A genetically inducible porcine model of intestinal cancer

Callesen, Morten M.; Árnadóttir, Sigrid S.; Lyskjær, Iben; Ørntoft, Mai-Britt W.; Høyer, Søren; Dagnæs‐Hansen, Frederik; Liu, Ying; Li, Rong; Callesen, Henrik; Rasmussen, Mads Heilskov; Berthelsen, Martin F.; Thomsen, Martin K.; Schweiger, Pawel J.; Jensen, Kim B.; Laurberg, Søren; Ørntoft, Torben F.; Elverløv-Jakobsen, Jannik Ejnar; Andersen, Claus Lindbjerg

doi:10.1002/1878-0261.12136

Cited by 36 publications

(20 citation statements)

References 53 publications

(60 reference statements)

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“…The information in the present report as well as the potential to induce leukemia via bone marrow transplantation (19) suggests that it may be possible to induce CML in Yucatan swine with genetically modified bone marrow cells. Such a model may provide important insight into pathogenic mechanisms and validation of novel therapeutic targets like tyrosine kinase inhibitor drugs that target the BCR-ABL protein (9) and microRNAs against genes associated with CML (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

“…A BCR-ABL translocation between chromosomes 9 and 26, the "Raleigh" chromosome, was identified in several cases of canine CML (12)(13)(14). A potential association between chronic myelogenous (basophilic) leukemia and a Philadelphia gene sequence in Yucatan pigs is lacking in currently available literature (5,9,11,12,15,16). Material in this novel report provides vital information that will contribute to accurate, pre-mortem diagnosis of Ph+ CML in outbred Yucatan swine.…”

Section: Introductionmentioning

confidence: 96%

“…More than 90% of CML cases in humans are associated with the Philadelphia gene (Ph+) (5,9) while it is present in only 0.5-3% human cases of de novo acute myeloid leukemia (AML) (10). The gene results from fusion of the Abelson murine leukemia oncogene on chromosome 9 with the breakpoint cluster region of chromosome 22 (BCR-ABL translocation) (11).…”

Section: Introductionmentioning

confidence: 99%

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Association of Chronic Myelogenous (Basophilic) Leukemia and the BCR/ABL Mutation in a Yucatan Barrow (Sus scrofa domestica)

et al. 2020

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Background: Chronic myelogenous leukemia (CML) is a clonal proliferative disorder of the myeloid, megakaryocyte, and erythroid lineages. The onset and subsequent progression of CML is well-described in humans. There is comparably little information surrounding CML progression in veterinary species, including Yucatan miniature swine that are common for preclinical pharmaceutical and device testing. In humans, more than 90% of CML cases are associated with a chromosomal translocation that results in the Philadelphia gene (BCR/ABL mutation). In this report, the presence of the Philadelphia gene in a Yucatan burrow was confirmed in white blood cells collected prior to onset of clinical signs with primers designed from the human BCR/ABL sequence. Case Presentation: A 24 month old, 70 kg, Yucatan barrow received a prefabricated bovine cortical bone xenograft following a unilateral zygomatic ostectomy for a preclinical study. Complete blood count and serum chemistries were performed prior to and 28, 53, 106, and 129 days after facial surgery. Fifty three days after surgery, a bone marrow biopsy was performed due to anorexia, severe basophilia, and mild anemia. A finding of a moderate increase in basophilic precursors in bone marrow cytology was followed by lymphocyte immunophenotyping via flow cytometry and RT-PCR amplification of the Philadelphia gene in white blood cell samples from the affected barrow and an unaffected barrow in the same treatment group. Bone marrow, lymph node, liver, spleen, lung, kidney, and adrenal gland lesions of mostly myeloblasts were identified after the affected barrow died 146 days after surgery. Flow cytometry confirmed lymphopenia and suggested basophilia, and RT-PCR established the presence of the BCR/ABL gene. Conclusions: The information in this report confirms the presence of the BCR/ABL mutation and documents progression of chronic myelogenous (basophilic) leukemia from a chronic phase to a terminal blast crisis in an adult Yucatan barrow. The natural occurrence and progression of CML associated with the BCR/ABL mutation in miniature Takawira et al. Porcine Chronic Myelogenous Leukemia swine establishes potential for future porcine models of human CML. The information also establishes a genetic test to confirm porcine CML to prevent inadvertent attribution of clinical signs to treatment complications during preclinical testing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Association of Chronic Myelogenous (Basophilic) Leukemia and the BCR/ABL Mutation in a Yucatan Barrow (Sus scrofa domestica)

et al. 2020

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“…A genetically-engineered animal with Cre recombinase-induced simultaneous expression of mutated tumor suppressor TP53 and active K-ras oncogene, called ‘oncopig’, has been successfully used as a model for soft-tissue sarcoma (78, 79) and hepatocellular carcinoma (80). Another transgenic pig line with simultaneous transgene expression (active Kras and cMyc, and a repressor of p53) has been described as a conditional intestinal cancer model (81). The transgene is under the control of Flp recombinase, which is conditionally-induced by tamoxifen under the control of an intestinal epithelium-specific promoter.…”

Section: Porcine Modelmentioning

confidence: 99%

Non-murine models to investigate tumor-immune interactions in head and neck cancer

Rossa

D’Silva

2019

Oncogene

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The immune response has important roles in the biology of solid tumors, including oncogenesis, tumor growth, invasion and metastasis, and response to treatment. Improved understanding of tumor-immune system interactions has provided promising therapeutic options that are based on the rescue and enhancement of the anti-tumoral host response. Immune-based treatments have been approved for clinical use in various types of cancer, including head and neck cancer (HNC); other strategies involving combination therapies are currently in development. These novel therapies were developed based on knowledge derived from in vitro, in silico, and in vivo pre-clinical studies. However, clinical trials seldom replicate the efficacy observed in pre-clinical animal studies. This lack of correlation between pre-clinical studies and clinical trials may be related to limitations of the models used; which highlights the relevance of considering immune-related aspects of different pre-clinical models. Murine models are the most frequently used pre-clinical models of HNC and are discussed elsewhere. Non-murine models have characteristics that offer unique opportunities for the study of HNC etiology, therapeutic strategies, and tumor-immune system interactions. The current review focuses on immune-related aspects of non-murine models, including dog, cat, pig, zebrafish, and frog, that could be used to investigate tumor-immune interactions in HNC.

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“…More recently, a genetic model of intestinal cancer was developed using a Flp-recombinase inducible oncogene cassette containing KRAS G12D , cMYC , and SV40LT in addition to a 4-hydroxytamoxifen (4-OHT) activator cassette controlled by an intestinal epithelium tissue-specific promoter. Activation of the oncogene cassette in vivo resulted in a duodenal neuroendocrine carcinoma with a lymph node metastasis in the minipig ( Callesen et al, 2017 ). Finally, an attempt to develop a breast cancer model was performed using a recombinant adeno-associated virus (rAAV) mediated BRCA1 knockout.…”

Section: Genetically Defined Swine Models Of Cancermentioning

confidence: 99%

The Oncopig Cancer Model as a Complementary Tool for Phenotypic Drug Discovery

et al. 2017

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The screening of potential therapeutic compounds using phenotypic drug discovery (PDD) is being embraced once again by researchers and pharmaceutical companies as an approach to enhance the development of new effective therapeutics. Before the genomics and molecular biology era and the consecutive emergence of targeted-drug discovery approaches, PDD was the most common platform used for drug discovery. PDD, also known as phenotypic screening, consists of screening potential compounds in either in vitro cellular or in vivo animal models to identify compounds resulting in a desirable phenotypic change. Using this approach, the biological targets of the compounds are not taken into consideration. Suitable animal models are crucial for the continued validation and discovery of new drugs, as compounds displaying promising results in phenotypic in vitro cell-based and in vivo small animal model screenings often fail in clinical trials. Indeed, this is mainly a result of differential anatomy, physiology, metabolism, immunology, and genetics between humans and currently used pre-clinical small animal models. In contrast, pigs are more predictive of therapeutic treatment outcomes in humans than rodents. In addition, pigs provide an ideal platform to study cancer due to their similarities with humans at the anatomical, physiological, metabolic, and genetic levels. Here we provide a mini-review on the reemergence of PDD in drug development, highlighting the potential of porcine cancer models for improving pre-clinical drug discovery and testing. We also present precision medicine based genetically defined swine cancer models developed to date and their potential as biomedical models.

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A genetically inducible porcine model of intestinal cancer

Cited by 36 publications

References 53 publications

Association of Chronic Myelogenous (Basophilic) Leukemia and the BCR/ABL Mutation in a Yucatan Barrow (Sus scrofa domestica)

Association of Chronic Myelogenous (Basophilic) Leukemia and the BCR/ABL Mutation in a Yucatan Barrow (Sus scrofa domestica)

Non-murine models to investigate tumor-immune interactions in head and neck cancer

The Oncopig Cancer Model as a Complementary Tool for Phenotypic Drug Discovery

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