Thyroid regeneration and carcinogenesis

Division Of Basic Sciences - Nci

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Abstract

Tshr (TSH receptor)-null and littermate wild-type mice were subjected to partial thyroidectomy (acute thyroid injury model) that activates thyroid regeneration. A cluster of thin and elongated shaped cells were found near the tracheal cartilage and muscle in both Tshr-null and wild-type mouse thyroids that were positive for NKX2-1, with some cells also positive for Pax8. NXK2-1 and PAX8 are the transcription factors critical for development, differentiation, and function of the thyroid, and are considered thyroid differentiation markers. The thin and elongated cells were clearly different from matured NKX2-1-positive round-shaped thyroid follicular cells. The results suggested that a cluster of thin elongated cells may be a precursor to thyroid follicular cells. In fact, we found a cluster of NKX2-1 positive thin elongated cells that are connected to a follicle consisting of mature NKX2-1-positive thyroid follicular cells. These clusters of thin elongated cells were present in both genotyped mouse thyroids, which may become more visible after partial thyroidectomy, particularly in wild-type thyroids. Changes in expression patterns of mRNAs for various thyroid-specific genes, growth factors, their receptors, and related signaling molecules before and after partial thyroidectomy were similar between thyroids of Tshr-null and wild-type mice. These results suggested that a cluster of thin elongated cells present near the tracheal cartilage and muscle are a source of newly formed follicles, and at least this type of thyroid regeneration does not require TSH signaling. This is critical in terms of possible restoring thyroid functions in humans after thyroidectomy due to various thyroid diseases including cancer. Whether the thin elongated cells can be considered as thyroid stem/progenitor cells and what are the origin of these cells remain to be understood. In order to address these questions and to better understand the nature of these thin elongated thyroid stem/progenitor-like cells, we carried out Nanostring GeoMX analysis, where cells from the area of a cluster of thin elongated cells, the surrounding tissues, and normal thyroid tissues are captured by laser microdissection, followed by RNAseq analysis of each area of cells. Bioinformatic analysis and further confirmatory experiments are currently under way. We also study mouse thyroid adenoma-derived cells to understand what genes mutations might be responsible for thyroid cells becoming adenomas, and whether and/or how these genes mutations relate to cancer stem cells. To this end, mouse thyroid adenoma-derived cell lines were established in our laboratory from mice that were fed a diet containing amitrole (3-amino-1,2,4-triazole), a non-food herbicide. Amitrole is a known goitrogen, inducing thyroid tumors by inhibiting thyroid hormone synthesis. Mice fed amitrole developed adenoma within 6-12 months. Adenomas from individual mouse were collected, pooled and subjected to cell culture. Five cell lines were established and named CAT (cells from amitrole treated thyroids). Two CAT cell lines CAT458 and 459, out of five established, showed epithelial characteristics with one line clearly expressing NKX2-1, indicating that CAT458 and CAT459 are derived from thyroid follicular cells. They were subjected to whole genome sequencing and the analysis is on the way to identify and understand what genes might be contributing to adenoma development, and possibly to understand if there is any correlation to cancer stem cells of the thyroid.