the identification of SNPs impacting the primary structure of the tumorigenesis orthologs may provide clues about the basis of cancer susceptibility between dog breeds.

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“…226 Interestingly, lesions of porcine melanoma models display a high tendency of spontaneous regression, with the MeLiM model showing complete clearance in up to 96% of the cases. 227,228 From this, it could be speculated that porcine models with their apparant efficient antitumor immunity provide a unique model for studying both the elimination and equilibrium phases of cancer. In contrast, the spontaneous canine tumor models with well-established, long-term tumors provide a platform for studying and testing immunotherapeutic agents aimed at the escape phase of cancer.…”

Section: Ongoing and Future Translational Opportunitiesmentioning

confidence: 99%

Of Mice, Dogs, Pigs, and Men: Choosing the Appropriate Model for Immuno-Oncology Research

et al. 2018

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The immune system plays dual roles in response to cancer. The host immune system protects against tumor formation via immunosurveillance; however, recognition of the tumor by immune cells also induces sculpting mechanisms leading to a Darwinian selection of tumor cell variants with reduced immunogenicity. Cancer immunoediting is the concept used to describe the complex interplay between tumor cells and the immune system. This concept, commonly referred to as the three E’s, is encompassed by 3 distinct phases of elimination, equilibrium, and escape. Despite impressive results in the clinic, cancer immunotherapy still has room for improvement as many patients remain unresponsive to therapy. Moreover, many of the preclinical results obtained in the widely used mouse models of cancer are lost in translation to human patients. To improve the success rate of immuno-oncology research and preclinical testing of immune-based anticancer therapies, using alternative animal models more closely related to humans is a promising approach. Here, we describe 2 of the major alternative model systems: canine (spontaneous) and porcine (experimental) cancer models. Although dogs display a high rate of spontaneous tumor formation, an increased number of genetically modified porcine models exist. We suggest that the optimal immuno-oncology model may depend on the stage of cancer immunoediting in question. In particular, the spontaneous canine tumor models provide a unique platform for evaluating therapies aimed at the escape phase of cancer, while genetically engineered swine allow for elucidation of tumor-immune cell interactions especially during the phases of elimination and equilibrium.

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Germline gene polymorphisms predisposing domestic mammals to carcinogenesis

Cited by 15 publications

References 77 publications

Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1

Spontaneous and Engineered Large Animal Models of Neurofibromatosis Type 1

Leveraging Naked Mole Rat (Heterocephalus glaber) Comparative Genomics to Identify Canine Genes Modulating Susceptibility to Tumorigenesis and Cancer Phenotypes

Of Mice, Dogs, Pigs, and Men: Choosing the Appropriate Model for Immuno-Oncology Research

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