Effect of low-dose tungsten on human thyroid stem/precursor cells and their progeny

Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied. We investigated in vitro the effect tungsten on both human thyrocytes in primary culture, thyrospheres (aggregates of stem/precursor thyroid cells) and thyrocytes differentiated from tungsten-exposed thyrospheres. Chronic exposure to low-dose (nanomolar range, as in the urines of volcanic area residents) soluble tungsten had major biological effects on thyroid stem/precursor cells, promoting growth with a biphasic (hormetic) dose-response and reducing apoptosis. No such effects were observed in mature thyrocytes. In addition, tungsten-exposed thyrospheres had abnormal expression of genes commonly altered also in thyroid cancer and increased activation of the DNA-repair proteins H2AX and 53BP1. Moreover, exposure to tungsten decreased thyrosphere differentiation, as indicated by the reduced expression of thyroid-specific genes in derived thyrocytes that also showed preneoplastic changes such as increased anchorage-independent growth, clonogenic growth and migration capacity. The mechanism of action of tungsten on thyroid stem/precursor cells is unclear but involves membrane G-proteins and activation of the ERK signaling pathway. These data indicate that chronic exposure to slightly increased tungsten, harmless for mature thyrocytes, importantly affects the biology of stem/precursor thyroid cells and of their progeny, inducing characteristics of preneoplastic transformation.

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Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals

Frontiers in Endocrinology ◽

10.3389/fendo.2021.652675 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fiorenza Gianì ◽

Roberta Masto ◽

Maria Antonietta Trovato ◽

Annarita Franco ◽

Giuseppe Pandini ◽

...

Keyword(s):

Heavy Metals ◽

Thyroid Cancer ◽

Response Curve ◽

Living Cells ◽

Human Thyroid ◽

Target Cells ◽

Volcanic Area ◽

Thyroid Cells ◽

Biphasic Pattern ◽

Thyroid Cancer Incidence

Thyroid cancer incidence is markedly increased in volcanic areas where residents are biocontaminated by chronic lifelong exposure to slightly increased metals in the environment. Metals can influence the biology of living cells by a variety of mechanisms, depending not only on the dose and length of exposure but also on the type and stage of differentiation of target cells. We explored the effect of five heavy metals (Cu, Hg, Pd, W and Zn) at nanomolar concentrations (the biocontamination level in residents of the volcanic area in Sicily where thyroid cancer is increased) on stimulating the proliferation of undifferentiated (thyrospheres) and differentiated human thyroid cells. Thyrosphere proliferation was significantly increased after exposure to each individual metal and a greater stimulating effect was observed when a mixture of the examined metals was used. No effect was seen in differentiated thyrocytes. For all metals, the dose-response curve followed a biphasic pattern that is typical of hormesis. Thyrosphere growth concerned the size rather than number, except with the metal mixture. An altered morphology was also observed in metal-treated thyrospheres. Metal-induced proliferation was due to activation of the ERK1/2 pathway, as confirmed by growth inhibition when ERK1/2 signaling was blocked. These studies show that stem/precursor thyroid cells are sensitive to small increases in environmental metal concentrations that are harmless for differentiated thyrocytes.

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Formation of carcinogenic chromosomal rearrangements in human thyroid cells after induction of double-strand DNA breaks by restriction endonucleases

Endocrine Related Cancer ◽

10.1530/erc-11-0314 ◽

2012 ◽

Vol 19 (3) ◽

pp. 271-281 ◽

Cited By ~ 12

Author(s):

Viktoria Evdokimova ◽

Manoj Gandhi ◽

Jayanagendra Rayapureddi ◽

James R Stringer ◽

Yuri E Nikiforov

Keyword(s):

Thyroid Cancer ◽

Chromosomal Rearrangements ◽

Restriction Endonucleases ◽

Human Thyroid ◽

Fusion Partner ◽

Dependent Manner ◽

Dna Breaks ◽

Thyroid Cells ◽

Restriction Sites

Ionizing radiation (IR) exposure increases the risk of thyroid cancer and other cancer types. Chromosomal rearrangements, such asRET/PTC, are characteristic features of radiation-associated thyroid cancer and can be induced by radiationin vitro. IR causes double-strand breaks (DSBs), suggesting that such damage leads toRET/PTC, but the rearrangement mechanism has not been established. To study the mechanism, we explored the possibility of inducingRET/PTCby electroporation of restriction endonucleases (REs) into HTori-3 human thyroid cells. We used five REs, which induced DSB in a dose-dependent manner similar to that seen with IR. Although all but one RE caused DSB in one or more of the three genes involved inRET/PTC, rearrangement was detected only in cells electroporated with either PvuII (25 and 100 U) or StuI (100 and 250 U). The predominant rearrangement type wasRET/PTC3, which is characteristic of human thyroid cancer arising early after Chernobyl-related radioactive iodine exposure. Both enzymes that producedRET/PTChad restriction sites only in one of the two fusion partner genes. Moreover, the two enzymes that producedRET/PTChad restriction sites present in clusters, which was not the case for RE that failed to induceRET/PTC. In summary, we establish a model of DSB induction by RE and report for the first time the formation of carcinogenic chromosomal rearrangements, predominantlyRET/PTC3, as a result of DSB produced by RE. Our data also raise a possibility thatRET/PTCrearrangement can be initiated by a complex DSB that is induced in one of the fusion partner genes.

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Role of chemokine receptors in thyroid cancer and immunotherapy

Endocrine Related Cancer ◽

10.1530/erc-19-0163 ◽

2019 ◽

Vol 26 (8) ◽

pp. R465-R478 ◽

Cited By ~ 12

Author(s):

Francesca Coperchini ◽

Laura Croce ◽

Michele Marinò ◽

Luca Chiovato ◽

Mario Rotondi

Keyword(s):

Thyroid Cancer ◽

Tumor Microenvironment ◽

Chemokine Receptors ◽

Current Knowledge ◽

Biological Effects ◽

Biological Behavior ◽

Thyroid Cells

Inflammation is currently regarded as an essential component of malignancies. It is now known that the tumor microenvironment may profoundly influence the biological behavior of cancer cells and ultimately the patient’s outcome. Chemokine and their receptor play a major role in determining the immune phenotype of the cells infiltrating the thyroid tumor microenvironment. Experimental evidence shows that both normal and cancer thyroid cells express specific chemokine receptors. The expression of at least some of these receptors exerts several biological effects, which influence the course of the disease. The present review article will take into account the role of the most studied chemokine receptors (CXCR1, CXCR2, CXCR3, CXCR4, CXCR7, DARC, CCR3, CCR6 and CCR7) in the context of thyroid cancer. This review will focus on current knowledge provided by in vitro and in vivo studies specifically performed on thyroid cancer including (i) expression of chemokine receptors in normal and cancer thyroid cells; (ii) role of chemokine receptors in affecting the biological behavior of thyroid tumors including the metastatic process; (iii) current knowledge about immunotherapies through targeting of chemokine receptors in thyroid cancer.

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FOXE1-Dependent Regulation of Macrophage Chemotaxis by Thyroid Cells In Vitro and In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms22147666 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7666

Author(s):

Sara C. Credendino ◽

Marta De Menna ◽

Irene Cantone ◽

Carmen Moccia ◽

Matteo Esposito ◽

...

Keyword(s):

Thyroid Cancer ◽

Immune Cells ◽

Cancer Susceptibility ◽

Macrophage Infiltration ◽

M2 Macrophage ◽

Thyroid Cells ◽

Transcriptional Alterations ◽

Cancer Phenotypes

Forkhead box E1 (FOXE1) is a lineage-restricted transcription factor involved in thyroid cancer susceptibility. Cancer-associated polymorphisms map in regulatory regions, thus affecting the extent of gene expression. We have recently shown that genetic reduction of FOXE1 dosage modifies multiple thyroid cancer phenotypes. To identify relevant effectors playing roles in thyroid cancer development, here we analyse FOXE1-induced transcriptional alterations in thyroid cells that do not express endogenous FOXE1. Expression of FOXE1 elicits cell migration, while transcriptome analysis reveals that several immune cells-related categories are highly enriched in differentially expressed genes, including several upregulated chemokines involved in macrophage recruitment. Accordingly, FOXE1-expressing cells induce chemotaxis of co-cultured monocytes. We then asked if FOXE1 was able to regulate macrophage infiltration in thyroid cancers in vivo by using a mouse model of cancer, either wild type or with only one functional FOXE1 allele. Expression of the same set of chemokines directly correlates with FOXE1 dosage, and pro-tumourigenic M2 macrophage infiltration is decreased in tumours with reduced FOXE1. These data establish a novel link between FOXE1 and macrophages recruitment in the thyroid cancer microenvironment, highlighting an unsuspected function of this gene in the crosstalk between neoplastic and immune cells that shape tumour development and progression.

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In Vitro Culture of Human Thyroid Cells: Preliminary Findings on the Role of the Pathological Condition of the Donors

Alternatives to Laboratory Animals ◽

10.1177/026119299702500208 ◽

1997 ◽

Vol 25 (2) ◽

pp. 153-160

Author(s):

Francesca Mattioli ◽

Marianna Angiola ◽

Laura Fazzuoli ◽

Francesco Razzetta ◽

Antonietta Martelli

Keyword(s):

Pathological Condition ◽

Primary Cultures ◽

S Phase ◽

Human Thyroid ◽

Thyroid Cells ◽

Toxicological Studies ◽

Predictive Indicator

Although primary cultures of human thyroid cells are used for endocrinological and toxicological studies, until now no attention has been paid toward verifying whether the hormonal conditions to which the gland was exposed in vivo prior to surgery could influence in vitro responses. Our findings suggest that the hormonal situation in vivo cannot be used as a predictive indicator of triiodothyronine and thyroxine release and/or S-phase frequency in vitro, either with or without the addition of bovine thyrotropin.

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Trace Amine-Associated Receptor 1 Trafficking to Cilia of Thyroid Epithelial Cells

Cells ◽

10.3390/cells10061518 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1518

Author(s):

Maria Qatato ◽

Vaishnavi Venugopalan ◽

Alaa Al-Hashimi ◽

Maren Rehders ◽

Aaron D. Valentine ◽

...

Keyword(s):

Cell Surface ◽

Cell Lines ◽

Human Thyroid ◽

Apical Plasma Membrane ◽

Thyroid Cell ◽

Thyroid Cells ◽

Trace Amine ◽

Rat Thyroid

Trace amine-associated receptor 1 (rodent Taar1/human TAAR1) is a G protein-coupled receptor that is mainly recognized for its functions in neuromodulation. Previous in vitro studies suggested that Taar1 may signal from intracellular compartments. However, we have shown Taar1 to localize apically and on ciliary extensions in rodent thyrocytes, suggesting that at least in the thyroid, Taar1 may signal from the cilia at the apical plasma membrane domain of thyrocytes in situ, where it is exposed to the content of the follicle lumen containing putative Taar1 ligands. This study was designed to explore mouse Taar1 (mTaar1) trafficking, heterologously expressed in human and rat thyroid cell lines in order to establish an in vitro system in which Taar1 signaling from the cell surface can be studied in future. The results showed that chimeric mTaar1-EGFP traffics to the apical cell surface and localizes particularly to spherical structures of polarized thyroid cells, procilia, and primary cilia upon serum-starvation. Moreover, mTaar1-EGFP appears to form high molecular mass forms, possibly homodimers and tetramers, in stably expressing human thyroid cell lines. However, only monomeric mTaar1-EGFP was cell surface biotinylated in polarized human thyrocytes. In polarized rat thyrocytes, mTaar1-EGFP is retained in the endoplasmic reticulum, while cilia were reached by mTaar1-EGFP transiently co-expressed in combination with an HA-tagged construct of the related mTaar5. We conclude that Taar1 trafficking to cilia depends on their integrity. The results further suggest that an in vitro cell model was established that recapitulates Taar1 trafficking in thyrocytes in situ, in principle, and will enable studying Taar1 signaling in future, thus extending our general understanding of its potential significance for thyroid autoregulation.

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P III C.3 Cytogenetic analysis of the effect of p53 mutation on chromosome stability in an in vitro human thyroid cancer cell model system

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis ◽

10.1016/s0027-5107(97)82678-4 ◽

1997 ◽

Vol 379 (1) ◽

pp. S25

Author(s):

Elizabeth M. Parry ◽

Hakan Ulucan

Keyword(s):

Thyroid Cancer ◽

Cytogenetic Analysis ◽

Cell Model ◽

P53 Mutation ◽

Model System ◽

Human Thyroid ◽

Chromosome Stability ◽

Thyroid Cancer Cell ◽

Cell Model System

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An Engineered Heparin-Binding Form of VEGF-E (hbVEGF-E). Biological effects in vitro and mobilizatiion of precursor cells

Angiogenesis ◽

10.1023/b:agen.0000021391.88601.92 ◽

2003 ◽

Vol 6 (3) ◽

pp. 201-211 ◽

Cited By ~ 14

Author(s):

Matthias Heil ◽

Rita Mitnacht-Krauss ◽

Katja Issbrücker ◽

Joop van den Heuvel ◽

Christoph Dehio ◽

...

Keyword(s):

Biological Effects ◽

Precursor Cells ◽

Heparin Binding

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A systems biology approach reveals neuronal and muscle developmental defects after chronic exposure to ionising radiation in zebrafish

Scientific Reports ◽

10.1038/s41598-019-56590-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Sophia Murat El Houdigui ◽

Christelle Adam-Guillermin ◽

Giovanna Loro ◽

Caroline Arcanjo ◽

Sandrine Frelon ◽

...

Keyword(s):

Chronic Exposure ◽

Nuclear Power ◽

Muscle Development ◽

Low Dose ◽

Neuromuscular Junctions ◽

Biological Effects ◽

Cardiac Activity ◽

Developmental Defects ◽

Dose Rates ◽

Larval Behaviour

AbstractContamination of the environment after the Chernobyl and Fukushima Daiichi nuclear power plant (NPP) disasters led to the exposure of a large number of humans and wild animals to radioactive substances. However, the sub-lethal consequences induced by these absorbed radiological doses remain understudied and the long-term biological impacts largely unknown. We assessed the biological effects of chronic exposure to ionizing radiation (IR) on embryonic development by exposing zebrafish embryo from fertilization and up to 120 hours post-fertilization (hpf) at dose rates of 0.5 mGy/h, 5 mGy/h and 50 mGy/h, thereby encompassing the field of low dose rates defined at 6 mGy/h. Chronic exposure to IR altered larval behaviour in a light-dark locomotor test and affected cardiac activity at a dose rate as low as 0.5 mGy/h. The multi-omics analysis of transcriptome, proteome and transcription factor binding sites in the promoters of the deregulated genes, collectively points towards perturbations of neurogenesis, muscle development, and retinoic acid (RA) signaling after chronic exposure to IR. Whole-mount RNA in situ hybridization confirmed the impaired expression of the transcription factors her4.4 in the central nervous system and myogenin in the developing muscles of exposed embryos. At the organ level, the assessment of muscle histology by transmission electron microscopy (TEM) demonstrated myofibers disruption and altered neuromuscular junctions in exposed larvae at 5 mGy/h and 50 mGy/h. The integration of these multi-level data demonstrates that chronic exposure to low dose rates of IR has an impact on neuronal and muscle progenitor cells, that could lead to motility defects in free swimming larvae at 120 hpf. The mechanistic understanding of these effects allows us to propose a model where deregulation of RA signaling by chronic exposure to IR has pleiotropic effects on neurogenesis and muscle development.

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