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A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
Nucleotide excision repair- and p53-deficient mouse models in cancer research
Esther M Hoogervorst1, Harry van Steeg, Annemieke de Vries
1Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands.
Abstract:
Cancer is caused by the loss of controlled cell growth due to mutational (in)activation of critical genes known to be involved in cell cycle regulation. Three main mechanisms are known to be involved in the prevention of cells from becoming cancerous; DNA repair and cell cycle control, important to remove DNA damage before it will be fixed into mutations and apoptosis, resulting in the elimination of cells containing severe DNA damage. Several human syndromes are known to have (partially) deficiencies in these pathways, and are therefore highly cancer prone. Examples are xeroderma pigmentosum (XP) caused by an inborn defect in the nucleotide excision repair (NER) pathway and the Li-Fraumeni syndrome, which is the result of a germ line mutation in the p53 gene. XP patients develop skin cancer on sun exposed areas at a relatively early age, whereas Li-Fraumeni patients spontaneously develop a wide variety of early onset tumors, including sarcomas, leukemia's and mammary gland carcinomas. Several mouse models have been generated to mimic these human syndromes, providing us information about the role of these particular gene defects in the tumorigenesis process. In this review, spontaneous phenotypes of mice deficient for nucleotide excision repair and/or the p53 gene will be described, together with their responses upon exposure to either chemical carcinogens or radiation. Furthermore, possible applications of these and newly generated mouse models for cancer will be given.
Insights
Understanding cancer requires studying DNA repair and cell cycle control. Mouse models with defects in nucleotide excision repair (NER) or p53 gene mutations offer insights into cancer development and prevention strategies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Cancer arises from uncontrolled cell growth due to genetic mutations affecting cell cycle regulation.
- DNA repair, cell cycle control, and apoptosis are crucial mechanisms preventing cancerous cell formation.
- Human syndromes like xeroderma pigmentosum (XP) and Li-Fraumeni syndrome highlight genetic deficiencies predisposing individuals to cancer.
Purpose of the Study:
- To review spontaneous phenotypes in mice lacking nucleotide excision repair (NER) and/or p53.
- To analyze the response of these mouse models to chemical carcinogens and radiation.
- To discuss the applications of these mouse models in cancer research.
Main Methods:
- Review of existing literature on mouse models with specific gene deficiencies.
- Analysis of spontaneous tumor development in genetically modified mice.
- Evaluation of carcinogen and radiation exposure effects on these models.
Main Results:
- XP mouse models exhibit increased susceptibility to skin cancer upon UV exposure.
- Li-Fraumeni mouse models develop a broad spectrum of early-onset tumors.
- Combined deficiencies in NER and p53 pathways exacerbate cancer predisposition.
Conclusions:
- Mouse models deficient in DNA repair or cell cycle control pathways are invaluable for studying tumorigenesis.
- These models aid in understanding the mechanisms of cancer development and evaluating potential therapeutic strategies.
- Further research utilizing these and novel mouse models holds promise for advancing cancer prevention and treatment.
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