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Genetically Engineered Pigs to Study Cancer.

ABSTRACT: Recent decades have seen groundbreaking advances in cancer research. Genetically engineered animal models, mainly in mice, have contributed to a better understanding of the underlying mechanisms involved in cancer. However, mice are not ideal for translating basic research into studies closer to the clinic. There is a need for complementary information provided by non-rodent species. Pigs are well suited for translational biomedical research as they share many similarities with humans such as body and organ size, aspects of anatomy, physiology and pathophysiology and can provide valuable means of developing and testing novel diagnostic and therapeutic procedures. Porcine oncology is a new field, but it is clear that replication of key oncogenic mutation in pigs can usefully mimic several human cancers. This review briefly outlines the technology used to generate genetically modified pigs, provides an overview of existing cancer models, their applications and how the field may develop in the near future.

SUBMITTER: Kalla D

PROVIDER: S-EPMC7013672 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Genetically Engineered Pigs to Study Cancer.

Kalla Daniela D Kind Alexander A Schnieke Angelika A

International journal of molecular sciences 20200113 2

Recent decades have seen groundbreaking advances in cancer research. Genetically engineered animal models, mainly in mice, have contributed to a better understanding of the underlying mechanisms involved in cancer. However, mice are not ideal for translating basic research into studies closer to the clinic. There is a need for complementary information provided by non-rodent species. Pigs are well suited for translational biomedical research as they share many similarities with humans such as bo ...[more]

PMID: 31940967

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Project description:BACKGROUND: Pancreatic cancer remains one of the deadliest cancers due to lack of early detection and absence of effective treatments. Gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer, has limited clinical benefit. Treatment of pancreatic cancer cells with gemcitabine has been shown to induce the activity of the transcription factor nuclear factor-kappaB (NF-?B) which regulates the expression of genes involved in the inflammatory response and tumorigenesis. It has therefore been proposed that gemcitabine-induced NF-?B activation may result in chemoresistance. We hypothesize that NF-?B suppression by the novel inhibitor dimethylaminoparthenolide (DMAPT) may enhance the effect of gemcitabine in pancreatic cancer. METHODS: The efficacy of DMAPT and gemcitabine was evaluated in a chemoprevention trial using the mutant Kras and p53-expressing LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mouse model of pancreatic cancer. Mice were randomized to treatment groups (placebo, DMAPT [40 mg/kg/day], gemcitabine [50 mg/kg twice weekly], and the combination DMAPT/gemcitabine). Treatment was continued until mice showed signs of ill health at which time they were sacrificed. Plasma cytokine levels were determined using a Bio-Plex immunoassay. Statistical tests used included log-rank test, ANOVA with Dunnett's post-test, Student's t-test, and Fisher exact test. RESULTS: Gemcitabine or the combination DMAPT/gemcitabine significantly increased median survival and decreased the incidence and multiplicity of pancreatic adenocarcinomas. The DMAPT/gemcitabine combination also significantly decreased tumor size and the incidence of metastasis to the liver. No significant differences in the percentages of normal pancreatic ducts or premalignant pancreatic lesions were observed between the treatment groups. Pancreata in which no tumors formed were analyzed to determine the extent of pre-neoplasia; mostly normal ducts or low grade pancreatic lesions were observed, suggesting prevention of higher grade lesions in these animals. While gemcitabine treatment increased the levels of the inflammatory cytokines interleukin 1? (IL-1?), IL-1?, and IL-17 in mouse plasma, DMAPT and DMAPT/gemcitabine reduced the levels of the inflammatory cytokines IL-12p40, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 beta (MIP-1?), eotaxin, and tumor necrosis factor-alpha (TNF-?), all of which are NF-?B target genes. CONCLUSION: In summary, these findings provide preclinical evidence supporting further evaluation of agents such as DMAPT and gemcitabine for the prevention and treatment of pancreatic cancer.

Dataset Information

Genetically Engineered Pigs to Study Cancer.

Publications

Genetically Engineered Pigs to Study Cancer.

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