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Mice with a mutation in the thyroid hormone receptor beta gene spontaneously develop thyroid carcinoma: a mouse model
Hideyo Suzuki1, Mark C Willingham, Sheue-Yann Cheng
1Gene Regulation Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4264, USA.
Abstract:
The molecular genetic basis of thyroid carcinogenesis is not well understood. Most of the existing models of thyroid cancer only rarely show metastases, and this has limited progress in the understanding of the molecular events in thyroid cancer invasion and metastasis. We have recently generated a mutant mouse by introducing a dominant negative mutant thyroid hormone nuclear receptor gene, TRbetaPV, into the TRbeta gene locus. In this TRbetaPV mouse, the regulation of the thyroid-pituitary axis is disrupted, leading to a mouse with high levels of circulating thyroid-stimulating hormone and extensive hyperplasia of follicular epithelium within the thyroid. As TRbeta(PV/PV) mice, but not TRbeta(PV/+) mice, aged, metastatic thyroid carcinoma developed. Histologic evaluation of thyroids of 5-14-month-old mice showed capsular invasion (91%), vascular invasion (74%), anaplasia (35%), and metastasis to the lung and heart (30%). Previous models of thyroid cancer have focused on genes that control initial carcinogenesis, but this model provides an unusual opportunity to study the alterations in gene regulation that occur with clinically relevant changes during progression and metastasis in a predictable fashion.
Insights
A novel mouse model with a disrupted thyroid hormone nuclear receptor (TRbetaPV) spontaneously develops metastatic thyroid cancer. This model aids in understanding thyroid cancer progression and metastasis.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- The molecular drivers of thyroid cancer invasion and metastasis remain poorly understood.
- Existing thyroid cancer models often fail to exhibit metastasis, limiting research.
- Understanding metastasis is crucial for improving patient outcomes in thyroid cancer.
Purpose of the Study:
- To develop a novel animal model for studying thyroid cancer metastasis.
- To investigate the role of thyroid hormone nuclear receptor mutations in thyroid carcinogenesis and progression.
- To provide a platform for analyzing gene regulation changes during thyroid cancer metastasis.
Main Methods:
- Generation of a mutant mouse model (TRbetaPV) by introducing a dominant-negative mutant thyroid hormone nuclear receptor gene.
- Disruption of the thyroid-pituitary axis, leading to elevated thyroid-stimulating hormone and follicular epithelial hyperplasia.
- Longitudinal monitoring and histological evaluation of aged TRbeta(PV/PV) mice for thyroid carcinoma development and metastasis.
Main Results:
- TRbeta(PV/PV) mice, unlike TRbeta(PV/+) mice, developed metastatic thyroid carcinoma with age.
- High incidence of capsular invasion (91%) and vascular invasion (74%) observed.
- Significant rates of anaplasia (35%) and distant metastasis to lung and heart (30%) were documented.
Conclusions:
- The TRbetaPV mouse model reliably recapitulates key features of human thyroid cancer progression and metastasis.
- This model offers a unique opportunity to study gene regulatory alterations associated with clinical metastasis.
- Further research using this model can elucidate molecular mechanisms underlying thyroid cancer spread.