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Thyroid adenocarcinomas secondary to tissue-specific expression of simian virus-40 large T-antigen in transgenic mice
Abstract:
A hybrid gene comprising the bovine thyroglobulin gene promoter and the coding region for the simian virus-40 large T- and small t-antigens was used to generate 30 transgenic mice by microinjection into the pronuclei of single cell embryos. All animals except three developed, as single primitive pathology, a dramatic enlargement of the thyroid gland. Compression of trachea and esophagus, accompanied by dyspnea, inspiratory stridor, and dysphagia, led to a progressive cachexia and premature death attributed to respiratory failure. Despite the large thyroid volume, T4 levels were abnormally low, and the progression of the syndrome could be delayed by a substitutive treatment with thyroid hormones. The rapid evolution of the disease, leading to the death of most founder transgenic animals before the breeding age, prevented transmission of the transgene to their offspring. Only two transgenic lines are presently surviving. Immunohistochemical analysis of the tissues revealed a specific expression of the simian virus-40 antigens in the thyroid cells. Hyperplasia was already obvious at birth. Older animals displayed moderately to poorly differentiated thyroid adenocarcinomas. Electron microscopy revealed, however, the persistence of cell polarity and the presence of microfollicles between the densely packed cells. Cell lines derived from these large T-expressing thyroids were shown to have lost expression of both thyroglobulin and thyroperoxidase, while expressing low levels of TSH receptors. These transgenic mice could constitute an interesting model of aggressive adenocarcinoma, sharing phenotypical similarities with the anaplastic type of human thyroid tumors.
Insights
Transgenic mice with a hybrid gene developed aggressive thyroid tumors, leading to premature death. This model offers insights into human anaplastic thyroid cancer, despite challenges in transmitting the genetic modification.
Area of Science:
- Endocrinology
- Oncology
- Genetics
Background:
- Thyroid cancer is a significant health concern with various subtypes.
- Developing accurate animal models is crucial for understanding thyroid tumor progression and testing therapies.
Purpose of the Study:
- To create and characterize a novel transgenic mouse model for aggressive thyroid adenocarcinoma.
- To investigate the role of simian virus-40 (SV40) antigens in thyroid tumorigenesis.
Main Methods:
- Generation of transgenic mice by microinjecting a hybrid gene (bovine thyroglobulin promoter-SV40 T-antigens) into single-cell embryos.
- Phenotypic analysis including gross pathology, hormone level assessment (T4), and survival studies.
- Histopathological examination (immunohistochemistry, electron microscopy) and cell line characterization.
Main Results:
- Transgenic mice exhibited dramatic thyroid gland enlargement (hyperplasia) from birth.
- Progressive cachexia and premature death due to respiratory failure from tracheal/esophageal compression.
- Development of moderately to poorly differentiated thyroid adenocarcinomas, phenotypically similar to anaplastic thyroid cancer.
- Loss of thyroglobulin and thyroperoxidase expression, with low TSH receptor levels in derived cell lines.
Conclusions:
- The generated transgenic mice represent a valuable model for studying aggressive thyroid adenocarcinoma.
- This model exhibits similarities to human anaplastic thyroid tumors, aiding research into their pathogenesis.
- The rapid disease progression and mortality present challenges for germline transmission but highlight the model's aggressive nature.