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Sheueyann Cheng - One of the best experts on this subject based on the ideXlab platform.
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Inflammation suppression prevents tumor cell proliferation in a mouse model of Thyroid cancer.
American journal of cancer research, 2020Co-Authors: Sunmi Park, Minjun Kim, Jack Zhu, Woo Kyung Lee, Grégoire Altan-bonnet, Paul S. Meltzer, Sheueyann ChengAbstract:The incidence of Thyroid cancer, the most frequent endocrine neoplasia, is rapidly increasing. Significant progress has recently been made in the identification of genetic lesions in Thyroid cancer; however, whether inflammation contributes to Thyroid cancer progression remains unknown. Using a mouse model of aggressive follicular Thyroid cancer (FTC; ThrbPV/PVPten+/- mice), we aimed to elucidate a cause-effect relationship at the molecular level. The ThrbPV/PVPten+/- mouse expresses a dominantly negative Thyroid hormone receptor β (denoted as PV) and a deletion of a single allele of the Pten gene. These two oncogenic signaling pathways synergistically activate PI3K-AKT signaling to drive cancer progression as in human FTC. At the age of 5-7 weeks, Thyroids of ThrbPV/PVPten+/- mice exhibited extensive hyperplasia accompanied by 77.5-fold infiltration of inflammatory monocytes as compared with normal Thyroids. Global gene expression profiling identified altered expression of 2387 genes, among which 1353 were upregulated and 1034 were down-regulated. Further analysis identified markedly elevated expression of inflammation mediators and cytokines such as, Csf1r, Csf1, SPP1, Aif1, IL6, Ccl9, Ccl3, Ccl12, and Ccr2 genes and decreased expression of Kit, Ephx2, Cd163, IL15, Ccl11, and Cxcl13 genes. These changes elicited the inflammatory responses in the hyperplastic Thyroid of ThrbPV/PVPten+/- mice, reflecting early events in Thyroid carcinogenesis. We next tested whether attenuating the inflammatory responses could mitigate Thyroid cancer progression. We treated the mice with an inhibitor of colony-stimulating factor 1 receptor (CSF1R), pexidartinib (PLX-3397; PLX). CSF1R mediates the activity of the cytokine, colony stimulating factor 1 (CSF1), in the production, differentiation, and functions of monocytes and macrophages. Treatment with PLX decreased 94% and 62% of inflammatory monocytes in the Thyroid and bone marrow, respectively, versus controls. Further, PLX suppressed the expression of critical cytokine and inflammation-regulating genes such as Csf1r, SPP1 (OPN), Aif1, IL6, Ccl9, Ccl3, Ccl12, and Ccr2 (25%-80%), resulting in inhibition of 89% tumor cell proliferation, evidenced by Ki-67 immunostaining. These preclinical findings suggest that inflammation occurs in the early stage of Thyroid carcinogenesis and plays a critical in cancer progression. Importantly, attenuation of inflammation by inhibitors such as PLX would be beneficial in preventing Thyroid cancer.
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oncogenic actions of the nuclear receptor corepressor ncor1 in a mouse model of Thyroid cancer
PLOS ONE, 2013Co-Authors: Laura Fozzatti, Jeong Won Park, Li Zhao, Mark C Willingham, Sheueyann ChengAbstract:Studies have suggested that the nuclear receptor corepressor 1 (NCOR1) could play an important role in human cancers. However, the detailed molecular mechanisms by which it functions in vivo to affect cancer progression are not clear. The present study elucidated the in vivo actions of NCOR1 in carcinogenesis using a mouse model (ThrbPV/PV mice) that spontaneously develops Thyroid cancer. ThrbPV/PV mice harbor a dominantly negative Thyroid hormone receptor β (TRβ) mutant (denoted as PV). We adopted the loss-of-the function approach by crossing ThrbPV mice with mice that globally express an NCOR1 mutant protein (NCOR1ΔID) in which the receptor interaction domains have been modified so that it cannot interact with the TRβ, or PV, in mice. Remarkably, expression of NCOR1ΔID protein reduced Thyroid tumor growth, markedly delayed tumor progression, and prolonged survival of ThrbPV/PVNcor1ΔID/ΔID mice. Tumor cell proliferation was inhibited by increased expression of cyclin-dependent kinase inhibitor 1 (p21waf1/cip1; Cdkn1A), and apoptosis was activated by elevated expression of pro-apoptotic BCL-Associated X (Bax). Further analyses showed that p53 was recruited to the p53-binding site on the proximal promoter of the Cdkn1A and the Bax gene as a co-repressor complex with PV/NCOR1/histone deacetylas-3 (HDAC-3), leading to repression of the Cdkn1A as well as the Bax gene in Thyroids of ThrbPV/PV mice. In Thyroids of ThrbPV/PVNcor1ΔID/ΔID mice, the p53/PV complex could not recruit NCOR1ΔID and HDAC-3, leading to de-repression of both genes to inhibit cancer progression. The present studies provided direct evidence in vivo that NCOR1 could function as an oncogene via transcription regulation in a mouse model of Thyroid cancer.
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growth activation alone is not sufficient to cause metastatic Thyroid cancer in a mouse model of follicular Thyroid carcinoma
Endocrinology, 2010Co-Authors: Li Zhao, Mark C Willingham, Hao Ying, Sheueyann ChengAbstract:TSH is the major stimulator of thyrocyte proliferation, but its role in Thyroid carcinogenesis remains unclear. To address this question, we used a mouse model of follicular Thyroid carcinoma (FTC) (TRβPV/PV mice). These mice, harboring a dominantly negative mutation (PV) of the Thyroid hormone-β receptor (TRβ), exhibit increased serum Thyroid hormone and elevated TSH. To eliminate TSH growth-stimulating effect, TRβPV/PV mice were crossed with TSH receptor gene knockout (TSHR−/−) mice. Wild-type siblings of TRβPV/PV mice were treated with an antiThyroid agent, propylthiouracil, to elevate serum TSH for evaluating long-term TSH effect (WT-PTU mice). Thyroids from TRβPV/PVTSHR−/− showed impaired growth with no occurrence of FTC. Both WT-PTU and TRβPV/PV mice displayed enlarged Thyroids, but only TRβPV/PV mice developed metastatic FTC. Molecular analyses indicate that PV acted, via multiple mechanisms, to activate the integrins-Src-focal adhesion kinase-p38 MAPK pathway and affect cytoskeletal restructuring to increase tumor cell migration and invasion. Thus, growth stimulated by TSH is a prerequisite but not sufficient for metastatic cancer to occur. Additional genetic alterations (such as PV), destined to alter focal adhesion and migration capacities, are required to empower hyperplastic follicular cells to invade and metastasize. These in vivo findings provide new insights in understanding carcinogenesis of the human Thyroid.
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the pituitary tumor transforming gene promotes angiogenesis in a mouse model of follicular Thyroid cancer
Carcinogenesis, 2006Co-Authors: Caroline S Kim, Mark C Willingham, Hao Ying, Sheueyann ChengAbstract:Overexpression of the pituitary tumor-transforming gene (PTTG) has been associated with tumorigenesis. In a mouse model that spontaneously develops follicular Thyroid cancer (FTC) with distant metastasis (TRbPV mouse), PTTG is overexpressed, similar to human Thyroid cancer. To evaluate the role of PTTG in Thyroid carcinogenesis, we studied the offspring of TRbPV mice with mice lacking PTTG (PTTG � /� mice). The Thyroids of TRb PV/PV PTTG � /� mice were significantly smaller than TRb PV/PV mice. Ki-67 staining showed a decrease in Thyroid proliferation in TRb PV/PV PTTG � /� mice. Our evaluation of the Rb‐E2F pathway, a central mediator of cell growth, found that TRb PV/PV PTTG � /� mice exhibited a decrease in protein levels of phosphorylated Rb along with an elevation of the cdk inhibitor p21. Histological examination documented no difference in FTC occurrence between TRb PV/PV and TRb PV/PV PTTG � /� mice, which indicates that PTTG removal does not prevent the initiation of FTC. However, TRb PV/PV PTTG � /� mice had a significant decrease in vascular invasion and less development of lung metastasis as they progressively aged. CD31 staining also showed a decrease invessel density in TRb PV/PV PTTG � /� versus TRb PV/PV Thyroids. Given the decreased vascular invasion in the PTTG knockout mice, we studied genesinvolvedinangiogenesis.Real-time reverse transcription‐polymerase chain reaction showed a consistent decrease in pro-angiogenic factors, fibroblast growth factor (FGF2), its receptor FGFR1 and vascular endothelial growth factor. Our results highlight the dual roles of PTTG as a regulator of Thyroid growth and contributor to tumor progression. The separation of the pathways regulating cell proliferation, tumor initiation and tumor progression should direct future therapeutic options.
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akt activation promotes metastasis in a mouse model of follicular Thyroid carcinoma
Endocrinology, 2005Co-Authors: Caroline S Kim, Vasily Vasko, Sheueyann Cheng, Yasuhito Kato, Michael Kruhlak, Motoyasu Saji, Matthew D RingelAbstract:The phosphatidylinositol 3-kinase/AKT pathway is crucial to many cell functions, and its dysregulation in tumors is a common finding. The molecular basis of follicular Thyroid cancer metastasis is not well understood but may also be influenced by AKT activation. We previously created a knockin mutant mouse that expresses a mutant Thyroid hormone receptorgene (TRPV mouse) that spontaneously develops Thyroid cancer and distant metastasis similar to human follicular Thyroid cancer. In this study, we investigated whether our mouse model exhibits similar AKT activation as human follicular Thyroid cancer. Western blot analysis on Thyroids from both wild-type and TR PV/PV mice revealed elevation of activated AKT in TR PV/PV mice. Immunohistochemistry and confocal microscopy reveal activated AKT in both the Thyroid and metastatic lesions of TR PV/PV mice. Whereas all three AKT isoforms were overexpressed in primary tumors from TR PV/PV mice in the cytoplasm of Thyroid cancer cells, only AKT1 was also found in the nucleus, matching the localization of activated AKT in a pattern similar to human follicular Thyroid cancer. In the metastases, all AKT isoforms correlated with phosphorylated AKT nuclear localization. We created primary Thyroid cell lines derived from TR PV/PV mice and found reduction of phosphorylated AKT levels or AKT downstream targets diminishes cell motility. Activated AKT is common to both human and mouse follicular Thyroid cancer and is correlated with increased cell motility in vitro and metastasis in vivo. Thus, TR PV/PV mice could be used to further dissect the detailed pathways underlying the progression and metastasis of follicular Thyroid carcinoma. (Endocrinology 146: 4456–4463, 2005)
Mark C Willingham - One of the best experts on this subject based on the ideXlab platform.
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oncogenic actions of the nuclear receptor corepressor ncor1 in a mouse model of Thyroid cancer
PLOS ONE, 2013Co-Authors: Laura Fozzatti, Jeong Won Park, Li Zhao, Mark C Willingham, Sheueyann ChengAbstract:Studies have suggested that the nuclear receptor corepressor 1 (NCOR1) could play an important role in human cancers. However, the detailed molecular mechanisms by which it functions in vivo to affect cancer progression are not clear. The present study elucidated the in vivo actions of NCOR1 in carcinogenesis using a mouse model (ThrbPV/PV mice) that spontaneously develops Thyroid cancer. ThrbPV/PV mice harbor a dominantly negative Thyroid hormone receptor β (TRβ) mutant (denoted as PV). We adopted the loss-of-the function approach by crossing ThrbPV mice with mice that globally express an NCOR1 mutant protein (NCOR1ΔID) in which the receptor interaction domains have been modified so that it cannot interact with the TRβ, or PV, in mice. Remarkably, expression of NCOR1ΔID protein reduced Thyroid tumor growth, markedly delayed tumor progression, and prolonged survival of ThrbPV/PVNcor1ΔID/ΔID mice. Tumor cell proliferation was inhibited by increased expression of cyclin-dependent kinase inhibitor 1 (p21waf1/cip1; Cdkn1A), and apoptosis was activated by elevated expression of pro-apoptotic BCL-Associated X (Bax). Further analyses showed that p53 was recruited to the p53-binding site on the proximal promoter of the Cdkn1A and the Bax gene as a co-repressor complex with PV/NCOR1/histone deacetylas-3 (HDAC-3), leading to repression of the Cdkn1A as well as the Bax gene in Thyroids of ThrbPV/PV mice. In Thyroids of ThrbPV/PVNcor1ΔID/ΔID mice, the p53/PV complex could not recruit NCOR1ΔID and HDAC-3, leading to de-repression of both genes to inhibit cancer progression. The present studies provided direct evidence in vivo that NCOR1 could function as an oncogene via transcription regulation in a mouse model of Thyroid cancer.
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growth activation alone is not sufficient to cause metastatic Thyroid cancer in a mouse model of follicular Thyroid carcinoma
Endocrinology, 2010Co-Authors: Li Zhao, Mark C Willingham, Hao Ying, Sheueyann ChengAbstract:TSH is the major stimulator of thyrocyte proliferation, but its role in Thyroid carcinogenesis remains unclear. To address this question, we used a mouse model of follicular Thyroid carcinoma (FTC) (TRβPV/PV mice). These mice, harboring a dominantly negative mutation (PV) of the Thyroid hormone-β receptor (TRβ), exhibit increased serum Thyroid hormone and elevated TSH. To eliminate TSH growth-stimulating effect, TRβPV/PV mice were crossed with TSH receptor gene knockout (TSHR−/−) mice. Wild-type siblings of TRβPV/PV mice were treated with an antiThyroid agent, propylthiouracil, to elevate serum TSH for evaluating long-term TSH effect (WT-PTU mice). Thyroids from TRβPV/PVTSHR−/− showed impaired growth with no occurrence of FTC. Both WT-PTU and TRβPV/PV mice displayed enlarged Thyroids, but only TRβPV/PV mice developed metastatic FTC. Molecular analyses indicate that PV acted, via multiple mechanisms, to activate the integrins-Src-focal adhesion kinase-p38 MAPK pathway and affect cytoskeletal restructuring to increase tumor cell migration and invasion. Thus, growth stimulated by TSH is a prerequisite but not sufficient for metastatic cancer to occur. Additional genetic alterations (such as PV), destined to alter focal adhesion and migration capacities, are required to empower hyperplastic follicular cells to invade and metastasize. These in vivo findings provide new insights in understanding carcinogenesis of the human Thyroid.
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the pituitary tumor transforming gene promotes angiogenesis in a mouse model of follicular Thyroid cancer
Carcinogenesis, 2006Co-Authors: Caroline S Kim, Mark C Willingham, Hao Ying, Sheueyann ChengAbstract:Overexpression of the pituitary tumor-transforming gene (PTTG) has been associated with tumorigenesis. In a mouse model that spontaneously develops follicular Thyroid cancer (FTC) with distant metastasis (TRbPV mouse), PTTG is overexpressed, similar to human Thyroid cancer. To evaluate the role of PTTG in Thyroid carcinogenesis, we studied the offspring of TRbPV mice with mice lacking PTTG (PTTG � /� mice). The Thyroids of TRb PV/PV PTTG � /� mice were significantly smaller than TRb PV/PV mice. Ki-67 staining showed a decrease in Thyroid proliferation in TRb PV/PV PTTG � /� mice. Our evaluation of the Rb‐E2F pathway, a central mediator of cell growth, found that TRb PV/PV PTTG � /� mice exhibited a decrease in protein levels of phosphorylated Rb along with an elevation of the cdk inhibitor p21. Histological examination documented no difference in FTC occurrence between TRb PV/PV and TRb PV/PV PTTG � /� mice, which indicates that PTTG removal does not prevent the initiation of FTC. However, TRb PV/PV PTTG � /� mice had a significant decrease in vascular invasion and less development of lung metastasis as they progressively aged. CD31 staining also showed a decrease invessel density in TRb PV/PV PTTG � /� versus TRb PV/PV Thyroids. Given the decreased vascular invasion in the PTTG knockout mice, we studied genesinvolvedinangiogenesis.Real-time reverse transcription‐polymerase chain reaction showed a consistent decrease in pro-angiogenic factors, fibroblast growth factor (FGF2), its receptor FGFR1 and vascular endothelial growth factor. Our results highlight the dual roles of PTTG as a regulator of Thyroid growth and contributor to tumor progression. The separation of the pathways regulating cell proliferation, tumor initiation and tumor progression should direct future therapeutic options.
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mice with a mutation in the Thyroid hormone receptor beta gene spontaneously develop Thyroid carcinoma a mouse model of Thyroid carcinogenesis
Thyroid, 2002Co-Authors: Hideyo Suzuki, Mark C Willingham, Sheueyann ChengAbstract: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, TRβPV, into the TRβ gene locus. In this TRβPV 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 TRβPV/PV mice, but not TRβPV/+ 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 m...
Kubota Yoshiaki - One of the best experts on this subject based on the ideXlab platform.
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VEGFR2 but not VEGFR3 governs integrity and remodeling of Thyroid angiofollicular unit in normal state and during goitrogenesis
'EMBO', 2017Co-Authors: Jang, Jeon Yeob, Choi, Sung Yong, Park Intae, Park, Do Young, Choe Kibaek, Kim Pilhan, Kim, Young Keum, Lee Byung-joo, Hirashima Masanori, Kubota YoshiakiAbstract:Thyroid gland vasculature has a distinguishable characteristic of endothelial fenestrae, a critical component for proper molecular transport. However, the signaling pathway that critically governs the maintenance of Thyroid vascular integrity, including endothelial fenestrae, is poorly understood. Here, we found profound and distinct expression of follicular epithelial VEGF-A and vascular VEGFR2 that were precisely regulated by circulating thyrotropin, while there were no meaningful expression of angiopoietin-Tie2 system in the Thyroid gland. Our genetic depletion experiments revealed that VEGFR2, but not VEGFR3, is indispensable for maintenance of Thyroid vascular integrity. Notably, blockade of VEGF-A or VEGFR2 not only abrogated vascular remodeling but also inhibited follicular hypertrophy, which led to the reduction of Thyroid weights during goitrogenesis. Importantly, VEGFR2 blockade alone was sufficient to cause a reduction of endothelial fenestrae with decreases in thyrotropin-responsive genes in goitrogen-fed Thyroids. Collectively, these findings establish follicular VEGF-Avascular VEGFR2 axis as a main regulator for thyrotropindependent Thyroid angiofollicular remodeling and goitrogenesis.Peer reviewe
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VEGFR2 but not VEGFR3 governs integrity and remodeling of Thyroid angiofollicular unit in normal state and during goitrogenesis
'EMBO', 2017Co-Authors: Jang, Jeon Yeob, Choi, Sung Yong, Park Intae, Park, Do Young, Choe Kibaek, Kim Pilhan, Kim, Young Keum, Lee Byung-joo, Hirashima Masanori, Kubota YoshiakiAbstract:Thyroid gland vasculature has a distinguishable characteristic of endothelial fenestrae, a critical component for proper molecular transport. However, the signaling pathway that critically governs the maintenance of Thyroid vascular integrity, including endothelial fenestrae, is poorly understood. Here, we found profound and distinct expression of follicular epithelial VEGF-A and vascular VEGFR2 that were precisely regulated by circulating thyrotropin, while there were no meaningful expression of angiopoietin-Tie2 system in the Thyroid gland. Our genetic depletion experiments revealed that VEGFR2, but not VEGFR3, is indispensable for maintenance of Thyroid vascular integrity. Notably, blockade of VEGF-A or VEGFR2 not only abrogated vascular remodeling but also inhibited follicular hypertrophy, which led to the reduction of Thyroid weights during goitrogenesis. Importantly, VEGFR2 blockade alone was sufficient to cause a reduction of endothelial fenestrae with decreases in thyrotropin-responsive genes in goitrogen-fed Thyroids. Collectively, these findings establish follicular VEGF-Avascular VEGFR2 axis as a main regulator for thyrotropindependent Thyroid angiofollicular remodeling and goitrogenesis
Matthew D Ringel - One of the best experts on this subject based on the ideXlab platform.
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follicular Thyroid cancers demonstrate dual activation of pka and mtor as modeled by Thyroid specific deletion of prkar1a and pten in mice
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Daphne R Pringle, Vasily Vasko, Audrey A Lee, Parmeet Kaur Manchanda, David Jarjoura, Motoyasu Saji, Xiaoli Zhang, Jessica M Kirschner, Albert F Parlow, Matthew D RingelAbstract:Context: Thyroid cancer is the most common form of endocrine cancer, and it is a disease whose incidence is rapidly rising. Well-differentiated epithelial Thyroid cancer can be divided into papillary Thyroid cancer (PTC) and follicular Thyroid cancer (FTC). Although FTC is less common, patients with this condition have more frequent metastasis and a poorer prognosis than those with PTC. Objective: The objective of this study was to characterize the molecular mechanisms contributing to the development and metastasis of FTC. Design: We developed and characterized mice carrying Thyroid-specific double knockout of the Prkar1a and Pten tumor suppressor genes and compared signaling alterations observed in the mouse FTC to the corresponding human tumors. Setting: The study was conducted at an academic research laboratory. Human samples were obtained from academic hospitals. Patients: Deidentified, formalin-fixed, paraffin-embedded (FFPE) samples were analyzed from 10 control Thyroids, 30 PTC cases, five follicul...
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akt activation promotes metastasis in a mouse model of follicular Thyroid carcinoma
Endocrinology, 2005Co-Authors: Caroline S Kim, Vasily Vasko, Sheueyann Cheng, Yasuhito Kato, Michael Kruhlak, Motoyasu Saji, Matthew D RingelAbstract:The phosphatidylinositol 3-kinase/AKT pathway is crucial to many cell functions, and its dysregulation in tumors is a common finding. The molecular basis of follicular Thyroid cancer metastasis is not well understood but may also be influenced by AKT activation. We previously created a knockin mutant mouse that expresses a mutant Thyroid hormone receptorgene (TRPV mouse) that spontaneously develops Thyroid cancer and distant metastasis similar to human follicular Thyroid cancer. In this study, we investigated whether our mouse model exhibits similar AKT activation as human follicular Thyroid cancer. Western blot analysis on Thyroids from both wild-type and TR PV/PV mice revealed elevation of activated AKT in TR PV/PV mice. Immunohistochemistry and confocal microscopy reveal activated AKT in both the Thyroid and metastatic lesions of TR PV/PV mice. Whereas all three AKT isoforms were overexpressed in primary tumors from TR PV/PV mice in the cytoplasm of Thyroid cancer cells, only AKT1 was also found in the nucleus, matching the localization of activated AKT in a pattern similar to human follicular Thyroid cancer. In the metastases, all AKT isoforms correlated with phosphorylated AKT nuclear localization. We created primary Thyroid cell lines derived from TR PV/PV mice and found reduction of phosphorylated AKT levels or AKT downstream targets diminishes cell motility. Activated AKT is common to both human and mouse follicular Thyroid cancer and is correlated with increased cell motility in vitro and metastasis in vivo. Thus, TR PV/PV mice could be used to further dissect the detailed pathways underlying the progression and metastasis of follicular Thyroid carcinoma. (Endocrinology 146: 4456–4463, 2005)
Anamaria A Camargo - One of the best experts on this subject based on the ideXlab platform.
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histopathological characterization and whole exome sequencing of ectopic Thyroid fetal architecture in a functional ectopic gland from adult patient
International Journal of Endocrinology, 2018Co-Authors: Rosalinda Camargo, Cristina Takami Kanamura, Celso Ubirajara Friguglietti, Celia Regina Nogueira, Sonia Iorcansky, Alfio Jose Tincani, Ana Karina Bezerra, Ester Saraiva Brust, Fernanda C Koyama, Anamaria A CamargoAbstract:Ectopic Thyroid results from a migration defect of the developing gland during embryogenesis causing congenital hypoThyroidism. But it has also been detected in asymptomatic individuals. This study aimed to investigate the histopathological, functional, and genetic features of human ectopic Thyroids. Six samples were histologically examined, and the expression of the specific Thyroid proteins was assessed by immunohistochemistry. Two samples were submitted to whole exome sequencing. An oropharynx sample showed immature fetal architecture tissue with clusters or cords of oval thyrocytes and small follicles; one sample exhibited a normal Thyroid pattern while four showed colloid goiter. All ectopic Thyroids expressed the specific Thyroid genes and T4 at similar locations to those observed in normal Thyroid. No somatic mutations associated with ectopic Thyroid were found. This is the first immature Thyroid fetal tissue observed in an ectopic Thyroid due to the arrest of structural differentiation early in the colloid stage of development that proved able to synthesize Thyroid hormone but not to respond to TSH. Despite the ability of all ectopic Thyroids to synthetize specific Thyroid proteins and T4, at some point in life, it may be insufficient to support body growth leading to hypoThyroidism, as observed in some of the patients.
