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Published on: August 23, 2019
Production of thyroid tumours in mice by demethylating agents
1Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Abstract:
Previous studies on thyroid tumorigenesis in rodents have explored the role of oncogene mutation in tumour development. However, many mutagens are also known to decrease DNA methylation, another factor known to be important in the regulation of gene expression. We report the results of a small study to examine whether the demethylating agents 5-azacytidine and 5-aza-2-deoxycytidine could promote radiation- or goitrogen-induced tumorigenesis in the mouse, and whether they could potentiate the effect of a combined radiation and goitrogen regime. Three single doses of either 5-azacytidine or 5-aza-2-deoxycytidine increased the frequency of lesions in the goitrogen-treated animals; one of these lesions was a metastasising carcinoma. Thyroid carcinomas are very rare in mice in the absence of mutagen treatment, and metastasis is particularly unusual. There was no significant difference, at the dosages used, between the number of tumours induced by demethylating agents and those induced by a mutagen (radiation) in goitrogen-treated animals. Unlike goitrogens, demethylating agents did not promote radiation-induced tumorigenesis, and they did not produce any significant potentiation of the conventional regime of radiation and goitrogen at the dosages used. This study suggests that the role of non-genotoxic factors, such as agents affecting patterns of DNA methylation, warrants consideration in thyroid tumorigenesis.
Insights
Demethylating agents, like 5-azacytidine, increased thyroid lesions and rare metastatic carcinomas in mice treated with goitrogens. These agents did not enhance radiation-induced thyroid tumors.
Area of Science:
- Endocrinology
- Molecular Biology
- Toxicology
Background:
- Thyroid tumorigenesis research often focuses on oncogene mutations.
- Mutagens can decrease DNA methylation, impacting gene expression.
- The role of DNA methylation changes in thyroid cancer requires further investigation.
Purpose of the Study:
- To investigate if demethylating agents (5-azacytidine, 5-aza-2-deoxycytidine) promote radiation- or goitrogen-induced thyroid tumorigenesis in mice.
- To assess if these agents potentiate combined radiation and goitrogen treatment effects.
Main Methods:
- Mice were administered single doses of 5-azacytidine or 5-aza-2-deoxycytidine.
- Animals were also subjected to radiation and/or goitrogen treatments.
- Tumorigenesis and lesion frequency, including metastasis, were analyzed.
Main Results:
- Demethylating agents increased lesion frequency in goitrogen-treated mice, including one case of metastasizing carcinoma.
- No significant difference in tumor induction was observed between demethylating agents and radiation in goitrogen-treated mice.
- Demethylating agents did not enhance radiation-induced tumorigenesis or potentiate combined radiation and goitrogen treatment.
Conclusions:
- Non-genotoxic factors, specifically DNA methylation changes, play a significant role in thyroid tumorigenesis.
- Demethylating agents can induce rare, aggressive thyroid lesions in conjunction with goitrogens.
- Further research into epigenetic modifications is crucial for understanding thyroid cancer development.
