|
1
|
Chen R, Gao W, Liang L, Yu H, Song W. Stem cell index-based RiskScore model for predicting prognosis in thyroid cancer and experimental verification. Heliyon 2024; 10:e31970. [PMID: 38868069 PMCID: PMC11167363 DOI: 10.1016/j.heliyon.2024.e31970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 05/22/2024] [Accepted: 05/24/2024] [Indexed: 06/14/2024] Open
Abstract
Objective An mRNA expression-based stemness index (mRNAsi) has been developed to characterize cancer stemness. However, the predictive value of mRNAsi-based signature in therapeutic resistance and immunotherapy in thyroid cancer (THCA) remains unclarified. This study evaluated and validated the role of mRNAsi in drug sensitivity, its relationship between mRNAsi and THCA clinical features and immunity based on bioinformatics. Methods Based on transcriptome data of THCA patients from the Tumor Genome Atlas Project (TCGA) database, and expression data of multifunctional stem cell samples from the Progenitor Cell Biology Consortium (PCBC) databases, mRNAsi was calculated by the " one class logistic regression (OCLR)" method, Molecular subtypes of TCGA-THCA samples were identified with mRNAsi-related genes using ConsensusClusterPlus method. The gene mutation, clinical characteristics, immune characteristics, TIDE and drug sensitivity were compared among molecular subtypes. A prognostic model was designed with Lasso cox method. Modulation of malignant phenotype of THCA cell lines by model characterization genes is validated by CCK-8, flow cytometry. DNA methylation disorder in promoter region was analyzed between risk groups. The model was validated for survival in the internal Test dataset, while TCGA pan-cancer and immunotherapy datasets were further employed to validate the performance of this model. Results We obtained a total of 78 stem cell samples, each containing the expression profile of 8087 mRNA genes. Based on mRNAsi, THCA was divided into 3 subtypes. Subtype C2 had the poorest prognosis and highest immune score, while subtype C3 had the best prognosis, lowest mRANsi and highest TIDE score. Patients in subtype C2 showed higher sensitivity to Cisplatin, Erlotinib, Paclitaxel, and Lapatinib. The prognostic signature was generated using 5 mRNAsi-related genes, which could predict prognosis for THCA. qRT-PCR results showed that the expression of 5 genes were various in Hth7 and KTC-1 cells, and inhibition CELSR3 expression increased percentage of apoptosis in Hth7 and KTC-1 cells. mRNAsi related DNA methylation sites were mainly enriched in tumor related pathways. Good performance of this model was validated in Test dataset, pan-cancer and immunotherapy datasets. Conclusion This study identified three subtypes for classification and developed a prognostic model with mRNAsi-related genes, which provided great potential for prognosis and immunotherapy prediction.
Collapse
Affiliation(s)
- Ruoran Chen
- Department of Endocrinology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| | - Wei Gao
- Department of Endocrinology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| | - Linlang Liang
- Department of Endocrinology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| | - Hao Yu
- Department of Endocrinology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| | - Wei Song
- Department of Endocrinology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| |
Collapse
|
|
2
|
Li L, Sheng Q, Zeng H, Li W, Wang Q, Ma G, Qiu M, Zhang W, Shan C. Engineering a functional thyroid as a potential therapeutic substitute for hypothyroidism treatment: A systematic review. Front Endocrinol (Lausanne) 2022; 13:1065410. [PMID: 36531472 PMCID: PMC9755335 DOI: 10.3389/fendo.2022.1065410] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 11/17/2022] [Indexed: 12/04/2022] Open
Abstract
Background Hypothyroidism is a common hormone deficiency disorder. Although hormone supplemental therapy can be easily performed by daily levothyroxine administration, a proportion of patients suffer from persisting complaints due to unbalanced hormone levels, leaving room for new therapeutic strategies, such as tissue engineering and regenerative medicine. Methods Electronic searches of databases for studies of thyroid regeneration or thyroid organoids were performed. A systematic review including both in vitro and in vivo models of thyroid regenerative medicine was conducted. Results Sixty-six independent studies published between 1959 and May 1st, 2022 were included in the current systematic review. Among these 66 studies, the most commonly involved species was human (19 studies), followed by mouse (18 studies), swine (14 studies), rat (13 studies), calf/bovine (4 studies), sheep/lamb (4 studies) and chick (1 study). In addition, in these experiments, the most frequently utilized tissue source was adult thyroid tissue (46 studies), followed by embryonic stem cells (ESCs)/pluripotent stem cells (iPSCs) (10 studies), rat thyroid cell lines (7 studies), embryonic thyroid tissue (2 studies) and newborn or fetal thyroid tissue (2 studies). Sixty-three studies reported relevant thyroid follicular regeneration experiments in vitro, while 21 studies showed an in vivo experiment section that included transplanting engineered thyroid tissue into recipients. Together, 12 studies were carried out using 2D structures, while 50 studies constructed 3D structures. Conclusions Each aspect of thyroid regenerative medicine was comprehensively described in this review. The recovery of optimal hormonal equilibrium by the transplantation of an engineered functional thyroid holds great therapeutic promise.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Wei Zhang
- Department of Thyroid and Breast Surgery of Changzheng Hospital Affiliated with Naval Military Medical University, Shanghai, China
| | - Chengxiang Shan
- Department of Thyroid and Breast Surgery of Changzheng Hospital Affiliated with Naval Military Medical University, Shanghai, China
| |
Collapse
|
|
3
|
Karabiyik Acar Ö, Nozhatzadeh GD, Tuncer A, Torun Köse G, Hacihasanoğlu E, Sahin F, Aysan E. Production of parathyroid-like cells from thyroid stem cells in co-culture environment. Medicine (Baltimore) 2022; 101:e32009. [PMID: 36482540 PMCID: PMC9726294 DOI: 10.1097/md.0000000000032009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Parathyroid-like cells were aimed to be developed using cells isolated from thyroid since their embryological origins are the same. METHOD Activin A and sonic hedgehog (Shh) are the proteins used in differentiation (dif) medium. Parathyroid and thyroid cells were cultured in a 3-dimensional environment and divided into five groups: thyroid standard (st) medium, thyroid dif medium, parathyroid st medium, thyroid-parathyroid co-culture st medium, and thyroid-parathyroid co-culture dif medium. Throughout 28 days of incubation, groups were investigated by carrying out the live dead assay, confocal microscopy, real-time PCR, immunohistochemistry and biochemical assays. RESULTS Thyroid-parathyroid co-culture cells grown in dif medium exhibited upregulated expressions of parathormone (PTH) (5.1-fold), PTH1R (3.6-fold), calcium sensing receptor (CaSR) (8.8-fold), and loss of thyroid-specific thyroid transcription factor 1 (TTF1) expression when compared to the thyroid st medium group. PTH secretion decreased by 35% in the parathyroid st medium group and 99.9% in the thyroid-parathyroid co-culture st medium group but decreased only 3.5% in the thyroid-parathyroid co-culture dif medium group on day 28. CONCLUSION Using Activin A and Shh proteins, thyroid stem/progenitor cells were differentiated to parathyroid-like cells successfully in a co-culture environment. A potentially effective novel method for cell differenatiation is co-culture of cells having the same embryological origin.
Collapse
Affiliation(s)
- Özge Karabiyik Acar
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Istanbul, Turkey
| | - Gülçin Delal Nozhatzadeh
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Istanbul, Turkey
| | - Alperen Tuncer
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey
| | - Gamze Torun Köse
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey
| | - Ezgi Hacihasanoğlu
- Department of Pathology, Faculty of Medicine, Yeditepe University, Istanbul, Turkey
| | - Fikrettin Sahin
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey
| | - Erhan Aysan
- Department of General Surgery, Faculty of Medicine, Yeditepe University, Istanbul, Turkey
- * Correspondence: Erhan Aysan, Department of General Surgery, Faculty of Medicine, Yeditepe University, ATA-2 Sitesi, Akasya Cad. No:25, Cengelkoy, Uskudar, Istanbul 34900, Turkey (e-mail: )
| |
Collapse
|
|
4
|
Yi S, Kim HJ, Koo BS, Lee SE, Choi J, Kang YE. Efficient Dissociation Protocol for Generation of Single Cell Suspension from Human Thyroid Tissue for Single Cell RNA Sequencing. Endocrinol Metab (Seoul) 2022; 37:698-700. [PMID: 36065649 PMCID: PMC9449111 DOI: 10.3803/enm.2022.1536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Shinae Yi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Hyun Jung Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
| | - Bon Seok Koo
- Department of Otolaryngoloy-Head and Neck Surgery, Chungnam National University College of Medicine, Daejeon, Korea
| | - Seong Eun Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Jahyun Choi
- Department of NGS Business, Macrogen Inc., Seoul, Korea
| | - Yea Eun Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
- Corresponding author: Yea Eun Kang. Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University College of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea Tel: +82-42-280-7140, Fax: +82-42-280-7140 E-mail:
| |
Collapse
|
|
5
|
Stem cells therapy for thyroid diseases: progress and challenges. Curr Ther Res Clin Exp 2022; 96:100665. [PMID: 35371349 PMCID: PMC8968462 DOI: 10.1016/j.curtheres.2022.100665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 02/25/2022] [Indexed: 11/18/2022] Open
Abstract
Background Thyroid hormones are indispensable for organ development and maintaining homeostasis. Thyroid diseases, including thyroiditis and thyroid cancer, affect the normal secretion of hormones and result in thyroid dysfunction. Objective This review focuses on therapeutic applications of stem cells for thyroid diseases. Methods A literature search of Medline and PubMed was conducted (January 2000–July 2021) to identify recent reports on stem cell therapy for thyroid diseases. Results Stem cells are partially developed cell types. They have the capacity to form specialized cells. Besides embryonic stem cells and mesenchymal stem cells, organ resident stem cells and cancer stem cells are recently reported to have important roles in forming organ specific cells and cancers. Stem cells, especially mesenchymal stem cells, have anti-inflammatory and anticancer functions as well. Conclusions This review outlines the therapeutic potency of embryonic stem cells, mesenchymal stem cells, thyroid resident stem cells, and thyroid cancer stem cells in thyroid cells’ regeneration, thyroid function modulation, thyroiditis suppression, and antithyroid cancers. Stem cells represent a promising form of treatment for thyroid disorders.
Collapse
|
|
6
|
Adult mouse and human organoids derived from thyroid follicular cells and modeling of Graves' hyperthyroidism. Proc Natl Acad Sci U S A 2021; 118:2117017118. [PMID: 34916298 PMCID: PMC8713972 DOI: 10.1073/pnas.2117017118] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2021] [Indexed: 12/16/2022] Open
Abstract
The thyroid is essential for maintaining systemic homeostasis by regulating thyroid hormone concentrations in the bloodstream. This study describes an organoid-based model system to study mouse and human thyroid biology. Moreover, the study explores the potential of human organoids for modeling autoimmune disease, the anti-TSH receptor (TSHR) antibody-driven Graves’ hyperthyroidism. The thyroid maintains systemic homeostasis by regulating serum thyroid hormone concentrations. Here we report the establishment of three-dimensional (3D) organoids from adult thyroid tissue representing murine and human thyroid follicular cells (TFCs). The TFC organoids (TFCOs) harbor the complete machinery of hormone production as visualized by the presence of colloid in the lumen and by the presence of essential transporters and enzymes in the polarized epithelial cells that surround a central lumen. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1, while the thyroid hormone precursor thyroglobulin is expressed at comparable levels to tissue. Single-cell RNA sequencing and transmission electron microscopy confirm that TFCOs phenocopy primary thyroid tissue. Thyroid hormones are readily detectable in conditioned medium of human TFCOs. We show clinically relevant responses (increased proliferation and hormone secretion) of human TFCOs toward a panel of Graves’ disease patient sera, demonstrating that organoids can model human autoimmune disease.
Collapse
|
|
7
|
Davies TF, Latif R, Sachidanandam R, Ma R. The Transient Human Thyroid Progenitor Cell: Examining the Thyroid Continuum from Stem Cell to Follicular Cell. Thyroid 2021; 31:1151-1159. [PMID: 33678005 PMCID: PMC8377509 DOI: 10.1089/thy.2020.0930] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background: The development of the thyroid follicular cell has been well characterized as it progresses from the original stem cell, either embryonic or adult, through a series of transitions to form a differentiated and functional thyroid cell. Summary: In this review, we briefly outline what is known about this transitional process with emphasis on characterizing the thyroid progenitor stem cell by using data obtained from both in vitro and in vivo studies and both mouse and human cells. It is of particular importance to note the influence of independent factors that guide the transcriptional control of the developing thyroid cell as it is subjected to extracellular signals, often working via epigenetic changes, and initiating intrinsic transcriptional changes leading to a functional cell. Conclusion: Thyroid stem cells fall into the category of dispositional stem cells and are greatly influenced by their environment.
Collapse
Affiliation(s)
- Terry F. Davies
- Thyroid Research Unit, Department of Medicine and Icahn School of Medicine at Mount Sinai and James J. Peters VA Medical Center, New York, New York, USA
| | - Rauf Latif
- Thyroid Research Unit, Department of Medicine and Icahn School of Medicine at Mount Sinai and James J. Peters VA Medical Center, New York, New York, USA
| | - Ravi Sachidanandam
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai and James J. Peters VA Medical Center, New York, New York, USA
| | - Risheng Ma
- Thyroid Research Unit, Department of Medicine and Icahn School of Medicine at Mount Sinai and James J. Peters VA Medical Center, New York, New York, USA
- Address correspondence to: Risheng Ma, MD, PhD, Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and James J. Peters VA Medical Center, Dr. R. Ma, Room 4-23, 1 Gustave L. Levy Place, Box #1055, New York, NY 10029-5674, USA
| |
Collapse
|
|
8
|
He JL, Zhang C, Hu MJ, Wu HB, Lu XL, Hao JH, Huang F. Reproductive and menstrual factors for papillary thyroid cancer risk: A case-control study in Chinese women. Cancer Epidemiol 2021; 73:101964. [PMID: 34098220 DOI: 10.1016/j.canep.2021.101964] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 05/15/2021] [Accepted: 05/29/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Thyroid cancer (TC) is threefold more common in women than men. Reproductive and menstrual factors may be related to the onset of papillary thyroid cancer (PTC). This study aims to determine the association of reproductive and menstrual factors with PTC in Chinese females. METHODS A total of 335 histologically confirmed cases of PTC were recruited in this case-control study. The controls were matched for age with a deviation of ± 2 years, which conducted from September 2016 to February 2019. Logistic regression models were applied to identify the association of reproductive and menstrual factors with PTC. RESULTS After adjustment by some variables, early menarche age (OR ≤ 13 years vs. > 13years = 2.40, 95 % CI 1.12-5.13) and shorter lifetime breastfeeding (OR <6 months vs. ≥ 6 months = 1.99, 95 % CI 1.11-3.55) significantly increased the risk of PTC, whereas younger age at first pregnancy had a protective effect against PTC (OR ≤ 24years vs. > 24 years = 0.66, 95 % CI 0.44-0.98). There was a positive correlation between premenopausal and PTC in the lower age group (OR premenopausal vs. Menopause by natural =2.34, 95 %CI 1.03-5.28). CONCLUSIONS Early menarche age, abortion, shorter breastfeeding duration and premenopausal may be related to the occurrence of PTC. Early age at first pregnancy and larger number of full-time pregnancies were possible to decrease the risk of PTC.
Collapse
Affiliation(s)
- Jia-Liu He
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China
| | - Chi Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China; Xuzhou Institution of Health Inspection, Xuzhou, Jiangsu, 221000, PR China
| | - Ming-Jun Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China
| | - Hua-Bing Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China
| | - Xue-Lei Lu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China
| | - Jia-Hu Hao
- Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China.
| | - Fen Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China.
| |
Collapse
|
|
9
|
The Possible Role of Cancer Stem Cells in the Resistance to Kinase Inhibitors of Advanced Thyroid Cancer. Cancers (Basel) 2020; 12:cancers12082249. [PMID: 32796774 PMCID: PMC7465706 DOI: 10.3390/cancers12082249] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/03/2020] [Accepted: 08/10/2020] [Indexed: 02/06/2023] Open
Abstract
Target therapy with various kinase inhibitors (KIs) has been extended to patients with advanced thyroid cancer, but only a subset of these compounds has displayed efficacy in clinical use. However, after an initial response to KIs, dramatic disease progression occurs in most cases. With the discovery of cancer stem cells (CSCs), it is possible to postulate that thyroid cancer resistance to KI therapies, both intrinsic and acquired, may be sustained by this cell subtype. Indeed, CSCs have been considered as the main drivers of metastatic activity and therapeutic resistance, because of their ability to generate heterogeneous secondary cell populations and survive treatment by remaining in a quiescent state. Hence, despite the impressive progress in understanding of the molecular basis of thyroid tumorigenesis, drug resistance is still the major challenge in advanced thyroid cancer management. In this view, definition of the role of CSCs in thyroid cancer resistance may be crucial to identifying new therapeutic targets and preventing resistance to anti-cancer treatments and tumor relapse. The aim of this review is to elucidate the possible role of CSCs in the development of resistance of advanced thyroid cancer to current anti-cancer therapies and their potential implications in the management of these patients.
Collapse
|
|
10
|
Lv J, Chen FK, Liu C, Liu PJ, Feng ZP, Jia L, Yang ZX, Hou F, Deng ZY. Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt/β-catenin pathway. Life Sci 2020; 256:117925. [PMID: 32522570 DOI: 10.1016/j.lfs.2020.117925] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 05/22/2020] [Accepted: 06/05/2020] [Indexed: 02/07/2023]
Abstract
AIMS This study aims to explore the effect and underlying mechanism of zoledronic acid (ZA) on the incidence of thyroid cancer (TC) tumorigenesis. MATERIALS AND METHODS Human mononuclear cells THP-1 were differentiated into M2-like tumor associated macrophages (TAMs) by incubation with PMA followed by additional incubation of IL-4 and IL-13. TC cells TPC-1 and IHH4 were co-cultured with M2-like TAMs. Identification of M2-like TAMs markers were determined by immunohistochemistry or flow cytometry. Cell proliferation, stemness and migration/invasion ability were measured by colony, sphere formation assay and transwell assay, respectively. The expression levels of cell stemness, EMT and Wnt/β-catenin pathway-related factors were verified by qRT-PCR, Western blotting, and immunofluorescence. A subcutaneous tumor model was established in nude mice to examine the in vivo effects of ZA. KEY FINDINGS M2-like TAMs were enriched in TC tissues, and they promoted the colony/sphere formation, accompanied with a down-regulated expression in E-cadherin and an up-regulated expression in N-cadherin, Vimentin and other stemness-associated markers (CD133, Oct4, c-Myc) in TC cells. The effects were suppressed when ZA co-treatment was given, because ZA inhibited the polarization of M2-like TAMs and β-catenin entry into the nucleus. Moreover, in agreement with in vitro data, ZA also limited subcutaneous tumor formation and macrophage enrichment in nude mice. SIGNIFICANCE ZA suppressed M2-like TAMs induced TC cell proliferation, stemness and metastasis through inhibiting M2-like TAMs polarization and Wnt/β-catenin pathway, which sheds light on the mechanisms of TC and provides avenues for the development of clinical therapy to TC.
Collapse
Affiliation(s)
- Juan Lv
- Department of Nuclear Medicine, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, Yunnan Province, China
| | - Fu-Kun Chen
- Department of Nuclear Medicine, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, Yunnan Province, China
| | - Chao Liu
- Department of Nuclear Medicine, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, Yunnan Province, China
| | - Peng-Jie Liu
- Department of Nuclear Medicine, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, Yunnan Province, China
| | - Zhi-Ping Feng
- Department of Nuclear Medicine, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, Yunnan Province, China
| | - Li Jia
- Department of Nuclear Medicine, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, Yunnan Province, China
| | - Zhi-Xian Yang
- Department of Nuclear Medicine, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, Yunnan Province, China
| | - Fei Hou
- Department of Nuclear Medicine, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, Yunnan Province, China
| | - Zhi-Yong Deng
- Department of Nuclear Medicine, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, Yunnan Province, China.
| |
Collapse
|
|
11
|
Moroni L, Barbaro F, Caiment F, Coleman O, Costagliola S, Di Conza G, Elviri L, Giselbrecht S, Krause C, Mota C, Nazzari M, Pennington SR, Ringwald A, Sandri M, Thomas S, Waddington J, Toni R. SCREENED: A Multistage Model of Thyroid Gland Function for Screening Endocrine-Disrupting Chemicals in a Biologically Sex-Specific Manner. Int J Mol Sci 2020; 21:E3648. [PMID: 32455722 PMCID: PMC7279272 DOI: 10.3390/ijms21103648] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/04/2020] [Accepted: 05/14/2020] [Indexed: 12/12/2022] Open
Abstract
Endocrine disruptors (EDs) are chemicals that contribute to health problems by interfering with the physiological production and target effects of hormones, with proven impacts on a number of endocrine systems including the thyroid gland. Exposure to EDs has also been associated with impairment of the reproductive system and incidence in occurrence of obesity, type 2 diabetes, and cardiovascular diseases during ageing. SCREENED aims at developing in vitro assays based on rodent and human thyroid cells organized in three different three-dimensional (3D) constructs. Due to different levels of anatomical complexity, each of these constructs has the potential to increasingly mimic the structure and function of the native thyroid gland, ultimately achieving relevant features of its 3D organization including: 1) a 3D organoid based on stem cell-derived thyrocytes, 2) a 3D organoid based on a decellularized thyroid lobe stromal matrix repopulated with stem cell-derived thyrocytes, and 3) a bioprinted organoid based on stem cell-derived thyrocytes able to mimic the spatial and geometrical features of a native thyroid gland. These 3D constructs will be hosted in a modular microbioreactor equipped with innovative sensing technology and enabling precise control of cell culture conditions. New superparamagnetic biocompatible and biomimetic particles will be used to produce "magnetic cells" to support precise spatiotemporal homing of the cells in the 3D decellularized and bioprinted constructs. Finally, these 3D constructs will be used to screen the effect of EDs on the thyroid function in a unique biological sex-specific manner. Their performance will be assessed individually, in comparison with each other, and against in vivo studies. The resulting 3D assays are expected to yield responses to low doses of different EDs, with sensitivity and specificity higher than that of classical 2D in vitro assays and animal models. Supporting the "Adverse Outcome Pathway" concept, proteogenomic analysis and biological computational modelling of the underlying mode of action of the tested EDs will be pursued to gain a mechanistic understanding of the chain of events from exposure to adverse toxic effects on thyroid function. For future uptake, SCREENED will engage discussion with relevant stakeholder groups, including regulatory bodies and industry, to ensure that the assays will fit with purposes of ED safety assessment. In this project review, we will briefly discuss the current state of the art in cellular assays of EDs and how our project aims at further advancing the field of cellular assays for EDs interfering with the thyroid gland.
Collapse
Affiliation(s)
- Lorenzo Moroni
- MERLN Institute for Technology-Inspired Regenerative Medicine, Department of Complex Tissue Regeneration, Maastricht University, 6229ET Maastricht, The Netherlands;
| | - Fulvio Barbaro
- Department of Medicine and Surgery—DIMEC, Unit of Biomedical, Biotechnological and Translational Sciences (S.BI.BI.T.), Laboratory of Regenerative Morphology and Bioartificial Structures (Re.Mo.Bio.S. Lab.), University of Parma, 43121 Parma, Italy; (F.B.); (G.D.C.); (R.T.)
| | - Florian Caiment
- Toxicogenomics, Maastricht University, 6229ET Maastricht, The Netherlands; (F.C.); (M.N.)
| | - Orla Coleman
- Atturos Ltd., c/o Conway Research Institute, University College Dublin, Dublin 4, Ireland; (O.C.); (S.R.P.)
| | - Sabine Costagliola
- Institute of Interdisciplinary Research in Molecular Human Biology (IRIBHM), Université Libre de Bruxelles, 1050 Brussels, Belgium;
| | - Giusy Di Conza
- Department of Medicine and Surgery—DIMEC, Unit of Biomedical, Biotechnological and Translational Sciences (S.BI.BI.T.), Laboratory of Regenerative Morphology and Bioartificial Structures (Re.Mo.Bio.S. Lab.), University of Parma, 43121 Parma, Italy; (F.B.); (G.D.C.); (R.T.)
| | - Lisa Elviri
- Food and Drug Department, University of Parma, 43121 Parma, Italy;
| | - Stefan Giselbrecht
- MERLN Institute for Technology-Inspired Regenerative Medicine, Department of Instruct Biomaterials Engineering, Maastricht University, 6229ET Maastricht, The Netherlands;
| | | | - Carlos Mota
- MERLN Institute for Technology-Inspired Regenerative Medicine, Department of Complex Tissue Regeneration, Maastricht University, 6229ET Maastricht, The Netherlands;
| | - Marta Nazzari
- Toxicogenomics, Maastricht University, 6229ET Maastricht, The Netherlands; (F.C.); (M.N.)
| | - Stephen R. Pennington
- Atturos Ltd., c/o Conway Research Institute, University College Dublin, Dublin 4, Ireland; (O.C.); (S.R.P.)
- UCD Conway Institute, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland;
| | | | - Monica Sandri
- Institute of Science and Technology for Ceramics, National Research Council of Italy (ISTEC-CNR), 48018 Faenza, Italy;
| | - Simon Thomas
- Cyprotex Discovery Ltd., No. 24 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK;
| | - James Waddington
- UCD Conway Institute, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland;
| | - Roberto Toni
- Department of Medicine and Surgery—DIMEC, Unit of Biomedical, Biotechnological and Translational Sciences (S.BI.BI.T.), Laboratory of Regenerative Morphology and Bioartificial Structures (Re.Mo.Bio.S. Lab.), University of Parma, 43121 Parma, Italy; (F.B.); (G.D.C.); (R.T.)
- Division of Endocrinology, Diabetes, and Metabolism, Tufts Medical Center - Tufts University School of Medicine, Boston, MA 02111, USA
| |
Collapse
|
|
12
|
Ma R, Morshed SA, Latif R, Davies TF. A Stem Cell Surge During Thyroid Regeneration. Front Endocrinol (Lausanne) 2020; 11:606269. [PMID: 33551997 PMCID: PMC7859487 DOI: 10.3389/fendo.2020.606269] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/04/2020] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Many tissues, including the thyroid, contain resident (adult) stem cells that are responsible for regeneration and repair after injury. The mechanisms of thyroid regeneration and the role of thyroid stem cells and thyroid progenitor cells in this process are not well understood. We have now used a new mouse thyroid injury model to gain insight into this phenomenon. METHODS Tamoxifen induced TPO-Cre mice (TPOCreER2) were crossed with inducible Diphtheria Toxin Receptor homozygous mice (ROSA26iDTR) to give rise to TPOCreER2/iDTR mice, allowing for the Cre-mediated expression of the DTR and rendering TPO expressing thyroid cells highly sensitive to diphtheria toxin (DT). This model of TPOCreER2/iDTR mice allowed us to study the repair/regeneration of thyroid follicles after diphtheria toxin induced thyroid damage by measuring serum thyroid hormones and cell fate. RESULTS In TPOCreER2/iDTR double transgenic mice we observed severe thyroid damage as early as 2 weeks after initiating intraperitoneal DT injections. There was marked thyroid tissue apoptosis and a ~50% drop in serum T4 levels (from 5.86 to 2.43 ug/dl) and a corresponding increase in serum TSH (from 0.18 to 8.39 ng/dl). In addition, there was a ~50% decrease in transcription of thyroid specific genes (thyroglobulin, TSH receptor, and sodium-iodide symporter). After suspending the DT administration, the thyroid rapidly recovered over a 4-week period during which we observed a transient surge in stem cell marker expression (including Oct4, Nanog, Sox2, and Rex1). In addition, cells immunostaining with stem cell markers Oct4 and Ssea-1 were found in clusters around new thyroid follicles in TPOCreER2/iDTR double transgenic mice. Furthermore, the presence of clusters of thyroid progenitor cells was also identified by Pax8 staining of thyroglobulin negative cells. This recovery of the injured gland was followed by a rapid and sequential restoration of thyroid function. CONCLUSION These data demonstrate that a new model of thyroid cell damage induced by DT can be used to study the mobilization of resident adult stem cells. Furthermore, the model clearly demonstrates the involvement of both stem and progenitor cells in the in vivo regeneration of the thyroid after severe destruction.
Collapse
|
|
13
|
Mariniello K, Ruiz-Babot G, McGaugh EC, Nicholson JG, Gualtieri A, Gaston-Massuet C, Nostro MC, Guasti L. Stem Cells, Self-Renewal, and Lineage Commitment in the Endocrine System. Front Endocrinol (Lausanne) 2019; 10:772. [PMID: 31781041 PMCID: PMC6856655 DOI: 10.3389/fendo.2019.00772] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 10/23/2019] [Indexed: 12/15/2022] Open
Abstract
The endocrine system coordinates a wide array of body functions mainly through secretion of hormones and their actions on target tissues. Over the last decades, a collective effort between developmental biologists, geneticists, and stem cell biologists has generated a wealth of knowledge related to the contribution of stem/progenitor cells to both organogenesis and self-renewal of endocrine organs. This review provides an up-to-date and comprehensive overview of the role of tissue stem cells in the development and self-renewal of endocrine organs. Pathways governing crucial steps in both development and stemness maintenance, and that are known to be frequently altered in a wide array of endocrine disorders, including cancer, are also described. Crucially, this plethora of information is being channeled into the development of potential new cell-based treatment modalities for endocrine-related illnesses, some of which have made it through clinical trials.
Collapse
Affiliation(s)
- Katia Mariniello
- Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Gerard Ruiz-Babot
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, United States
- Harvard Stem Cell Institute, Cambridge, MA, United States
| | - Emily C. McGaugh
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - James G. Nicholson
- Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Angelica Gualtieri
- Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Carles Gaston-Massuet
- Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Maria Cristina Nostro
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Leonardo Guasti
- Centre for Endocrinology, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| |
Collapse
|
|
14
|
Abstract
Thyroid gland has been implicated in the regulation of many functions using endocrine, paracrine and autocrine signals. Functional thyroid follicular cells derived from stem cells attracted a great interest from researchers as a strategy for thyroid's regenerative therapy. Thyroid has a very low rate of turnover; however, studies showed that the regenerative ability is enhanced following diseases or thyroidectomy, which promotes the role of stem cell. The objective of this review is to summarize the morphological characterization and the expression of stem cell genes/markers in the thyroid. Also, to highlight the mechanisms of tumor formation in thyroid via its stem cells. The most important thyroid stem cell's markers are: stem cell antigen 1 (SCA-1), octamer-binding transcription 4 (OCT-4), p63, CD34+ CD45-, paired box gene 8 (PAX-8), thyroid transcription factor 1 (TTF-1), thyroid transcription factor 2 (TTF-2), hematopoietically expressed homeobox protein HHEX, the transcription factor GATA-4, hepatocyte nuclear factor 4-α (HNF-4-α) and homeobox transcription factor Nanog (hNanog). This review highlights the functional characterization describing the mechanisms of stem cell's differentiation into functional thyroid follicle and proposing mechanisms involving in cancer formation through one of these cell types: fetal cell, thyroblasts, prothyrocytes, certain genetic mutation in the mature thyroid cells or presence of a special type of cells (cancer stem cell) which are responsible for different types of cancer formation. Understanding the mechanisms of thyroid's stem cell in cancer formation and the expression of the biomarkers in normal and abnormal thyroid status are promising physiological tools in promoting thyroid regeneration and in provision management for thyroid cancer.
Collapse
Affiliation(s)
- Ebtesam A Al-Suhaimi
- Department of Biology, College of Sciences, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, Saudi Arabia.
- Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, Saudi Arabia.
| | - Khulood Al-Khater
- Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, Saudi Arabia
- Department of Anatomy, College of Medicine, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, Saudi Arabia
| |
Collapse
|
|
15
|
Vella V, Nicolosi ML, Cantafio P, Massimino M, Lappano R, Vigneri P, Ciuni R, Gangemi P, Morrione A, Malaguarnera R, Belfiore A. DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop. Endocr Relat Cancer 2019; 26:197-214. [PMID: 30121624 DOI: 10.1530/erc-18-0310] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 08/16/2018] [Indexed: 12/31/2022]
Abstract
Patients with thyroid cancers refractory to radioiodine (RAI) treatment show a limited response to various therapeutic options and a low survival rate. The recent use of multikinase inhibitors has also met limited success. An alternative approach relies on drugs that induce cell differentiation, as the ensuing increased expression of the cotransporter for sodium and iodine (NIS) may partially restore sensitivity to radioiodine. The inhibition of the ERK1/2 pathway has shown some efficacy in this context. Aggressive thyroid tumors overexpress the isoform-A of the insulin receptor (IR-A) and its ligand IGF-2; this IGF-2/IR-A loop is associated with de-differentiation and stem-like phenotype, resembling RAI-refractory tumors. Importantly, IR-A has been shown to be positively modulated by the non-integrin collagen receptor DDR1 in human breast cancer. Using undifferentiated human thyroid cancer cells, we now evaluated the effects of DDR1 on IGF-2/IR-A loop and on markers of cell differentiation and stemness. DDR1 silencing or downregulation caused significant reduction of IR-A and IGF-2 expression, and concomitant increased levels of differentiation markers (NIS, Tg, TSH, TPO). Conversely, markers of epithelial-to-mesenchymal transition (Vimentin, Snail-2, Zeb1, Zeb2 and N-Cadherin) and stemness (OCT-4, SOX-2, ABCG2 and Nanog) decreased. These effects were collagen independent. In contrast, overexpression of either DDR1 or its kinase-inactive variant K618A DDR1-induced changes suggestive of less differentiated and stem-like phenotype. Collagen stimulation was uneffective. In conclusion, in poorly differentiated thyroid cancer, DDR1 silencing or downregulation blocks the IGF-2/IR-A autocrine loop and induces cellular differentiation. These results may open novel therapeutic approaches for thyroid cancer.
Collapse
Affiliation(s)
- Veronica Vella
- School of Human and Social Sciences, 'Kore' University of Enna, Enna, Italy
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Maria Luisa Nicolosi
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Patrizia Cantafio
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Michele Massimino
- Center of Experimental Oncology and Hematology, AOU Policlinico Vittorio Emanuele, Catania, Italy
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Paolo Vigneri
- Center of Experimental Oncology and Hematology, AOU Policlinico Vittorio Emanuele, Catania, Italy
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Roberto Ciuni
- Unit of Thyroid and Neck Surgery, Policlinico Vittorio Emanuele, University of Catania, Catania, Italy
| | - Pietro Gangemi
- Unit of Pathology, Policlinico Vittorio Emanuele, University of Catania, Catania, Italy
| | - Andrea Morrione
- Department of Urology and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Roberta Malaguarnera
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| |
Collapse
|
|
16
|
Zito G, Coppola A, Pizzolanti G, Giordano C. Heterogeneity of Stem Cells in the Thyroid. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1169:81-93. [PMID: 31487020 DOI: 10.1007/978-3-030-24108-7_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Identification of thyroid stem cells in the past few years has made important contributions to our understanding of the cellular and molecular mechanisms that induce tissue regeneration and repair. Embryonic stem (ES) cells and induced-pluripotent stem cells have been used to establish reliable protocols to obtain mature thyrocytes and functional follicles for the treatment of thyroid diseases in mice. In addition, the discovery of resident thyroid progenitor cells, along with other sources of stem cells, has defined in detail the mechanisms responsible for tissue repair upon moderate or severe organ injury.In this chapter, we highlight in detail the current state of research on thyroid stem cells by focusing on (1) the description of the first experiments performed to obtain thyroid follicles from embryonic stem cells, (2) the identification of resident stem cells in the thyroid gland, and (3) the definition of the current translational in vivo and in vitro models used for thyroid tissue repair and regeneration.
Collapse
Affiliation(s)
- Giovanni Zito
- Biomedical Department of Internal and Specialist Medicine (DI.BI.MIS), Laboratory of Regenerative Medicine, Section of Endocrinology, Diabetology and Metabolism, University of Palermo, Palermo, Italy.,Advanced Technologies Network (ATeN) Center, Laboratory of Stem Cells and Cellular Cultures, University of Palermo, Palermo, Italy
| | - Antonina Coppola
- Biomedical Department of Internal and Specialist Medicine (DI.BI.MIS), Laboratory of Regenerative Medicine, Section of Endocrinology, Diabetology and Metabolism, University of Palermo, Palermo, Italy.,Advanced Technologies Network (ATeN) Center, Laboratory of Stem Cells and Cellular Cultures, University of Palermo, Palermo, Italy
| | - Giuseppe Pizzolanti
- Biomedical Department of Internal and Specialist Medicine (DI.BI.MIS), Laboratory of Regenerative Medicine, Section of Endocrinology, Diabetology and Metabolism, University of Palermo, Palermo, Italy.,Advanced Technologies Network (ATeN) Center, Laboratory of Stem Cells and Cellular Cultures, University of Palermo, Palermo, Italy
| | - Carla Giordano
- Biomedical Department of Internal and Specialist Medicine (DI.BI.MIS), Laboratory of Regenerative Medicine, Section of Endocrinology, Diabetology and Metabolism, University of Palermo, Palermo, Italy. .,Advanced Technologies Network (ATeN) Center, Laboratory of Stem Cells and Cellular Cultures, University of Palermo, Palermo, Italy.
| |
Collapse
|
|
17
|
Iwadate M, Takizawa Y, Shirai YT, Kimura S. An in vivo model for thyroid regeneration and folliculogenesis. J Transl Med 2018; 98:1126-1132. [PMID: 29946134 PMCID: PMC6138525 DOI: 10.1038/s41374-018-0068-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 03/23/2018] [Accepted: 03/29/2018] [Indexed: 01/11/2023] Open
Abstract
While thyroid is considered to be a dormant organ, when required, it can regenerate through increased cell proliferation. However, the mechanism for regeneration remains unknown. Nkx2-1(fl/fl);TPO-cre mouse thyroids exhibit a very disorganized appearance because their thyroids continuously degenerate and regenerate. In mouse thyroids, a cluster of cells are found near the tracheal cartilage and muscle, which are positive for expression of NKX2-1, the master transcription factor governing thyroid development and function. In the present study, we propose that this cluster of NKX2-1-positive cells may be the precursor cells that mature to become thyroid follicular cells, forming thyroid follicles. We also found that phosphorylation of AKT is induced by NKX2-1 in the proposed thyroid progenitor-like side-population cell-derived thyroid cell line (SPTL) cells, suggesting the possibility that NKX2-1 plays a role in differentiation through the modulation of AKT signaling. This study revealed that Nkx2-1(fl/fl);TPO-cre mice provide a suitable model to study in vivo regeneration and folliculogenesis of the thyroid.
Collapse
Affiliation(s)
- Manabu Iwadate
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
- Department of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Yoshinori Takizawa
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
- Department of Otorhinolaryngology, Seirei Mikatahara General Hospital, Hamamatsu, Shizuoka, 433-8558, Japan
| | - Yo-Taro Shirai
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Shioko Kimura
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
18
|
Cirello V, Vaira V, Grassi ES, Vezzoli V, Ricca D, Colombo C, Bosari S, Vicentini L, Persani L, Ferrero S, Fugazzola L. Multicellular spheroids from normal and neoplastic thyroid tissues as a suitable model to test the effects of multikinase inhibitors. Oncotarget 2018; 8:9752-9766. [PMID: 28039458 PMCID: PMC5354768 DOI: 10.18632/oncotarget.14187] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 11/22/2016] [Indexed: 12/12/2022] Open
Abstract
Multicellular three-dimensional (3D) spheroids represent an experimental model that is intermediate in its complexity between monolayer cultures and patients’ tumor. In the present study, we characterize multicellular spheroids from papillary (PTC) and follicular (FTC) thyroid cancers and from the corresponding normal tissues. We show that these 3D structures well recapitulate the features of the original tissues, in either the differentiated and “stem-like” components. As a second step, we were aimed to test the effects of a small multikinase inhibitor, SP600125 (SP), previously shown to efficiently induce cell death in undifferentiated thyroid cancer monolayer cultures. We demonstrate the potent effect of SP on cell growth and survival in our 3D multicellular cultures. SP exerts its main effects through direct and highly significant inhibition of the ROCK pathway, known to be involved in the regulation of cell migration and β-catenin turnover. Consistently, SP treatment resulted in a significant decrease in β-catenin levels with respect to basal conditions in tumor but not in normal spheroids, indicating that the effect is promisingly selective on tumor cells. In conclusion, we provide the morphological and molecular characterization of thyroid normal and tumor spheroids. In this 3D model we tested in vitro the effects of the multikinase inhibitor SP and further characterized its mechanism of action in both normal and tumor spheroids, thus making it an ideal candidate for developing new drugs against thyroid cancer.
Collapse
Affiliation(s)
- Valentina Cirello
- Endocrine Unit, Fondazione IRCCS Ca' Granda, 20122 Milan, Italy.,Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
| | - Valentina Vaira
- Division of Pathology, Fondazione IRCCS Ca' Granda, 20122 Milan, Italy
| | - Elisa Stellaria Grassi
- Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, 20149 Milan, Italy
| | - Valeria Vezzoli
- Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, 20149 Milan, Italy
| | - Dario Ricca
- Division of Pathology, Fondazione IRCCS Ca' Granda, 20122 Milan, Italy
| | - Carla Colombo
- Endocrine Unit, Fondazione IRCCS Ca' Granda, 20122 Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Silvano Bosari
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy.,Division of Pathology, Fondazione IRCCS Ca' Granda, 20122 Milan, Italy
| | | | - Luca Persani
- Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, 20149 Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca' Granda, 20122 Milan, Italy.,Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Laura Fugazzola
- Endocrine Unit, Fondazione IRCCS Ca' Granda, 20122 Milan, Italy.,Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
| |
Collapse
|
|
19
|
The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors. J Transl Med 2017; 97:1142-1151. [PMID: 28394318 DOI: 10.1038/labinvest.2017.41] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 02/21/2017] [Accepted: 02/24/2017] [Indexed: 12/13/2022] Open
Abstract
The cancer stem-like cell (CSC) hypothesis postulates that a small population of cells in a cancer has self-renewal and clonal tumor initiation properties. These cells are responsible for tumor initiation, growth, recurrence and for resistance to chemotherapy and radiation therapy. CSCs can be characterized using markers such as SSEA-1, SSEA-4, CD44, CD24, ALDEFLUOR and others. CSCs form spheres when they are cultured in serum-free condition in low attachment plates and can generate tumors when injected into immune-deficient mice. During epithelial to mesenchymal transition (EMT), cells lose cellular adhesion and polarity and acquire an invasive phenotype. Recent studies have established a relationship between EMT and increased numbers of CSCs in some solid malignancies. Non-coding RNAs such as microRNAs and long non-coding RNAs (lncRNAs) have been shown to have important roles during EMT and some of these molecules also have regulatory roles in the proliferation of CSCs. Specific lncRNAs enhanced cell migration and invasion in breast carcinomas, which was associated with the generation of stem cell properties. The tumor microenvironment of CSCs also has an important role in tumor progression. Recent studies have shown that the interaction between tumor cells and the local microenvironment at the metastatic site leads to the development of premetastatic niche(s) and allows for the proliferation of the metastatic cells during colonization. The role of exosomes in the microenvironment during the EMT program is currently a major area of research. This review examines CSCs and the relationship between EMT and CSCs in solid tumors with emphasis on thyroid CSCs. The role of non-coding RNAs and of the microenvironment in EMT and in tumor progression are also examined. This review also highlights the growing number of studies that show the close association of EMT and CSCs and the role of exosomes and other elements of the tissue microenvironment in CSC metastasis. A better understanding of these mechanisms will lead to more effective targeting of primary and metastatic malignancies.
Collapse
|
|
20
|
EMT/MET at the Crossroad of Stemness, Regeneration and Oncogenesis: The Ying-Yang Equilibrium Recapitulated in Cell Spheroids. Cancers (Basel) 2017; 9:cancers9080098. [PMID: 28758926 PMCID: PMC5575601 DOI: 10.3390/cancers9080098] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Revised: 07/20/2017] [Accepted: 07/26/2017] [Indexed: 12/21/2022] Open
Abstract
The epithelial-to-mesenchymal transition (EMT) is an essential trans-differentiation process, which plays a critical role in embryonic development, wound healing, tissue regeneration, organ fibrosis, and cancer progression. It is the fundamental mechanism by which epithelial cells lose many of their characteristics while acquiring features typical of mesenchymal cells, such as migratory capacity and invasiveness. Depending on the contest, EMT is complemented and balanced by the reverse process, the mesenchymal-to-epithelial transition (MET). In the saving economy of the living organisms, the same (Ying-Yang) tool is integrated as a physiological strategy in embryonic development, as well as in the course of reparative or disease processes, prominently fibrosis, tumor invasion and metastasis. These mechanisms and their related signaling (e.g., TGF-β and BMPs) have been effectively studied in vitro by tissue-derived cell spheroids models. These three-dimensional (3D) cell culture systems, whose phenotype has been shown to be strongly dependent on TGF-β-regulated EMT/MET processes, present the advantage of recapitulating in vitro the hypoxic in vivo micro-environment of tissue stem cell niches and their formation. These spheroids, therefore, nicely reproduce the finely regulated Ying-Yang equilibrium, which, together with other mechanisms, can be determinant in cell fate decisions in many pathophysiological scenarios, such as differentiation, fibrosis, regeneration, and oncogenesis. In this review, current progress in the knowledge of signaling pathways affecting EMT/MET and stemness regulation will be outlined by comparing data obtained from cellular spheroids systems, as ex vivo niches of stem cells derived from normal and tumoral tissues. The mechanistic correspondence in vivo and the possible pharmacological perspective will be also explored, focusing especially on the TGF-β-related networks, as well as others, such as SNAI1, PTEN, and EGR1. This latter, in particular, for its ability to convey multiple types of stimuli into relevant changes of the cell transcriptional program, can be regarded as a heterogeneous "stress-sensor" for EMT-related inducers (growth factor, hypoxia, mechano-stress), and thus as a therapeutic target.
Collapse
|
|
21
|
Lee J, Yi S, Chang JY, Kang YE, Kim HJ, Park KC, Yang KJ, Sul HJ, Kim JO, Yi HS, Zhu X, Cheng SY, Shong M. Regeneration of thyroid follicles from primordial cells in a murine thyroidectomized model. J Transl Med 2017; 97:478-489. [PMID: 28112758 PMCID: PMC7886286 DOI: 10.1038/labinvest.2016.158] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 12/14/2016] [Indexed: 12/21/2022] Open
Abstract
The functional unit of the thyroid gland, the thyroid follicle, dynamically responds to various stimuli to maintain thyroid hormone homeostasis. However, thyroid follicles in the adult human thyroid gland have a very limited regenerative capacity following partial resection of the thyroid gland. To gain insight into follicle regeneration in the adult thyroid gland, we observed the regeneration processes of murine thyroid follicles after partial resection of the lower third of the thyroid gland in 10-week-old male C57BL/6 mice. Based on sequential observation of the partially resected thyroid lobe, we found primitive follicles forming in the area corresponding to the central zone of the intact lateral thyroid lobe. The primitive thyroid follicles were multiciliated and had coarsely vacuolated cytoplasm and large vesicular nuclei. Consistently, these primitive follicular cells did not express the differentiation markers paired box gene-8 and thyroid transcription factor-1 (clone SPT24), but were positive for forkhead box protein A2 and leucine-rich repeat-containing G-protein-coupled receptor 4/GPR48. Follicles newly generated from the primitive follicles had clear or vacuolar cytoplasm with dense, darkly stained nuclei. At day 21 after partial thyroidectomy, the tall cuboidal follicular epithelial cells had clear or vacuolar cytoplasm, and the intraluminal colloid displayed pale staining. Smaller activated follicles were found in the central zone of the lateral lobe, whereas larger mature follicles were located in the peripheral zone. Based on these observations, we propose that the follicle regeneration process in the partially resected adult murine thyroid gland associated with the appearance of primitive follicular cells may be a platform for the budding of differentiated follicles in mice.
Collapse
Affiliation(s)
- Junguee Lee
- Department of Pathology, Daejeon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Shinae Yi
- Research Center for Endocrine and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Joon Young Chang
- Research Center for Endocrine and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Yea Eun Kang
- Research Center for Endocrine and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Hyun Jung Kim
- Clinical Research Institute, Daejeon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Ki Cheol Park
- Clinical Research Institute, Daejeon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Keum-Jin Yang
- Clinical Research Institute, Daejeon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Hae Joung Sul
- Department of Pathology, Daejeon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Jong Ok Kim
- Department of Pathology, Daejeon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Hyon-Seung Yi
- Research Center for Endocrine and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Xuguang Zhu
- Gene Regulation Section, Laboratory of Molecular Biology, National Cancer Institut, NIH, Bethesda, MD, USA
| | - Sheue-yann Cheng
- Gene Regulation Section, Laboratory of Molecular Biology, National Cancer Institut, NIH, Bethesda, MD, USA
| | - Minho Shong
- Research Center for Endocrine and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| |
Collapse
|
|
22
|
Murata T, Iwadate M, Takizawa Y, Miyakoshi M, Hayase S, Yang W, Cai Y, Yokoyama S, Nagashima K, Wakabayashi Y, Zhu J, Kimura S. An Adult Mouse Thyroid Side Population Cell Line that Exhibits Enriched Epithelial-Mesenchymal Transition. Thyroid 2017; 27:460-474. [PMID: 28125936 PMCID: PMC5346910 DOI: 10.1089/thy.2016.0130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Studies of thyroid stem/progenitor cells have been hampered due to the small organ size and lack of tissue, which limits the yield of these cells. A continuous source that allows the study and characterization of thyroid stem/progenitor cells is desired to push the field forward. METHOD A cell line was established from Hoechst-resistant side population cells derived from mouse thyroid that were previously shown to contain stem/progenitor-like cells. Characterization of these cells were carried out by using in vitro two- and three-dimensional cultures and in vivo reconstitution of mice after orthotopic or intravenous injection, in conjunction with quantitative reverse transcription polymerase chain reaction, Western blotting, immunohisto(cyto)chemistry/immunofluorescence, and RNA seq analysis. RESULTS These cells were named SPTL (side population cell-derived thyroid cell line). Under low serum culturing conditions, SPTL cells expressed the thyroid differentiation marker NKX2-1, a transcription factor critical for thyroid differentiation and function, while no expression of other thyroid differentiation marker genes were observed. SPTL cells formed follicle-like structures in Matrigel® cultures, which did not express thyroid differentiation marker genes. In mouse models of orthotopic and intravenous injection, the latter following partial thyroidectomy, a few SPTL cells were found in part of the follicles, most of which expressed NKX2-1. SPTL cells highly express genes involved in epithelial-mesenchymal transition, as demonstrated by RNA seq analysis, and exhibit a gene-expression pattern similar to anaplastic thyroid carcinoma. CONCLUSION These results demonstrate that SPTL cells have the capacity to differentiate into thyroid to a limited degree. SPTL cells may provide an excellent tool to study stem cells, including cancer stem cells of the thyroid.
Collapse
Affiliation(s)
- Tsubasa Murata
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Manabu Iwadate
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Yoshinori Takizawa
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Masaaki Miyakoshi
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Suguru Hayase
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Wenjing Yang
- DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, Bethesda, Maryland
| | - Yan Cai
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Shigetoshi Yokoyama
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Kunio Nagashima
- Electron Microscope Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Yoshiyuki Wakabayashi
- DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, Bethesda, Maryland
| | - Jun Zhu
- Systems Biology Center, National Heart, Lung, and Blood Institute, Bethesda, Maryland
| | - Shioko Kimura
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| |
Collapse
|
|
23
|
Chimenti I, Pagano F, Angelini F, Siciliano C, Mangino G, Picchio V, De Falco E, Peruzzi M, Carnevale R, Ibrahim M, Biondi‐Zoccai G, Messina E, Frati G. Human Lung Spheroids as In Vitro Niches of Lung Progenitor Cells with Distinctive Paracrine and Plasticity Properties. Stem Cells Transl Med 2017; 6:767-777. [PMID: 28297570 PMCID: PMC5442776 DOI: 10.5966/sctm.2015-0374] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 08/09/2016] [Indexed: 02/05/2023] Open
Abstract
Basic and translational research on lung biology has discovered multiple progenitor cell types, specialized or facultative, responsible for turnover, renewal, and repair. Isolation of populations of resident lung progenitor cells (LPCs) has been described by multiple protocols, and some have been successfully applied to healthy human lung tissue. We aimed at understanding how different cell culture conditions may affect, in vitro, the phenotype of LPCs to create an ideal niche-like microenvironment. The influence of different substrates (i.e., fibronectin, gelatin, laminin) and the impact of a three-dimensional/two-dimensional (3D/2D) culture switch on the biology of LPCs isolated as lung spheroids (LSs) from normal adult human lung biopsy specimens were investigated. We applied a spheroid culture system as the selective/inductive step for progenitor cell culture, as described in many biological systems. The data showed a niche-like proepithelial microenvironment inside the LS, highly sensitive to the 3D culture system and significantly affecting the phenotype of adult LPCs more than culture substrate. LSs favor epithelial phenotypes and LPC maintenance and contain cells more responsive to specific commitment stimuli than 2D monolayer cultures, while secreting a distinctive set of paracrine factors. We have shown for the first time, to our knowledge, how culture as 3D LSs can affect LPC epithelial phenotype and produce strong paracrine signals with a distinctive secretomic profile compared with 2D monolayer conditions. These findings suggest novel approaches to maintain ex vivo LPCs for basic and translational studies. Stem Cells Translational Medicine 2017;6:767-777.
Collapse
Affiliation(s)
- Isotta Chimenti
- Department of Medical‐Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Rome, Italy
| | - Francesca Pagano
- Department of Medical‐Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Rome, Italy
| | - Francesco Angelini
- Department of Medical‐Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Rome, Italy
| | - Camilla Siciliano
- Department of Medical‐Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Rome, Italy
| | - Giorgio Mangino
- Department of Medical‐Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Rome, Italy
| | - Vittorio Picchio
- Department of Medical‐Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Rome, Italy
| | - Elena De Falco
- Department of Medical‐Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Rome, Italy
| | - Mariangela Peruzzi
- Department of Medical‐Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Rome, Italy
| | - Roberto Carnevale
- Department of Medical‐Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Rome, Italy
| | - Mohsen Ibrahim
- Department of Medical‐Surgical Science and Translational Medicine, “La Sapienza” University of Rome, Rome, Italy
| | - Giuseppe Biondi‐Zoccai
- Department of Medical‐Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Rome, Italy
- Department of AngioCardioNeurology, Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli, Italy
| | - Elisa Messina
- Department of Pediatrics and Neuropsychiatry, “Umberto I” Hospital, Rome, Italy
| | - Giacomo Frati
- Department of Medical‐Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Rome, Italy
- Department of AngioCardioNeurology, Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli, Italy
| |
Collapse
|
|
24
|
Niwa O, Barcellos-Hoff MH, Globus RK, Harrison JD, Hendry JH, Jacob P, Martin MT, Seed TM, Shay JW, Story MD, Suzuki K, Yamashita S. ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection. Ann ICRP 2016; 44:7-357. [PMID: 26637346 DOI: 10.1177/0146645315595585] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This report provides a review of stem cells/progenitor cells and their responses to ionising radiation in relation to issues relevant to stochastic effects of radiation that form a major part of the International Commission on Radiological Protection's system of radiological protection. Current information on stem cell characteristics, maintenance and renewal, evolution with age, location in stem cell 'niches', and radiosensitivity to acute and protracted exposures is presented in a series of substantial reviews as annexes concerning haematopoietic tissue, mammary gland, thyroid, digestive tract, lung, skin, and bone. This foundation of knowledge of stem cells is used in the main text of the report to provide a biological insight into issues such as the linear-no-threshold (LNT) model, cancer risk among tissues, dose-rate effects, and changes in the risk of radiation carcinogenesis by age at exposure and attained age. Knowledge of the biology and associated radiation biology of stem cells and progenitor cells is more developed in tissues that renew fairly rapidly, such as haematopoietic tissue, intestinal mucosa, and epidermis, although all the tissues considered here possess stem cell populations. Important features of stem cell maintenance, renewal, and response are the microenvironmental signals operating in the niche residence, for which a well-defined spatial location has been identified in some tissues. The identity of the target cell for carcinogenesis continues to point to the more primitive stem cell population that is mostly quiescent, and hence able to accumulate the protracted sequence of mutations necessary to result in malignancy. In addition, there is some potential for daughter progenitor cells to be target cells in particular cases, such as in haematopoietic tissue and in skin. Several biological processes could contribute to protecting stem cells from mutation accumulation: (a) accurate DNA repair; (b) rapidly induced death of injured stem cells; (c) retention of the DNA parental template strand during divisions in some tissue systems, so that mutations are passed to the daughter differentiating cells and not retained in the parental cell; and (d) stem cell competition, whereby undamaged stem cells outcompete damaged stem cells for residence in the niche. DNA repair mainly occurs within a few days of irradiation, while stem cell competition requires weeks or many months depending on the tissue type. The aforementioned processes may contribute to the differences in carcinogenic radiation risk values between tissues, and may help to explain why a rapidly replicating tissue such as small intestine is less prone to such risk. The processes also provide a mechanistic insight relevant to the LNT model, and the relative and absolute risk models. The radiobiological knowledge also provides a scientific insight into discussions of the dose and dose-rate effectiveness factor currently used in radiological protection guidelines. In addition, the biological information contributes potential reasons for the age-dependent sensitivity to radiation carcinogenesis, including the effects of in-utero exposure.
Collapse
|
|
25
|
Peng W, Wang K, Zheng R, Derwahl M. 1,25 dihydroxyvitamin D3 inhibits the proliferation of thyroid cancer stem-like cells via cell cycle arrest. Endocr Res 2016; 41:71-80. [PMID: 27030645 DOI: 10.3109/07435800.2015.1037048] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND An anti-proliferative effect of vitamin D has been reported in different carcinomas, including thyroid cancer. Cancer stem cells (CSCs), a very small fraction of cancer cells, are widely believed to be responsible for cancer initiation, relapse and metastasis. OBJECTIVES We addressed the question as to whether CSCs derived from the anaplastic thyroid carcinoma cell lines SW1736, C643, HTh74 and its doxorubicin- resistant subline HTh74R are also a target of vitamin D action. METHODS The effect of calcitriol on growth of HTh74, HTh74R, SW1736 and C643 cell lines was investigated by cell viability assays. In stem-enriched cells derived from thyro-spheres cell cycle analysis and apoptotic assays were performed. Furthermore, the role of calcitriol in the formation of cancer thyro-spheres and its putative differentiation-inducing effect were analysed. RESULTS CSCs isolated as thyro-spheres from all the four anaplastic thyroid carcinoma cells expressed vitamin D receptors as did their parental cells. Calcitriol inhibited proliferation of anaplastic thyroid carcinoma cells with a more pronounced effect on doxorubicin-resistant HTh74R cells, and it significantly reduced the capacity to form stem cell-derived spheres and decreased the size of these spheres that consist of CSCs and their progenitor cells. As revealed by cell cycle analysis, calcitriol induced G2/M phase arrest in thyro-sphere cells derived cells from HTh74, HTh74R and C643 but did not affect apoptosis. Finally, calcitriol altered morphology of CSCs. CONCLUSION Calcitriol inhibited the growth of CSCs derived from anaplastic thyroid cancer cells. It may also exert a pro-differentiation effect in thyroid CSCs.
Collapse
Affiliation(s)
- Wen Peng
- a Division of Endocrinology, Department of Medicine, St. Hedwig Hospital and Charite , University Medicine , Berlin , Germany
| | - Kun Wang
- a Division of Endocrinology, Department of Medicine, St. Hedwig Hospital and Charite , University Medicine , Berlin , Germany
| | - Rendong Zheng
- a Division of Endocrinology, Department of Medicine, St. Hedwig Hospital and Charite , University Medicine , Berlin , Germany
| | - Michael Derwahl
- a Division of Endocrinology, Department of Medicine, St. Hedwig Hospital and Charite , University Medicine , Berlin , Germany
| |
Collapse
|
|
26
|
Nagayama Y, Shimamura M, Mitsutake N. Cancer Stem Cells in the Thyroid. Front Endocrinol (Lausanne) 2016; 7:20. [PMID: 26973599 PMCID: PMC4770029 DOI: 10.3389/fendo.2016.00020] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 02/15/2016] [Indexed: 11/16/2022] Open
Abstract
The cancer stem cell (CSC) model posits that CSCs are a small, biologically distinct subpopulation of cancer cells in each tumor that have self-renewal and multi-lineage potential, and are critical for cancer initiation, metastasis, recurrence, and therapy-resistance. Numerous studies have linked CSCs to thyroid biology, but the candidate markers and signal transduction pathways that drive thyroid CSC growth are controversial, the origin(s) of thyroid CSCs remain elusive, and it is unclear whether thyroid CSC biology is consistent with the original hierarchical CSC model or the more recent dynamic CSC model. Here, we critically review the thyroid CSC literature with an emphasis on research that confirmed the presence of thyroid CSCs by in vitro sphere formation or in vivo tumor formation assays with dispersed cells from thyroid cancer tissues or bona fide thyroid cancer cell lines. Future perspectives of thyroid CSC research are also discussed.
Collapse
Affiliation(s)
- Yuji Nagayama
- Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
- *Correspondence: Yuji Nagayama,
| | - Mika Shimamura
- Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Norisato Mitsutake
- Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| |
Collapse
|
|
27
|
Gianì F, Vella V, Nicolosi ML, Fierabracci A, Lotta S, Malaguarnera R, Belfiore A, Vigneri R, Frasca F. Thyrospheres From Normal or Malignant Thyroid Tissue Have Different Biological, Functional, and Genetic Features. J Clin Endocrinol Metab 2015; 100:E1168-E1178. [PMID: 26151334 DOI: 10.1210/jc.2014-4163] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
CONTEXT Cancer stem cells from several human malignancies, including poorly differentiated thyroid carcinoma and thyroid cancer cell lines, have been cultured in vitro as sphere-forming cells. These thyroid cancer stem cells were proven to be able to reproduce the original tumor in a xenograft orthotopic model. OBJECTIVES The objective of the study was to characterize papillary thyroid carcinoma (PTC) spheres from well-differentiated thyroid cancer and normal thyroid (NT) spheres obtained from the contralateral thyroid tissue of the same patient. DESIGN Thyrospheres from PTCs and NTs were isolated. MAIN OUTCOME MEASURES Gene expression analysis by real-time PCR, immunofluorescence studies, and fluorescence-activated cell sorter analysis in thyrospheres from PTCs and NTs have been evaluated. CONCLUSIONS Compared with NT spheres, PTC spheres are larger, more irregular, and more clonogenic and have a higher rate of symmetric division. Moreover, PTC spheres express higher levels of stem cell markers and lower levels of thyroid-specific genes compared with NT spheres. Under appropriate conditions, NT spheres differentiated into thyrocytes, whereas PTC spheres did not, displaying a defect in the differentiation potential. Immunofluorescence experiments indicated that, in NT spheres, progenitor cells are mainly present in the sphere core, and the sphere periphery contains thyroid precursor cells already committed to differentiation. PTC spheres are not polarized like NT spheres. Unlike cells differentiated from NT spheres, TSH did not significantly stimulate cAMP production in cells differentiated from PTC spheres. A microarray analysis performed in paired samples (NT and PTC spheres from the same patient) indicated that NT and PTC spheres display a gene expression pattern typical of stem/progenitor cells; however, compared with NT spheres, PTC spheres display a unique gene expression pattern that might be involved in PTC progression.
Collapse
Affiliation(s)
- Fiorenza Gianì
- Department of Clinical and Molecular Bio-Medicine (F.G., V.V., M.L.N., S.L., R.V., F.F.), Endocrinology Unit, Garibaldi-Nesima Medical Center, University of Catania, 95122 Catania, Italy; Immunology and Pharmacotherapy Area (A.F.), Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy; Department of Motor Sciences (V.V.), School of Human and Social Sciences, "Kore" University of Enna, 94100 Enna, Italy; Division of Endocrinology (R.M., A.B.), Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and HUMANITAS (R.V.), Catania Oncology Center, 95126 Catania, Italy
| | - Veronica Vella
- Department of Clinical and Molecular Bio-Medicine (F.G., V.V., M.L.N., S.L., R.V., F.F.), Endocrinology Unit, Garibaldi-Nesima Medical Center, University of Catania, 95122 Catania, Italy; Immunology and Pharmacotherapy Area (A.F.), Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy; Department of Motor Sciences (V.V.), School of Human and Social Sciences, "Kore" University of Enna, 94100 Enna, Italy; Division of Endocrinology (R.M., A.B.), Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and HUMANITAS (R.V.), Catania Oncology Center, 95126 Catania, Italy
| | - Maria Luisa Nicolosi
- Department of Clinical and Molecular Bio-Medicine (F.G., V.V., M.L.N., S.L., R.V., F.F.), Endocrinology Unit, Garibaldi-Nesima Medical Center, University of Catania, 95122 Catania, Italy; Immunology and Pharmacotherapy Area (A.F.), Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy; Department of Motor Sciences (V.V.), School of Human and Social Sciences, "Kore" University of Enna, 94100 Enna, Italy; Division of Endocrinology (R.M., A.B.), Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and HUMANITAS (R.V.), Catania Oncology Center, 95126 Catania, Italy
| | - Alessandra Fierabracci
- Department of Clinical and Molecular Bio-Medicine (F.G., V.V., M.L.N., S.L., R.V., F.F.), Endocrinology Unit, Garibaldi-Nesima Medical Center, University of Catania, 95122 Catania, Italy; Immunology and Pharmacotherapy Area (A.F.), Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy; Department of Motor Sciences (V.V.), School of Human and Social Sciences, "Kore" University of Enna, 94100 Enna, Italy; Division of Endocrinology (R.M., A.B.), Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and HUMANITAS (R.V.), Catania Oncology Center, 95126 Catania, Italy
| | - Sonia Lotta
- Department of Clinical and Molecular Bio-Medicine (F.G., V.V., M.L.N., S.L., R.V., F.F.), Endocrinology Unit, Garibaldi-Nesima Medical Center, University of Catania, 95122 Catania, Italy; Immunology and Pharmacotherapy Area (A.F.), Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy; Department of Motor Sciences (V.V.), School of Human and Social Sciences, "Kore" University of Enna, 94100 Enna, Italy; Division of Endocrinology (R.M., A.B.), Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and HUMANITAS (R.V.), Catania Oncology Center, 95126 Catania, Italy
| | - Roberta Malaguarnera
- Department of Clinical and Molecular Bio-Medicine (F.G., V.V., M.L.N., S.L., R.V., F.F.), Endocrinology Unit, Garibaldi-Nesima Medical Center, University of Catania, 95122 Catania, Italy; Immunology and Pharmacotherapy Area (A.F.), Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy; Department of Motor Sciences (V.V.), School of Human and Social Sciences, "Kore" University of Enna, 94100 Enna, Italy; Division of Endocrinology (R.M., A.B.), Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and HUMANITAS (R.V.), Catania Oncology Center, 95126 Catania, Italy
| | - Antonino Belfiore
- Department of Clinical and Molecular Bio-Medicine (F.G., V.V., M.L.N., S.L., R.V., F.F.), Endocrinology Unit, Garibaldi-Nesima Medical Center, University of Catania, 95122 Catania, Italy; Immunology and Pharmacotherapy Area (A.F.), Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy; Department of Motor Sciences (V.V.), School of Human and Social Sciences, "Kore" University of Enna, 94100 Enna, Italy; Division of Endocrinology (R.M., A.B.), Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and HUMANITAS (R.V.), Catania Oncology Center, 95126 Catania, Italy
| | - Riccardo Vigneri
- Department of Clinical and Molecular Bio-Medicine (F.G., V.V., M.L.N., S.L., R.V., F.F.), Endocrinology Unit, Garibaldi-Nesima Medical Center, University of Catania, 95122 Catania, Italy; Immunology and Pharmacotherapy Area (A.F.), Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy; Department of Motor Sciences (V.V.), School of Human and Social Sciences, "Kore" University of Enna, 94100 Enna, Italy; Division of Endocrinology (R.M., A.B.), Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and HUMANITAS (R.V.), Catania Oncology Center, 95126 Catania, Italy
| | - Francesco Frasca
- Department of Clinical and Molecular Bio-Medicine (F.G., V.V., M.L.N., S.L., R.V., F.F.), Endocrinology Unit, Garibaldi-Nesima Medical Center, University of Catania, 95122 Catania, Italy; Immunology and Pharmacotherapy Area (A.F.), Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy; Department of Motor Sciences (V.V.), School of Human and Social Sciences, "Kore" University of Enna, 94100 Enna, Italy; Division of Endocrinology (R.M., A.B.), Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy; and HUMANITAS (R.V.), Catania Oncology Center, 95126 Catania, Italy
| |
Collapse
|
|
28
|
Zane M, Scavo E, Catalano V, Bonanno M, Todaro M, De Maria R, Stassi G. Normal vs cancer thyroid stem cells: the road to transformation. Oncogene 2015; 35:805-15. [PMID: 25961919 DOI: 10.1038/onc.2015.138] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Revised: 03/24/2015] [Accepted: 03/30/2015] [Indexed: 01/06/2023]
Abstract
Recent investigations in thyroid carcinogenesis have led to the isolation and characterisation of a subpopulation of stem-like cells, responsible for tumour initiation, progression and metastasis. Nevertheless, the cellular origin of thyroid cancer stem cells (SCs) remains unknown and it is still necessary to define the process and the target population that sustain malignant transformation of tissue-resident SCs or the reprogramming of a more differentiated cell. Here, we will critically discuss new insights into thyroid SCs as a potential source of cancer formation in light of the available information on the oncogenic role of genetic modifications that occur during thyroid cancer development. Understanding the fine mechanisms that regulate tumour transformation may provide new ground for clinical intervention in terms of prevention, diagnosis and therapy.
Collapse
Affiliation(s)
- M Zane
- Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.,Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - E Scavo
- Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy
| | - V Catalano
- Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy
| | - M Bonanno
- Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy
| | - M Todaro
- Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy
| | - R De Maria
- Regina Elena National Cancer Institute, Rome, Italy
| | - G Stassi
- Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy
| |
Collapse
|
|
29
|
Hayase S, Sasaki Y, Matsubara T, Seo D, Miyakoshi M, Murata T, Ozaki T, Kakudo K, Kumamoto K, Ylaya K, Cheng SY, Thorgeirsson SS, Hewitt SM, Ward JM, Kimura S. Expression of stanniocalcin 1 in thyroid side population cells and thyroid cancer cells. Thyroid 2015; 25:425-36. [PMID: 25647164 PMCID: PMC4390205 DOI: 10.1089/thy.2014.0464] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Mouse thyroid side population (SP) cells consist of a minor population of mouse thyroid cells that may have multipotent thyroid stem cell characteristics. However the nature of thyroid SP cells remains elusive, particularly in relation to thyroid cancer. Stanniocalcin (STC) 1 and 2 are secreted glycoproteins known to regulate serum calcium and phosphate homeostasis. In recent years, the relationship of STC1/2 expression to cancer has been described in various tissues. METHOD Microarray analysis was carried out to determine genes up- and down-regulated in thyroid SP cells as compared with non-SP cells. Among genes up-regulated, stanniocalcin 1 (STC1) was chosen for study because of its expression in various thyroid cells by Western blotting and immunohistochemistry. RESULTS Gene expression analysis revealed that genes known to be highly expressed in cancer cells and/or involved in cancer invasion/metastasis were markedly up-regulated in SP cells from both intact as well as partial thyroidectomized thyroids. Among these genes, expression of STC1 was found in five human thyroid carcinoma-derived cell lines as revealed by analysis of mRNA and protein, and its expression was inversely correlated with the differentiation status of the cells. Immunohistochemical analysis demonstrated higher expression of STC1 in the thyroid tumor cell line and thyroid tumor tissues from humans and mice. CONCLUSION These results suggest that SP cells contain a population of cells that express genes also highly expressed in cancer cells including Stc1, which warrants further study on the role of SP cells and/or STC1 expression in thyroid cancer.
Collapse
Affiliation(s)
- Suguru Hayase
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yoshihito Sasaki
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Kuwana East Medical Center, Kuwana, Mie, Japan
| | - Tsutomu Matsubara
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Daekwan Seo
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Bioinformatics Core, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Masaaki Miyakoshi
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Department of Oral Pathobiological Science, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Tsubasa Murata
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Dental and Oral Surgery, Tomakomai City Hospital, Tomakomai, Hokkaido, Japan
| | - Takashi Ozaki
- Department of Pathology, Wakayama Medical University, Wakayama City, Japan
| | - Kennichi Kakudo
- Department of Pathology, Nara Hospital Kinki University Faculty of Medicine, Ikoma, Japan
| | - Kensuke Kumamoto
- Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kris Ylaya
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sheue-yann Cheng
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Snorri S. Thorgeirsson
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stephen M. Hewitt
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | | | - Shioko Kimura
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| |
Collapse
|
|
30
|
Bhatia P, Tsumagari K, Abd Elmageed ZY, Friedlander P, Buell JF, Kandil E. Stem cell biology in thyroid cancer: Insights for novel therapies. World J Stem Cells 2014; 6:614-619. [PMID: 25426258 PMCID: PMC4178261 DOI: 10.4252/wjsc.v6.i5.614] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 09/17/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Currently, thyroid cancer is one of the most common endocrine cancer in the United States. A recent involvement of sub-population of stem cells, cancer stem cells, has been proposed in different histological types of thyroid cancer. Because of their ability of self-renewal and differentiation into various specialized cells in the body, these putative cells drive tumor genesis, metastatic activity and are responsible to provide chemo- and radioresistant nature to the cancer cells in the thyroid gland. Our Review was conducted from previously published literature to provide latest apprises to investigate the role of embryonic, somatic and cancer stem cells, and discusses the hypothesis of epithelial-mesenchymal transition. Different methods for their identification and isolation through stemness markers using various in vivo and in vitro methods such as flow cytometry, thyrosphere formation assay, aldehyde dehydrogenase activity and ATP-binding cassette sub-family G member 2 efflux-pump mediated Hoechst 33342 dye exclusion have been discussed. The review also outlines various setbacks that still remain to target these tumor initiating cells. Future perspectives of therapeutic strategies and their potential to treat advanced stages of thyroid cancer are also disclosed in this review.
Collapse
|
|
31
|
Abstract
Proliferative thyroid diseases are more prevalent in females than in males. Upon the onset of puberty, the incidence of thyroid cancer increases in females only and declines again after menopause. Estrogen is a potent growth factor both for benign and malignant thyroid cells that may explain the sex difference in the prevalence of thyroid nodules and thyroid cancer. It exerts its growth-promoting effect through a classical genomic and a non-genomic pathway, mediated via a membrane-bound estrogen receptor. This receptor is linked to the tyrosine kinase signaling pathways MAPK and PI3K. In papillary thyroid carcinomas, these pathways may be activated either by a chromosomal rearrangement of the tyrosine receptor kinase TRKA, by RET/PTC genes, or by a BRAF mutation and, in addition, in females they may be stimulated by high levels of estrogen. Furthermore, estrogen is involved in the regulation of angiogenesis and metastasis that are critical for the outcome of thyroid cancer. In contrast to other carcinomas, however, detailed knowledge on this regulation is still missing for thyroid cancer.
Collapse
Affiliation(s)
- Michael Derwahl
- Department of MedicineSt Hedwig Hospital and Charite, University Medicine Berlin, Grosse Hamburger Straße 5-11, 10115 Berlin, Germany
| | - Diana Nicula
- Department of MedicineSt Hedwig Hospital and Charite, University Medicine Berlin, Grosse Hamburger Straße 5-11, 10115 Berlin, Germany
| |
Collapse
|
|
32
|
Hardin H, Guo Z, Shan W, Montemayor-Garcia C, Asioli S, Yu XM, Harrison AD, Chen H, Lloyd RV. The roles of the epithelial-mesenchymal transition marker PRRX1 and miR-146b-5p in papillary thyroid carcinoma progression. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:2342-54. [PMID: 24946010 DOI: 10.1016/j.ajpath.2014.04.011] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 03/24/2014] [Accepted: 04/11/2014] [Indexed: 12/26/2022]
Abstract
Thyroid carcinoma is the most common endocrine malignancy, and papillary thyroid carcinoma represents the most common thyroid cancer. Papillary thyroid carcinomas that invade locally or metastasize are associated with a poor prognosis. We found that, during epithelial-mesenchymal transition (EMT) induced by transforming growth factor-β1 (TGF-β1), papillary thyroid carcinoma cells acquired increased cancer stem cell-like features and the transcription factor paired-related homeobox protein 1 (PRRX1; alias PRX-1), a newly identified EMT inducer, was markedly up-regulated. miR-146b-5p was also transiently up-regulated during EMT, and in siRNA experiments miR-146b-5p had an inhibitory role on cell proliferation and invasion during TGF-β1-induced EMT. We conclude that papillary thyroid carcinoma tumor cells exhibit increased cancer stem cell-like features during TGF-β1-induced EMT, that miR-146b-5p has a role in cell proliferation and invasion, and that PRRX1 plays an important role in papillary thyroid carcinoma EMT and disease progression.
Collapse
Affiliation(s)
- Heather Hardin
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Zhenying Guo
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Weihua Shan
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Celina Montemayor-Garcia
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Sofia Asioli
- Department of Biomedical Sciences and Human Oncology, University of Turin, Turin, Italy
| | - Xiao-Min Yu
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - April D Harrison
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Herbert Chen
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Ricardo V Lloyd
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
| |
Collapse
|
|
33
|
Ahn SH, Henderson YC, Williams MD, Lai SY, Clayman GL. Detection of thyroid cancer stem cells in papillary thyroid carcinoma. J Clin Endocrinol Metab 2014; 99:536-44. [PMID: 24302752 PMCID: PMC3913805 DOI: 10.1210/jc.2013-2558] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
CONTEXT Special populations of cells that can efficiently initiate tumor growth have been characterized, and this feature supports the cancer stem cell theory. These cancer stem cell populations have been identified with CD44 and POU5F1. Most cancer stem cells express high levels of CD44 and low levels of CD24. In thyroid lesions, cancer stem cells have been detected in anaplastic carcinoma. However, little is known about the presence of cancer stem cells in papillary thyroid carcinoma (PTC), especially in recurrent PTC. OBJECTIVE AND DESIGN PTC cells were labeled and sorted by flow cytometry to obtain two populations. Total RNA was prepared from cells with high CD44 and CD24 expressions (CD44+CD24+) and from cells with high CD44 and low CD24 expressions (CD44+CD24-). The expressions of the stem cell marker POU5F1 and several differentiated thyroid markers were measured via real-time PCR. RESULTS CD44+CD24- cells were present in all PTCs tested, and the percentage of these cells was higher in clinically aggressive recurrent PTC than in less aggressive primary PTCs. Higher expression of POU5F1 was found in CD44+CD24- cells compared with that of CD44+CD24+ cells. The expression of POU5F1 was higher in thyrospheroids grown in serum-free condition than in cells grown in the presence of serum from the same patient, and the tumor was initiated in mice using thyrospheroids. CONCLUSIONS The percentage of CD44+CD24- cells varied from tumor to tumor. Our findings suggest that cancer stem cells are present in PTC.
Collapse
Affiliation(s)
- Soon-Hyun Ahn
- Department of Otolaryngology-Head and Neck Surgery (S-H.A.), College of Medicine, Seoul National University Bundang Hospital, Kyunggi-do 463-707, South Korea; and Departments of Head and Neck Surgery (Y.C.H., S.Y.L., G.L.C.), Pathology (M.D.W.), Molecular and Cellular Oncology (S.Y.L.), and Cancer Biology (G.L.C.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
| | | | | | | | | |
Collapse
|
|
34
|
Ma R, Bonnefond S, Morshed SA, Latif R, Davies TF. Stemness is Derived from Thyroid Cancer Cells. Front Endocrinol (Lausanne) 2014; 5:114. [PMID: 25076938 PMCID: PMC4097959 DOI: 10.3389/fendo.2014.00114] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 07/01/2014] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND One hypothesis for thyroid cancer development is its derivation from thyroid cancer stem cells (CSCs). Such cells could arise via different paths including from mutated resident stem cells within the thyroid gland or via epithelial to mesenchymal transition (EMT) from malignant cells since EMT is known to confer stem-like characteristics. Furthermore, EMT is a critical process for epithelial tumor progression, local invasion, and metastasis formation. In addition, stemness provides cells with therapeutic resistance and is the likely cause of tumor recurrence. However, the relevance of EMT and stemness in thyroid cancer progression has not been extensively studied. METHODS To examine the status of stemness in thyroid papillary cancer, we employed a murine model of thyroid papillary carcinoma and examined the expression of stemness and EMT using qPCR and histochemistry in mice with a thyroid-specific knock-in of oncogenic Braf (LSL-Braf((V600E))/TPO-Cre). This construct is only activated at the time of thyroid peroxidase (TPO) expression in differentiating thyroid cells and cannot be activated by undifferentiated stem cells, which do not express TPO. RESULTS There was decreased expression of thyroid-specific genes such as Tg and NIS and increased expression of stemness markers, such as Oct4, Rex1, CD15, and Sox2 in the thyroid carcinoma tissue from 6-week-old BRAF(V600E) mice indicating the dedifferentiated status of the cells and the fact that stemness was derived in this model from differentiated thyroid cells. The decreased expression of the epithelial marker E-cadherin and increased EMT regulators including Snail, Slug, and TGF-β1 and TGF-β3, and the mesenchymal marker vimentin demonstrated the simultaneous progression of EMT and the CSC-like phenotype. Stemness was also found in a cancer thyroid cell line (named Marca cells) derived from one of the murine tumors. In this cell line, we also found that overexpression of Snail caused up-regulation of vimentin expression and up-regulation of stemness markers Oct4, Rex1, and CD15, with enhanced migration ability of the cells. We also showed that TGF-β1 was able to induce Snail and vimentin expression in the Marca cell thyroid cancer line, indicating the induction of EMT in these cells, and this induction of EMT and stemness was significantly inhibited by celastro a natural inhibitor of neoplastic cells. CONCLUSION Our findings support our earlier hypothesis that stemness in thyroid cancer is derived via EMT rather than from resident thyroid stem cells. In mice with a thyroid-specific knock-in of oncogenic Braf (LSL-Braf((V600E))/TPO-Cre), the neoplastic changes were dependent on thyroid cell differentiation and the onset of stemness must have been derived from differentiated thyroid epithelial cells. Furthermore, celastrol suppressed TGF-β1 induced EMT in thyroid cancer cells and may have therapeutic potential.
Collapse
Affiliation(s)
- Risheng Ma
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and the James J Peters VA Medical Center, New York, NY, USA
- *Correspondence: Risheng Ma, Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and the James J Peters VA Medical Center, Room 2F-28, 130 West Kingsbridge Road, New York, NY 10468, USA e-mail:
| | | | - Syed A. Morshed
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and the James J Peters VA Medical Center, New York, NY, USA
| | - Rauf Latif
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and the James J Peters VA Medical Center, New York, NY, USA
| | - Terry F. Davies
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and the James J Peters VA Medical Center, New York, NY, USA
| |
Collapse
|
|
35
|
Abstract
Many tissues if not all are thought to contain stem cells that are responsible for regeneration and repair of the tissue after injury. Dysregulation of tissue regeneration may result in various pathological conditions, among which cancer is the most extensively studied. Notably, the so-called cancer stem cells or tumor-initiating cells, have been studied in order to understand the mechanisms of carcinogenesis and/or metastasis. However, the nature of cancer stem cells, let alone normal stem/progenitor cells, particularly those of the thyroid remains elusive. There remains a gap in knowledge between adult thyroid stem/progenitor cells and cancer stem cells of the thyroid, and if and/or how they are related to each other. Understanding of the mechanism for thyroid regeneration and mode of participation of normal adult thyroid stem/progenitor cells in this process will hopefully yield a more complete understanding of the nature of thyroid cancer stem cells, and/or help understand the pathogenesis of other thyroid diseases. This review summarizes the current understanding of adult thyroid stem/progenitor cells, with particular emphasis on how they contribute to thyroid regeneration.
Collapse
Affiliation(s)
- Shioko Kimura
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- *Correspondence: Shioko Kimura, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD 20892, USA e-mail:
| |
Collapse
|
|
36
|
Abstract
Thyroid cancer incidence is rising annually largely related to enhanced detection and early stage well-differentiated primary tumors. The prognosis for patients with early stage thyroid cancer is outstanding with most patients being cured with surgery. In selected cases, I-131 is administered to treat known or suspected residual or metastatic disease. Even patients with loco-regional metastases typically have an outstanding long-term prognosis, albeit with monitoring and occasional intervention for residual or recurrent disease. By contrast, individuals with distant metastases from thyroid cancer, particularly older patients with larger metastatic burdens and those with poorly differentiated tumors, have a poor prognosis. Patients with metastatic anaplastic thyroid cancer have a particularly poor prognosis. Published clinical trials indicate that transient disease control and partial remissions can be achieved with kinase inhibitor therapy directed toward angiogenic targets and that in some cases I-131 uptake can be enhanced. However, the direct targets of activity in metastatic lesions are incompletely defined and clear evidence that these treatments increase the duration or quality of life of patients is lacking, underscoring the need for improved knowledge regarding the metastatic process to inform the development of new therapies. In this review, we will focus on current data and hypotheses regarding key regulators of metastatic dormancy, metastatic progression, and the role of putative cancer stem cells.
Collapse
Affiliation(s)
- John E. Phay
- Division of Surgical Oncology, Department of Surgery, The Ohio State University College of Medicine; Arthur G. James Comprehensive Cancer Center and Richard G. Solove Research Institute, Columbus, OH 43210
| | - Matthew D. Ringel
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University College of Medicine; Arthur G. James Comprehensive Cancer Center and Richard G. Solove Research Institute, Columbus, OH 43210
| |
Collapse
|
|
37
|
Okamoto M, Hayase S, Miyakoshi M, Murata T, Kimura S. Stem cell antigen 1-positive mesenchymal cells are the origin of follicular cells during thyroid regeneration. PLoS One 2013; 8:e80801. [PMID: 24278321 PMCID: PMC3836768 DOI: 10.1371/journal.pone.0080801] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Accepted: 10/16/2013] [Indexed: 01/02/2023] Open
Abstract
Many tissues are thought to contain adult stem/progenitor cells that are responsible for repair of the tissue where they reside upon damage and/or carcinogenesis, conditions when cellular homeostasis becomes uncontrolled. While the presence of stem/progenitor cells of the thyroid has been suggested, how these cells contribute to thyroid regeneration remains unclear. Here we show the origin of thyroid follicular cells and the process of their maturation to become follicular cells during regeneration. By using β-galactosidase (β-gal) reporter mice in conjunction with partial thyroidectomy as a model for thyroid regeneration, and bromodeoxyuridine (BrdU) long label-retaining cell analysis, we demonstrated that stem cell antigen 1 (Sca1) and BrdU-positive, but β-gal and NKX2-1 negative cells were found in the non-follicular mesenchymal area 7 days after partial thyroidectomy. They temporarily co-expressed cytokeratin 14, and were observed in part of follicles by day 35 post-partial thyroidectomy. Sca1, BrdU, β-gal, and NKX2-1-positive cells were found 120 days post-partial thyroidectomy. These results suggested that Sca1 and BrdU positive cells may participate in the formation of new thyroid follicles after partial thyroidectomy. The process of thyroid follicular cell regeneration was recapitulated in ex vivo thyroid slice collagen gel culture studies. These studies will facilitate research on thyroid stem/progenitor cells and their roles in thyroid diseases, particularly thyroid carcinomas.
Collapse
Affiliation(s)
- Minoru Okamoto
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Suguru Hayase
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Masaaki Miyakoshi
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Tsubasa Murata
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Shioko Kimura
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
- * E-mail:
| |
Collapse
|
|
38
|
Baldassarro VA, Lizzo G, Paradisi M, Fernández M, Giardino L, Calzà L. Neural stem cells isolated from amyloid precursor protein-mutated mice for drug discovery. World J Stem Cells 2013; 5:229-237. [PMID: 24179610 PMCID: PMC3812526 DOI: 10.4252/wjsc.v5.i4.229] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 08/07/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop an in vitro model based on neural stem cells derived from transgenic animals, to be used in the study of pathological mechanisms of Alzheimer’s disease and for testing new molecules.
METHODS: Neural stem cells (NSCs) were isolated from the subventricular zone of Wild type (Wt) and Tg2576 mice. Primary and secondary neurosphere generation was studied, analysing population doubling and the cell yield per animal. Secondary neurospheres were dissociated and plated on MCM Gel Cultrex 2D and after 6 d in vitro (DIVs) in mitogen withdrawal conditions, spontaneous differentiation was studied using specific neural markers (MAP2 and TuJ-1 for neurons, GFAP for astroglial cells and CNPase for oligodendrocytes). Gene expression pathways were analysed in secondary neurospheres, using the QIAGEN PCR array for neurogenesis, comparing the Tg2576 derived cell expression with the Wt cells. Proteins encoded by the altered genes were clustered using STRING web software.
RESULTS: As revealed by 6E10 positive staining, all Tg2576 derived cells retain the expression of the human transgenic Amyloid Precursor Protein. Tg2576 derived primary neurospheres show a decrease in population doubling. Morphological analysis of differentiated NSCs reveals a decrease in MAP2- and an increase in GFAP-positive cells in Tg2576 derived cells. Analysing the branching of TuJ-1 positive cells, a clear decrease in neurite number and length is observed in Tg2576 cells. The gene expression neurogenesis pathway revealed 11 altered genes in Tg2576 NSCs compared to Wt.
CONCLUSION: Tg2576 NSCs represent an appropriate AD in vitro model resembling some cellular alterations observed in vivo, both as stem and differentiated cells.
Collapse
|
|
39
|
Thyroid cancer stem-like cells and epithelial-mesenchymal transition in thyroid cancers. Hum Pathol 2013; 44:1707-13. [DOI: 10.1016/j.humpath.2013.01.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 12/19/2012] [Accepted: 01/01/2013] [Indexed: 02/07/2023]
|
|
40
|
Xu S, Chen G, Peng W, Renko K, Derwahl M. Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules? J Endocrinol 2013; 218:125-33. [PMID: 23645248 DOI: 10.1530/joe-13-0029] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Benign and malignant thyroid nodules are more prevalent in females than in males. Experimental data suggest that the proliferative effect of oestrogen rather than polymorphisms is responsible for this gender difference. This study analysed whether both differentiated thyroid cells and thyroid stem and progenitor cells are targets of oestrogen action. In thyroid stem/progenitor cells derived from nodular goitres, the ability of 17β-oestradiol (E₂) to induce the formation of thyrospheres and the expression of oestrogen receptors (ERs) and the effect of E₂ on the growth and expression of markers of stem cells and thyroid differentiation (TSH receptor, thyroperoxidase, thyroglobulin and sodium iodide symporter (NIS)) were analysed. E₂ induced thyrosphere formation, albeit to a lower extent than other growth factors. Thyroid stem and progenitor cells expressed ERα (ESR1) and ERβ (ESR2) with eight times higher expression levels of ERα mRNA compared with the differentiated thyrocytes. E₂ was a potent stimulator of the growth of thyroid stem/progenitor cells. In contrast, TSH-induced differentiation of progenitor cells, in particular, the expression of NIS, was significantly inhibited by E₂. In conclusion, oestrogen stimulated the growth and simultaneously inhibited the differentiation of thyroid nodule-derived stem/progenitor cells. From these data and based on the concept of cellular heterogeneity, we hypothesize a supportive role of oestrogen in the propagation of thyroid stem/progenitor cells leading to the selection of a progeny of growth-prone cells with a decreased differentiation. These cells may be the origin of hypofunctioning or non-functioning thyroid nodules in females.
Collapse
Affiliation(s)
- Shuhang Xu
- Division of Endocrinology, Department of Medicine, St Hedwig Hospital, Berlin, Germany
| | | | | | | | | |
Collapse
|
|
41
|
Lan L, Luo Y, Cui D, Shi BY, Deng W, Huo LL, Chen HL, Zhang GY, Deng LL. Epithelial-mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells. Int J Oncol 2013; 43:113-20. [PMID: 23604232 DOI: 10.3892/ijo.2013.1913] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2013] [Accepted: 03/14/2013] [Indexed: 11/06/2022] Open
Abstract
Increasing evidence has shown that cancer stem cells or tumor initiating cells are the 'root cause' of malignant cancers. However, the exact origin of cancer stem cells still remains obscure in thyroid research. EMT has been implicated in the initiation and conversion of early-stage tumors into invasive malignancies and is associated with the stemness of cancer cells. Based on these facts, a new hypothesis was suggested that EMT induces cancer stem cell generation and tumor progression in human thyroid cancer cells in vitro. In the present study, FTC133 cells identified as EMT-negative cells were used for EMT induction by HIF‑1α transfection. Overexpression of HIF-1α induced FTC133 cells to undergo EMT, downregulated the epithelial markers E-cadherin, upregulated the mesenchymal marker vimentin, and associated with highly invasive and metastatic properties. Most importantly, the induction of EMT promoted the stem-like side population cell proportion in the FTC133 cells. These results indicate that EMT induction promotes CSC traits and cell proportions in the thyroid cancer cells, which implies that EMT could induce cancer stem cell generation and tumor progression in thyroid cancers. Further understanding of the role of EMT and cancer stem cells in cancer progression may reveal new targets for the prevention or therapy of thyroid cancers.
Collapse
Affiliation(s)
- Ling Lan
- Department of Endocrinology, Beijing Ji Shui Tan Hospital, The 4th Medical College of Peking University, Beijing, P.R. China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Colin IM, Denef JF, Lengelé B, Many MC, Gérard AC. Recent insights into the cell biology of thyroid angiofollicular units. Endocr Rev 2013; 34:209-38. [PMID: 23349248 PMCID: PMC3610675 DOI: 10.1210/er.2012-1015] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Accepted: 11/07/2012] [Indexed: 01/06/2023]
Abstract
In thyrocytes, cell polarity is of crucial importance for proper thyroid function. Many intrinsic mechanisms of self-regulation control how the key players involved in thyroid hormone (TH) biosynthesis interact in apical microvilli, so that hazardous biochemical processes may occur without detriment to the cell. In some pathological conditions, this enzymatic complex is disrupted, with some components abnormally activated into the cytoplasm, which can lead to further morphological and functional breakdown. When iodine intake is altered, autoregulatory mechanisms outside the thyrocytes are activated. They involve adjacent capillaries that, together with thyrocytes, form the angiofollicular units (AFUs) that can be considered as the functional and morphological units of the thyroid. In response to iodine shortage, a rapid expansion of the microvasculature occurs, which, in addition to nutrients and oxygen, optimizes iodide supply. These changes are triggered by angiogenic signals released from thyrocytes via a reactive oxygen species/hypoxia-inducible factor/vascular endothelial growth factor pathway. When intra- and extrathyrocyte autoregulation fails, other forms of adaptation arise, such as euthyroid goiters. From onset, goiters are morphologically and functionally heterogeneous due to the polyclonal nature of the cells, with nodules distributed around areas of quiescent AFUs containing globules of compact thyroglobulin (Tg) and surrounded by a hypotrophic microvasculature. Upon TSH stimulation, quiescent AFUs are activated with Tg globules undergoing fragmentation into soluble Tg, proteins involved in TH biosynthesis being expressed and the local microvascular network extending. Over time and depending on physiological needs, AFUs may undergo repetitive phases of high, moderate, or low cell and tissue activity, which may ultimately culminate in multinodular goiters.
Collapse
Affiliation(s)
- Ides M Colin
- Pôle de Morphologie, Institut de Recherche Expérimentale et Clinique, Secteur des Sciences de la Santé, Université Catholique de Louvain (UCL), UCL-5251, 52 Avenue E. Mounier, B-1200, Bruxelles, Belgium.
| | | | | | | | | |
Collapse
|
|
43
|
Lloyd RV, Hardin H, Montemayor-Garcia C, Rotondo F, Syro LV, Horvath E, Kovacs K. Stem cells and cancer stem-like cells in endocrine tissues. Endocr Pathol 2013; 24:1-10. [PMID: 23435637 DOI: 10.1007/s12022-013-9235-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Cancer stem-like cells are a subpopulation of self-renewing cells that are more resistant to chemotherapy and radiation therapy than the other surrounding cancer cells. The cancer stem cell model predicts that only a subset of cancer cells possess the ability to self-renew and produce progenitor cells that can reconstitute and sustain tumor growth. Evidence supporting the existence of cancer stem-like cells in the thyroid, pituitary, and in other endocrine tissues is rapidly accumulating. These cells have been studied using specific biomarkers including: CD133, CD44, Nestin, Nanog, and aldehyde dehydrogenase enzyme. Putative cancer stem-like cells can be studied in vitro using serum-free media supplemented with basic fibroblast growth factor and epidermal growth factor grown in low attachment plates or in extracellular matrix leading to sphere formation in vitro. Cancer stem-like cells can also be separated by fluorescent cell sorting and used for in vitro or in vivo studies. Injection of enriched populations of cancer stem-like cells (also referred to as tumor initiating cells) into immunodeficient mice results in growth of xenografts which express cancer stem-like biomarkers. Human cancer stem-like cells have been identified in thyroid cancer cell lines, in primary thyroid cancers, in normal pituitary, and in pituitary tumors. Other recent studies suggest the existence of stem cells and cancer stem-like cells in endocrine tumors of the gastrointestinal tract, pancreas, lungs, adrenal, parathyroid, and skin. New discoveries in this field may lead to more effective therapies for highly aggressive and lethal endocrine cancers.
Collapse
Affiliation(s)
- Ricardo V Lloyd
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, K4/436 CSC 8550, Madison, WI 53705, USA.
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Chimenti I, Gaetani R, Barile L, Forte E, Ionta V, Angelini F, Frati G, Messina E, Giacomello A. Isolation and expansion of adult cardiac stem/progenitor cells in the form of cardiospheres from human cardiac biopsies and murine hearts. Methods Mol Biol 2012; 879:327-38. [PMID: 22610568 DOI: 10.1007/978-1-61779-815-3_19] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The successful isolation and ex vivo expansion of resident cardiac stem/progenitor cells from human heart biopsies has allowed us to study their biological characteristics and their applications in therapeutic approaches for the repair of ischemic/infarcted heart, the preparation of tissue-engineered cardiac grafts and, possibly, the design of cellular kits for drug screening applications. From the first publication of the original method in 2004, several adjustments and slight changes have been introduced to optimize and adjust the procedure to the evolving experimental and translational needs. Moreover, due to the wide applicability of such a method (which is based on the exploitation of intrinsic functional properties of cells with regenerative properties that are present in most tissues), the key steps of this procedure have been used to derive several kinds of tissue-specific adult stem cells for preclinical or clinical purposes.In order to define the original procedure, complete with the up-to-date modifications introduced through the years, an exhaustive description of the current protocol is performed in this chapter, with particular attention in highlighting critical steps and troubleshoots. The procedure described here consists of modular steps, that could be employed to derive cells from any kind of tissue biopsy, and needs to be considered the gold standard of all the so-called "explant methods" or "cardiosphere methods," and it represents a milestone in the clinical translation of autologous cell therapy.
Collapse
Affiliation(s)
- Isotta Chimenti
- Department of Medical Surgical Sciences and Biotechnology, Sapienza University of Rome, Latina, Italy
| | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Abstract
Continuing advances in stem cell science have prompted researchers to envisage the potential application of stem cells for the management of several debilitating disorders, thus raising the expectations of transplant clinicians. In particular, in order to find a source of adult stem cells alternative to embryonic stem cells (ESCs) for the exploration of novel strategies in regenerative medicine, researchers have attempted to identify and characterise adult stem/progenitor cells resident in compact organs, since these populations appear to be responsible for physiological tissue renewal and regeneration after injury. In particular, recent studies have also reported evidence for the existence of adult stem/progenitor cell populations in both mouse and human thyroids. Here, I provide a review of published findings about ESC lines capable of generating thyroid follicular cells, thyroid somatic stem cells and cancer stem cells within the thyroid. The three subjects are analysed by also considering the criticism recently raised against their existence and potential utility. I comment specifically on the significance of resident thyroid stem cells in the developmental biology of the gland and their putative role in the pathogenesis of thyroid disorders and on the protocols employed for their identification. I finally provide my opinion on whether from basic science results obtained to date it is possible to extrapolate any convincing basic for future treatment of thyroid disorders.
Collapse
Affiliation(s)
- Alessandra Fierabracci
- Research Laboratories, Ospedale Pediatrico Bambino Gesù Research Institute, Children's Hospital Bambino Gesù, Piazza S. Onofrio 4, Rome, Italy.
| |
Collapse
|
|
46
|
Mikhailov V, Sokolova A, Serikov V, Kaminskaya E, Churilov L, Trunin E, Sizova E, Kayukov A, Bud’ko M, Zaichik A. Bone marrow stem cells repopulate thyroid in X-ray regeneration in mice. PATHOPHYSIOLOGY 2012; 19:5-11. [DOI: 10.1016/j.pathophys.2011.07.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 06/30/2011] [Accepted: 07/07/2011] [Indexed: 12/17/2022] Open
|
|
47
|
Toni R, Tampieri A, Zini N, Strusi V, Sandri M, Dallatana D, Spaletta G, Bassoli E, Gatto A, Ferrari A, Martin I. Ex situ bioengineering of bioartificial endocrine glands: A new frontier in regenerative medicine of soft tissue organs. Ann Anat 2011; 193:381-94. [DOI: 10.1016/j.aanat.2011.06.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Revised: 06/14/2011] [Accepted: 06/17/2011] [Indexed: 01/14/2023]
|
|
48
|
Davies TF, Latif R, Minsky NC, Ma R. Clinical review: The emerging cell biology of thyroid stem cells. J Clin Endocrinol Metab 2011; 96:2692-702. [PMID: 21778219 PMCID: PMC3167664 DOI: 10.1210/jc.2011-1047] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Stem cells are undifferentiated cells with the property of self-renewal and give rise to highly specialized cells under appropriate local conditions. The use of stem cells in regenerative medicine holds great promise for the treatment of many diseases, including those of the thyroid gland. EVIDENCE ACQUISITION This review focuses on the progress that has been made in thyroid stem cell research including an overview of cellular and molecular events (most of which were drawn from the period 1990-2011) and discusses the remaining problems encountered in their differentiation. EVIDENCE SYNTHESIS Protocols for the in vitro differentiation of embryonic stem cells, based on normal developmental processes, have generated thyroid-like cells but without full thyrocyte function. However, agents have been identified, including activin A, insulin, and IGF-I, which are able to stimulate the generation of thyroid-like cells in vitro. In addition, thyroid stem/progenitor cells have been identified within the normal thyroid gland and within thyroid cancers. CONCLUSIONS Advances in thyroid stem cell biology are providing not only insight into thyroid development but may offer therapeutic potential in thyroid cancer and future thyroid cell replacement therapy.
Collapse
Affiliation(s)
- Terry F Davies
- Thyroid Research Unit, Mount Sinai School of Medicine, and the James J Peters Veterans Affairs Medical Center, New York, New York 10468, USA.
| | | | | | | |
Collapse
|
|
49
|
Dedifferentiation of human primary thyrocytes into multilineage progenitor cells without gene introduction. PLoS One 2011; 6:e19354. [PMID: 21556376 PMCID: PMC3083435 DOI: 10.1371/journal.pone.0019354] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Accepted: 03/31/2011] [Indexed: 12/30/2022] Open
Abstract
While identification and isolation of adult stem cells have potentially important implications, recent reports regarding dedifferentiation/reprogramming from differentiated cells have provided another clue to gain insight into source of tissue stem/progenitor cells. In this study, we developed a novel culture system to obtain dedifferentiated progenitor cells from normal human thyroid tissues. After enzymatic digestion, primary thyrocytes, expressing thyroglobulin, vimentin and cytokeratin-18, were cultured in a serum-free medium called SAGM. Although the vast majority of cells died, a small proportion (∼0.5%) survived and proliferated. During initial cell expansion, thyroglobulin/cytokeratin-18 expression was gradually declined in the proliferating cells. Moreover, sorted cells expressing thyroid peroxidase gave rise to proliferating clones in SAGM. These data suggest that those cells are derived from thyroid follicular cells or at least thyroid-committed cells. The SAGM-grown cells did not express any thyroid-specific genes. However, after four-week incubation with FBS and TSH, cytokeratin-18, thyroglobulin, TSH receptor, PAX8 and TTF1 expressions re-emerged. Moreover, surprisingly, the cells were capable of differentiating into neuronal or adipogenic lineage depending on differentiating conditions. In summary, we have developed a novel system to generate multilineage progenitor cells from normal human thyroid tissues. This seems to be achieved by dedifferentiation of thyroid follicular cells. The presently described culture system may be useful for regenerative medicine, but the primary importance will be as a tool to elucidate the mechanisms of thyroid diseases.
Collapse
|
|
50
|
Malaguarnera R, Frasca F, Garozzo A, Gianì F, Pandini G, Vella V, Vigneri R, Belfiore A. Insulin receptor isoforms and insulin-like growth factor receptor in human follicular cell precursors from papillary thyroid cancer and normal thyroid. J Clin Endocrinol Metab 2011; 96:766-74. [PMID: 21123448 DOI: 10.1210/jc.2010-1255] [Citation(s) in RCA: 122] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Factors involved in the biology of normal and cancer stem/precursor cells from the thyroid are unknown. Thyroid cancer cells are responsive to insulin and IGF-I and IGF-II and often overexpress the insulin receptor (IR) and the IGF-I receptor (IGF-IR). OBJECTIVE We investigated the role of IR isoforms (IR-A and IR-B), IGF-IR, and their ligands in thyroid follicular cell precursors both normal and malignant. DESIGN We established cultures of follicular cell precursors as thyrospheres from three papillary thyroid cancers and the corresponding nonaffected tissues. The expression of IR, IGF-IR, and their ligands was evaluated by quantitative RT-PCR and, in one case, also by Western blot. The effects of insulin and IGFs on thyrosphere growth and self-renewal were evaluated. RESULTS Thyrospheres were characterized by the expression of stem cell markers and low/absent thyroid specific markers. Thyrospheres from normal tissue, but not from cancer tissue, could be induced to differentiate. Both IR isoforms, IGF-IR, IGF-I and IGF-II, were expressed at high levels in thyrospheres and markedly decreased in differentiating cells. IR-A was the predominant isoform in thyrospheres, especially from cancer, while IR-B was predominant in differentiating cells. Cancer thyrosphere growth was stimulated by insulin and IGFs. CONCLUSIONS Our data suggest that IR isoforms and IGF-IR play a role in the biology of follicular thyroid precursors. Cell differentiation is associated with marked changes in the expression of these receptors and cognate ligands. These data may provide insight for future differentiation therapies in thyroid cancer.
Collapse
MESH Headings
- Blotting, Western
- Carcinoma, Papillary/genetics
- Carcinoma, Papillary/metabolism
- Cell Adhesion
- Cell Line, Tumor
- Cells, Cultured
- DNA Primers
- Gene Expression Regulation, Neoplastic/physiology
- Humans
- Ligands
- Neoplastic Stem Cells/metabolism
- Receptor, IGF Type 1/genetics
- Receptor, IGF Type 1/metabolism
- Receptor, IGF Type 2/genetics
- Receptor, IGF Type 2/metabolism
- Receptor, Insulin/genetics
- Receptor, Insulin/metabolism
- Receptors, Somatomedin/genetics
- Receptors, Somatomedin/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Thyroid Gland/cytology
- Thyroid Gland/metabolism
- Thyroid Neoplasms/genetics
- Thyroid Neoplasms/metabolism
Collapse
Affiliation(s)
- Roberta Malaguarnera
- Department of Clinical and Experimental Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | | | | | | | | | | | | | | |
Collapse
|