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Special Issue "Current Knowledge in Thyroid Cancer—From Bench to Bedside"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2017)

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Guest Editor
Prof. Dr. Daniela Gabriele Grimm

Institute of Biomedicine, Aarhus University, Wilhelm Meyers Allé 4, 8000 Aarhus C, Denmark
Website | E-Mail
Interests: cancer research; thyroid disorders; molecular biology; cell biology; angiogenesis; pharmacology; apoptosis; immunology; proteomics; genomics; metabolomics

Special Issue Information

Dear Colleagues,

In recent years, studies in the field of thyroid cancer have been performed in order to identify and verify thyroid specific biomarkers, as well as cancer-specific changes in gene expression patterns and alterations of the protein content. Furthermore, new drugs, small molecules and antibodies were developed and tested in vitro and in vivo. Trials investigated the ratio between therapeutic and adverse effects. Tyrosine kinase inhibitors (TKI) have become a new therapeutic option of both differentiated thyroid cancer and medullary thyroid cancer. In the last few years, new substances for targeted systemic therapy have been approved after their efficacy was demonstrated in Phase III trials. Most of them show a moderate response. However, adverse effects are common. TKI are used in patients with advanced metastatic thyroid cancer that is radioiodine (RAI)-refractory.

In this Special Issue, original studies on the pathophysiology, diagnosis, and therapy of thyroid cancer, including genetics, proteomics, metabolomics, molecular and cell biology, will be published. It will also cover reports on patients, providing novel mechanistic insights into the underlying pathogenesis or new aspects that may impact clinical therapy, and recent study results in order to review the current status of new therapy options in thyroid cancer.

Prof. Daniela Gabriele Grimm
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Thyroid cancer
  • Tyrosine kinase inhibitors
  • In vitro studies
  • Clinical studies
  • Molecular biology
  • Biomarker
  • Pathway analyses
  • OMICS investigations

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Published Papers (17 papers)

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Editorial

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Open AccessEditorial Current Knowledge in Thyroid Cancer—From Bench to Bedside
Int. J. Mol. Sci. 2017, 18(7), 1529; doi:10.3390/ijms18071529
Received: 30 June 2017 / Revised: 12 July 2017 / Accepted: 14 July 2017 / Published: 15 July 2017
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Research

Jump to: Editorial, Review

Open AccessArticle Integrity and Quantity of Total Cell-Free DNA in the Diagnosis of Thyroid Cancer: Correlation with Cytological Classification
Int. J. Mol. Sci. 2017, 18(7), 1350; doi:10.3390/ijms18071350
Received: 18 May 2017 / Revised: 19 June 2017 / Accepted: 22 June 2017 / Published: 24 June 2017
Cited by 1 | PDF Full-text (809 KB) | HTML Full-text | XML Full-text
Abstract
Cell-free DNA (cfDNA) quantity and quality in plasma has been investigated as a non-invasive biomarker in cancer. Previous studies have demonstrated increased cfDNA amount and length in different types of cancer with respect to healthy controls. The present study aims to test the
[...] Read more.
Cell-free DNA (cfDNA) quantity and quality in plasma has been investigated as a non-invasive biomarker in cancer. Previous studies have demonstrated increased cfDNA amount and length in different types of cancer with respect to healthy controls. The present study aims to test the hypothesis that the presence of longer DNA strands circulating in plasma can be considered a biomarker for tumor presence in thyroid cancer. We adopted a quantitative real-time PCR (qPCR) approach based on the quantification of two amplicons of different length (67 and 180 bp respectively) to evaluate the integrity index 180/67. Cell-free DNA quantity and integrity were higher in patients affected by nodular thyroid diseases than in healthy controls. Importantly, cfDNA integrity index was higher in patients with cytological diagnosis of thyroid carcinoma (Thy4/Thy5) than in subjects with benign nodules (Thy2). Therefore, cfDNA integrity index 180/67 is a suitable parameter for monitoring cfDNA fragmentation in thyroid cancer patients and a promising circulating biomarker in the diagnosis of thyroid nodules. Full article
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Open AccessArticle Gene Expression (mRNA) Markers for Differentiating between Malignant and Benign Follicular Thyroid Tumours
Int. J. Mol. Sci. 2017, 18(6), 1184; doi:10.3390/ijms18061184
Received: 3 April 2017 / Revised: 26 May 2017 / Accepted: 28 May 2017 / Published: 2 June 2017
Cited by 1 | PDF Full-text (2372 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Distinguishing between follicular thyroid cancer (FTC) and follicular thyroid adenoma (FTA) constitutes a long-standing diagnostic problem resulting in equivocal histopathological diagnoses. There is therefore a need for additional molecular markers. To identify molecular differences between FTC and FTA, we analyzed the gene expression
[...] Read more.
Distinguishing between follicular thyroid cancer (FTC) and follicular thyroid adenoma (FTA) constitutes a long-standing diagnostic problem resulting in equivocal histopathological diagnoses. There is therefore a need for additional molecular markers. To identify molecular differences between FTC and FTA, we analyzed the gene expression microarray data of 52 follicular neoplasms. We also performed a meta-analysis involving 14 studies employing high throughput methods (365 follicular neoplasms analyzed). Based on these two analyses, we selected 18 genes differentially expressed between FTA and FTC. We validated them by quantitative real-time polymerase chain reaction (qRT-PCR) in an independent set of 71 follicular neoplasms from formaldehyde-fixed paraffin embedded (FFPE) tissue material. We confirmed differential expression for 7 genes (CPQ, PLVAP, TFF3, ACVRL1, ZFYVE21, FAM189A2, and CLEC3B). Finally, we created a classifier that distinguished between FTC and FTA with an accuracy of 78%, sensitivity of 76%, and specificity of 80%, based on the expression of 4 genes (CPQ, PLVAP, TFF3, ACVRL1). In our study, we have demonstrated that meta-analysis is a valuable method for selecting possible molecular markers. Based on our results, we conclude that there might exist a plausible limit of gene classifier accuracy of approximately 80%, when follicular tumors are discriminated based on formalin-fixed postoperative material. Full article
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Open AccessArticle Histogram Analysis of Diffusion Weighted Imaging at 3T is Useful for Prediction of Lymphatic Metastatic Spread, Proliferative Activity, and Cellularity in Thyroid Cancer
Int. J. Mol. Sci. 2017, 18(4), 821; doi:10.3390/ijms18040821
Received: 9 March 2017 / Revised: 9 April 2017 / Accepted: 10 April 2017 / Published: 12 April 2017
Cited by 3 | PDF Full-text (5781 KB) | HTML Full-text | XML Full-text
Abstract
Pre-surgical diffusion weighted imaging (DWI) is increasingly important in the context of thyroid cancer for identification of the optimal treatment strategy. It has exemplarily been shown that DWI at 3T can distinguish undifferentiated from well-differentiated thyroid carcinoma, which has decisive implications for the
[...] Read more.
Pre-surgical diffusion weighted imaging (DWI) is increasingly important in the context of thyroid cancer for identification of the optimal treatment strategy. It has exemplarily been shown that DWI at 3T can distinguish undifferentiated from well-differentiated thyroid carcinoma, which has decisive implications for the magnitude of surgery. This study used DWI histogram analysis of whole tumor apparent diffusion coefficient (ADC) maps. The primary aim was to discriminate thyroid carcinomas which had already gained the capacity to metastasize lymphatically from those not yet being able to spread via the lymphatic system. The secondary aim was to reflect prognostically important tumor-biological features like cellularity and proliferative activity with ADC histogram analysis. Fifteen patients with follicular-cell derived thyroid cancer were enrolled. Lymph node status, extent of infiltration of surrounding tissue, and Ki-67 and p53 expression were assessed in these patients. DWI was obtained in a 3T system using b values of 0, 400, and 800 s/mm2. Whole tumor ADC volumes were analyzed using a histogram-based approach. Several ADC parameters showed significant correlations with immunohistopathological parameters. Most importantly, ADC histogram skewness and ADC histogram kurtosis were able to differentiate between nodal negative and nodal positive thyroid carcinoma. Conclusions: histogram analysis of whole ADC tumor volumes has the potential to provide valuable information on tumor biology in thyroid carcinoma. However, further studies are warranted. Full article
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Open AccessArticle Diagnostic Limitation of Fine-Needle Aspiration (FNA) on Indeterminate Thyroid Nodules Can Be Partially Overcome by Preoperative Molecular Analysis: Assessment of RET/PTC1 Rearrangement in BRAF and RAS Wild-Type Routine Air-Dried FNA Specimens
Int. J. Mol. Sci. 2017, 18(4), 806; doi:10.3390/ijms18040806
Received: 21 February 2017 / Revised: 28 March 2017 / Accepted: 7 April 2017 / Published: 12 April 2017
Cited by 1 | PDF Full-text (477 KB) | HTML Full-text | XML Full-text
Abstract
Molecular markers are helpful diagnostic tools, particularly for cytologically indeterminate thyroid nodules. Preoperative RET/PTC1 rearrangement analysis in BRAF and RAS wild-type indeterminate thyroid nodules would permit the formulation of an unambiguous surgical plan. Cycle threshold values according to the cell count for detection
[...] Read more.
Molecular markers are helpful diagnostic tools, particularly for cytologically indeterminate thyroid nodules. Preoperative RET/PTC1 rearrangement analysis in BRAF and RAS wild-type indeterminate thyroid nodules would permit the formulation of an unambiguous surgical plan. Cycle threshold values according to the cell count for detection of the RET/PTC1 rearrangement by real-time reverse transcription-polymerase chain reaction (RT-PCR) using fresh and routine air-dried TPC1 cells were evaluated. The correlation of RET/PTC1 rearrangement between fine-needle aspiration (FNA) and paired formalin-fixed paraffin-embedded (FFPE) specimens was analyzed. RET/PTC1 rearrangements of 76 resected BRAF and RAS wild-type classical PTCs were also analyzed. Results of RT-PCR and the Nanostring were compared. When 100 fresh and air-dried TPC1 cells were used, expression of RET/PTC1 rearrangement was detectable after 35 and 33 PCR cycles, respectively. The results of RET/PTC1 rearrangement in 10 FNA and paired FFPE papillary thyroid carcinoma (PTC) specimens showed complete correlation. Twenty-nine (38.2%) of 76 BRAF and RAS wild-type classical PTCs had RET/PTC1 rearrangement. Comparison of RET/PTC1 rearrangement analysis between RT-PCR and the Nanostring showed moderate agreement with a κ value of 0.56 (p = 0.002). The RET/PTC1 rearrangement analysis by RT-PCR using routine air-dried FNA specimen was confirmed to be technically applicable. A significant proportion (38.2%) of the BRAF and RAS wild-type PTCs harbored RET/PTC1 rearrangements. Full article
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Open AccessCommunication Proteome Analysis of Human Follicular Thyroid Cancer Cells Exposed to the Random Positioning Machine
Int. J. Mol. Sci. 2017, 18(3), 546; doi:10.3390/ijms18030546
Received: 26 October 2016 / Revised: 27 February 2017 / Accepted: 27 February 2017 / Published: 3 March 2017
Cited by 1 | PDF Full-text (3582 KB) | HTML Full-text | XML Full-text
Abstract
Several years ago, we detected the formation of multicellular spheroids in experiments with human thyroid cancer cells cultured on the Random Positioning Machine (RPM), a ground-based model to simulate microgravity by continuously changing the orientation of samples. Since then, we have studied cellular
[...] Read more.
Several years ago, we detected the formation of multicellular spheroids in experiments with human thyroid cancer cells cultured on the Random Positioning Machine (RPM), a ground-based model to simulate microgravity by continuously changing the orientation of samples. Since then, we have studied cellular mechanisms triggering the cells to leave a monolayer and aggregate to spheroids. Our work focused on spheroid-related changes in gene expression patterns, in protein concentrations, and in factors secreted to the culture supernatant during the period when growth is altered. We detected that factors inducing angiogenesis, the composition of integrins, the density of the cell monolayer exposed to microgravity, the enhanced production of caveolin-1, and the nuclear factor kappa B p65 could play a role during spheroid formation in thyroid cancer cells. In this study, we performed a deep proteome analysis on FTC-133 thyroid cancer cells cultured under conditions designed to encourage or discourage spheroid formation. The experiments revealed more than 5900 proteins. Their evaluation confirmed and explained the observations mentioned above. In addition, we learned that FTC-133 cells growing in monolayers or in spheroids after RPM-exposure incorporate vinculin, paxillin, focal adhesion kinase 1, and adenine diphosphate (ADP)-ribosylation factor 6 in different ways into the focal adhesion complex. Full article
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Open AccessArticle HER2 Analysis in Sporadic Thyroid Cancer of Follicular Cell Origin
Int. J. Mol. Sci. 2016, 17(12), 2040; doi:10.3390/ijms17122040
Received: 7 November 2016 / Revised: 28 November 2016 / Accepted: 30 November 2016 / Published: 6 December 2016
Cited by 1 | PDF Full-text (7177 KB) | HTML Full-text | XML Full-text
Abstract
The Epidermal Growth Factor Receoptor (EGFR) family member human epidermal growth factor receptor 2 (HER2) is overexpressed in many human epithelial malignancies, representing a molecular target for specific anti-neoplastic drugs. Few data are available on HER2 status in differentiated thyroid cancer (DTC). The
[...] Read more.
The Epidermal Growth Factor Receoptor (EGFR) family member human epidermal growth factor receptor 2 (HER2) is overexpressed in many human epithelial malignancies, representing a molecular target for specific anti-neoplastic drugs. Few data are available on HER2 status in differentiated thyroid cancer (DTC). The present study was aimed to investigate HER2 status in sporadic cancers of follicular cell origin to better clarify the role of this receptor in the stratification of thyroid cancer. By immunohistochemistry and fluorescence in-situ hybridization, HER2 expression was investigated in formalin-fixed paraffin-embedded surgical specimens from 90 DTC patients, 45 follicular (FTC) and 45 papillary (PTC) histotypes. No HER2 immunostaining was recorded in background thyroid tissue. By contrast, overall HER2 overexpression was found in 20/45 (44%) FTC and 8/45 (18%) PTC, with a significant difference between the two histotypes (p = 0.046). Five of the six patients who developed metastatic disease during a median nine-year follow-up had a HER2-positive tumor. Therefore, we suggest that HER2 expression may represent an additional aid to identify a subset of patients who are characterized by a worse prognosis and are potentially eligible for targeted therapy. Full article
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Open AccessArticle Genetic Heterogeneity of HER2 Amplification and Telomere Shortening in Papillary Thyroid Carcinoma
Int. J. Mol. Sci. 2016, 17(10), 1759; doi:10.3390/ijms17101759
Received: 4 August 2016 / Revised: 20 September 2016 / Accepted: 12 October 2016 / Published: 21 October 2016
Cited by 2 | PDF Full-text (2121 KB) | HTML Full-text | XML Full-text
Abstract
Extensive research is dedicated to understanding if sporadic and familial papillary thyroid carcinoma are distinct biological entities. We have previously demonstrated that familial papillary thyroid cancer (fPTC) cells exhibit short relative telomere length (RTL) in both blood and tissues and that these features
[...] Read more.
Extensive research is dedicated to understanding if sporadic and familial papillary thyroid carcinoma are distinct biological entities. We have previously demonstrated that familial papillary thyroid cancer (fPTC) cells exhibit short relative telomere length (RTL) in both blood and tissues and that these features may be associated with chromosome instability. Here, we investigated the frequency of HER2 (Human Epidermal Growth Factor Receptor 2) amplification, and other recently reported genetic alterations in sporadic PTC (sPTC) and fPTC, and assessed correlations with RTL and BRAF mutational status. We analyzed HER2 gene amplification and the integrity of ALK, ETV6, RET, and BRAF genes by fluorescence in situ hybridization in isolated nuclei and paraffin-embedded formalin-fixed sections of 13 fPTC and 18 sPTC patients. We analyzed BRAFV600E mutation and RTL by qRT-PCR. Significant HER2 amplification (p = 0.0076), which was restricted to scattered groups of cells, was found in fPTC samples. HER2 amplification in fPTCs was invariably associated with BRAFV600E mutation. RTL was shorter in fPTCs than sPTCs (p < 0.001). No rearrangements of other tested genes were observed. These findings suggest that the association of HER2 amplification with BRAFV600E mutation and telomere shortening may represent a marker of tumor aggressiveness, and, in refractory thyroid cancer, may warrant exploration as a site for targeted therapy. Full article
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Open AccessArticle A Comprehensive Characterization of Mitochondrial Genome in Papillary Thyroid Cancer
Int. J. Mol. Sci. 2016, 17(10), 1594; doi:10.3390/ijms17101594
Received: 5 July 2016 / Revised: 17 August 2016 / Accepted: 8 September 2016 / Published: 10 October 2016
Cited by 1 | PDF Full-text (4337 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Nuclear genetic alterations have been widely investigated in papillary thyroid cancer (PTC), however, the characteristics of the mitochondrial genome remain uncertain. We sequenced the entire mitochondrial genome of 66 PTCs, 16 normal thyroid tissues and 376 blood samples of healthy individuals. There were
[...] Read more.
Nuclear genetic alterations have been widely investigated in papillary thyroid cancer (PTC), however, the characteristics of the mitochondrial genome remain uncertain. We sequenced the entire mitochondrial genome of 66 PTCs, 16 normal thyroid tissues and 376 blood samples of healthy individuals. There were 2508 variations (543 sites) detected in PTCs, among which 33 variations were novel. Nearly half of the PTCs (31/66) had heteroplasmic variations. Among the 31 PTCs, 28 specimens harbored a total of 52 somatic mutations distributed in 44 sites. Thirty-three variations including seven nonsense, 11 frameshift and 15 non-synonymous variations selected by bioinformatic software were regarded as pathogenic. These 33 pathogenic mutations were associated with older age (p = 0.0176) and advanced tumor stage (p = 0.0218). In addition, they tended to be novel (p = 0.0003), heteroplasmic (p = 0.0343) and somatic (p = 0.0018). The mtDNA copy number increased in more than two-third (46/66) of PTCs, and the average content in tumors was nearly four times higher than that in adjacent normal tissues (p < 0.0001). Three sub-haplogroups of N (A4, B4a and B4g) and eight single-nucleotide polymorphisms (mtSNPs) (A16164G, C16266T, G5460A, T6680C, G9123A, A14587G, T16362C, and G709A) were associated with the occurrence of PTC. Here we report a comprehensive characterization of the mitochondrial genome and demonstrate its significance in pathogenesis and progression of PTC. This can help to clarify the molecular mechanisms underlying PTC and offer potential biomarkers or therapeutic targets for future clinical practice. Full article
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Open AccessArticle TNFSF4 Gene Variations Are Related to Early-Onset Autoimmune Thyroid Diseases and Hypothyroidism of Hashimoto’s Thyroiditis
Int. J. Mol. Sci. 2016, 17(8), 1369; doi:10.3390/ijms17081369
Received: 10 July 2016 / Revised: 14 August 2016 / Accepted: 16 August 2016 / Published: 20 August 2016
Cited by 2 | PDF Full-text (392 KB) | HTML Full-text | XML Full-text
Abstract
The aim of the current study was to examine whether the polymorphism loci of the tumor necrosis factor superfamily member 4 (TNFSF4) gene increase the risk of susceptibility to autoimmune thyroid diseases (AITDs) in the Han Chinese population, and a case-control
[...] Read more.
The aim of the current study was to examine whether the polymorphism loci of the tumor necrosis factor superfamily member 4 (TNFSF4) gene increase the risk of susceptibility to autoimmune thyroid diseases (AITDs) in the Han Chinese population, and a case-control study was performed in a set of 1,048 AITDs patients and 909 normal healthy controls in the study. A total of four tagging single nucleotide polymorphisms (SNPs) in the TNFSF4 region, including rs7514229, rs1234313, rs16845607 and rs3850641, were genotyped using the method of ligase detection reaction. An association between GG genotype of rs3850641 in TNFSF4 gene and AITDs was found (p = 0.046). Additionally, the clinical sub-phenotype analysis revealed a significant association between GG genotype in rs7514229 and AITDs patients who were ≤18 years of age. Furthermore, rs3850641 variant allele G was in strong association with hypothyroidism in Hashimoto’s thyroiditis (HT) (p = 0.018). The polymorphisms of the TNFSF4 gene may contribute to the susceptibility to AITDs pathogenesis. Full article
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Open AccessArticle Expression of Tenascin C, EGFR, E-Cadherin, and TTF-1 in Medullary Thyroid Carcinoma and the Correlation with RET Mutation Status
Int. J. Mol. Sci. 2016, 17(7), 1093; doi:10.3390/ijms17071093
Received: 15 May 2016 / Revised: 21 June 2016 / Accepted: 24 June 2016 / Published: 9 July 2016
Cited by 2 | PDF Full-text (1790 KB) | HTML Full-text | XML Full-text
Abstract
Tenascin C expression correlates with tumor grade and indicates worse prognosis in several tumors. Epidermal growth factor receptor (EGFR) plays an important role in driving proliferation in many tumors. Loss of E-cadherin function is associated with tumor invasion and metastasis. Thyroid transcription factor-1
[...] Read more.
Tenascin C expression correlates with tumor grade and indicates worse prognosis in several tumors. Epidermal growth factor receptor (EGFR) plays an important role in driving proliferation in many tumors. Loss of E-cadherin function is associated with tumor invasion and metastasis. Thyroid transcription factor-1 (TTF-1) is involved in rearranged during transfection (RET) transcription in Hirschsprung’s disease. Tenascin C, EGFR, E-cadherin, TTF-1-expression, and their correlations with RET mutation status were investigated in 30 patients with medullary thyroid carcinoma (MTC) (n = 26) or C-cell hyperplasia (n = 4). Tenascin C was found in all, EGFR in 4/26, E-cadherin in 23/26, and TTF-1 in 25/26 MTC. Tenascin C correlated significantly with tumor proliferation (overall, r = 0.61, p < 0.005; RET-mutated, r = 0.81, p < 0.01). E-cadherin showed weak correlation, whereas EGFR and TTF-1 showed no significant correlation with tumor proliferation. EGFR, E-cadherin, and TTF-1 showed weak correlation with proliferation of RET-mutated tumors. Correlation between TTF-1 and tenascin C, E-cadherin, and EGFR was r = −0.10, 0.37, and 0.21, respectively. In conclusion, MTC express tenascin C, E-cadherin, and TTF-1. Tenascin C correlates significantly with tumor proliferation, especially in RET-mutated tumors. EGFR is low, and tumors expressing EGFR do not exhibit higher proliferation. TTF-1 does not correlate with RET mutation status and has a weak correlation with tenascin C, E-cadherin, and EGFR expression. Full article

Review

Jump to: Editorial, Research

Open AccessReview New Insights in Thyroid Cancer and p53 Family Proteins
Int. J. Mol. Sci. 2017, 18(6), 1325; doi:10.3390/ijms18061325
Received: 10 April 2017 / Revised: 16 June 2017 / Accepted: 17 June 2017 / Published: 21 June 2017
Cited by 1 | PDF Full-text (1794 KB) | HTML Full-text | XML Full-text
Abstract
Thyroid cancers are common endocrine malignancies that comprise tumors with different clinical and histological features. Indeed, papillary and follicular thyroid cancers are slow-growing, well-differentiated tumors, whereas anaplastic thyroid cancers are undifferentiated neoplasias that behave much more aggressively. Well-differentiated thyroid carcinomas are efficiently cured
[...] Read more.
Thyroid cancers are common endocrine malignancies that comprise tumors with different clinical and histological features. Indeed, papillary and follicular thyroid cancers are slow-growing, well-differentiated tumors, whereas anaplastic thyroid cancers are undifferentiated neoplasias that behave much more aggressively. Well-differentiated thyroid carcinomas are efficiently cured by surgery and radioiodine, unlike undifferentiated tumors that fail to uptake radioactive iodine and are usually resistant to chemotherapy. Therefore, novel and more effective therapies for these aggressive neoplasias are urgently needed. Whereas most genetic events underlying the pathogenesis of well-differentiated thyroid cancers have been identified, the molecular mechanisms that generate undifferentiated thyroid carcinomas are still unclear. To date, one of the best-characterized genetic alterations leading to the development of poorly differentiated thyroid tumors is the loss of the p53 tumor suppressor gene. In addition, the existence of a complex network among p53 family members (p63 and p73) and their interactions with other factors that promote thyroid cancer progression has been well documented. In this review, we provide an update on the current knowledge of the role of p53 family proteins in thyroid cancer and their possible use as a therapeutic target for the treatment of the most aggressive variants of this disease. Full article
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Open AccessReview Differentiated Thyroid Cancer—Treatment: State of the Art
Int. J. Mol. Sci. 2017, 18(6), 1292; doi:10.3390/ijms18061292
Received: 6 April 2017 / Revised: 5 June 2017 / Accepted: 5 June 2017 / Published: 17 June 2017
Cited by 3 | PDF Full-text (617 KB) | HTML Full-text | XML Full-text
Abstract
Differentiated thyroid cancer (DTC) is a rare malignant disease, although its incidence has increased over the last few decades. It derives from follicular thyroid cells. Generally speaking, the prognosis is excellent. If treatment according to the current guidelines is given, cases of recurrence
[...] Read more.
Differentiated thyroid cancer (DTC) is a rare malignant disease, although its incidence has increased over the last few decades. It derives from follicular thyroid cells. Generally speaking, the prognosis is excellent. If treatment according to the current guidelines is given, cases of recurrence or persistence are rare. DTC requires special expertise by the treating physician. In recent years, new therapeutic options for these patients have become available. For this article we performed a systematic literature review with special focus on the guidelines of the American Thyroid Association, the European Association of Nuclear Medicine, and the German Society of Nuclear Medicine. For DTC, surgery and radioiodine therapy followed by levothyroxine substitution remain the established therapeutic procedures. Even metastasized tumors can be cured this way. However, in rare cases of radioiodine-refractory tumors, additional options are to be discussed. These include strict suppression of thyroid-stimulating hormone (also known as thyrotropin, TSH) and external local radiotherapy. Systemic cytostatic chemotherapy does not play a significant role. Recently, multikinase or tyrosine kinase inhibitors have been approved for the treatment of radioiodine-refractory DTC. Although a benefit for overall survival has not been shown yet, these new drugs can slow down tumor progression. However, they are frequently associated with severe side effects and should be reserved for patients with threatening symptoms only. Full article
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Open AccessReview Impact of Gravity on Thyroid Cells
Int. J. Mol. Sci. 2017, 18(5), 972; doi:10.3390/ijms18050972
Received: 30 March 2017 / Revised: 27 April 2017 / Accepted: 28 April 2017 / Published: 4 May 2017
Cited by 2 | PDF Full-text (1374 KB) | HTML Full-text | XML Full-text
Abstract
Physical and mental health requires a correct functioning of the thyroid gland, which controls cardiovascular, musculoskeletal, nervous, and immune systems, and affects behavior and cognitive functions. Microgravity, as occurs during space missions, induces morphological and functional changes within the thyroid gland. Here, we
[...] Read more.
Physical and mental health requires a correct functioning of the thyroid gland, which controls cardiovascular, musculoskeletal, nervous, and immune systems, and affects behavior and cognitive functions. Microgravity, as occurs during space missions, induces morphological and functional changes within the thyroid gland. Here, we review relevant experiments exposing cell cultures (normal and cancer thyroid cells) to simulated and real microgravity, as well as wild-type and transgenic mice to hypergravity and spaceflight conditions. Well-known mechanisms of damage are presented and new ones, such as changes of gene expression for extracellular matrix and cytoskeleton proteins, thyrocyte phenotype, sensitivity of thyrocytes to thyrotropin due to thyrotropin receptor modification, parafollicular cells and calcitonin production, sphingomyelin metabolism, and the expression and movement of cancer molecules from thyrocytes to colloids are highlighted. The identification of new mechanisms of thyroid injury is essential for the development of countermeasures, both on the ground and in space, against thyroid cancer. We also address the question whether normal and cancer cells show a different sensitivity concerning changes of environmental conditions. Full article
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Open AccessReview Radiation and Thyroid Cancer
Int. J. Mol. Sci. 2017, 18(5), 911; doi:10.3390/ijms18050911
Received: 17 February 2017 / Revised: 11 April 2017 / Accepted: 24 April 2017 / Published: 26 April 2017
Cited by 2 | PDF Full-text (844 KB) | HTML Full-text | XML Full-text
Abstract
Radiation-induced damage is a complex network of interlinked signaling pathways, which may result in apoptosis, cell cycle arrest, DNA repair, and cancer. The development of thyroid cancer in response to radiation, from nuclear catastrophes to chemotherapy, has long been an object of study.
[...] Read more.
Radiation-induced damage is a complex network of interlinked signaling pathways, which may result in apoptosis, cell cycle arrest, DNA repair, and cancer. The development of thyroid cancer in response to radiation, from nuclear catastrophes to chemotherapy, has long been an object of study. A basic overview of the ionizing and non-ionizing radiation effects of the sensitivity of the thyroid gland on radiation and cancer development has been provided. In this review, we focus our attention on experiments in cell cultures exposed to ionizing radiation, ultraviolet light, and proton beams. Studies on the involvement of specific genes, proteins, and lipids are also reported. This review also describes how lipids are regulated in response to the radiation-induced damage and how they are involved in thyroid cancer etiology, invasion, and migration and how they can be used as both diagnostic markers and drug targets. Full article
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Open AccessReview Molecular Signature of Indeterminate Thyroid Lesions: Current Methods to Improve Fine Needle Aspiration Cytology (FNAC) Diagnosis
Int. J. Mol. Sci. 2017, 18(4), 775; doi:10.3390/ijms18040775
Received: 15 March 2017 / Revised: 29 March 2017 / Accepted: 3 April 2017 / Published: 6 April 2017
Cited by 1 | PDF Full-text (237 KB) | HTML Full-text | XML Full-text
Abstract
Fine needle aspiration cytology (FNAC) represents the gold standard for determining the nature of thyroid nodules. It is a reliable method with good sensitivity and specificity. However, indeterminate lesions remain a diagnostic challenge and researchers have contributed molecular markers to search for in
[...] Read more.
Fine needle aspiration cytology (FNAC) represents the gold standard for determining the nature of thyroid nodules. It is a reliable method with good sensitivity and specificity. However, indeterminate lesions remain a diagnostic challenge and researchers have contributed molecular markers to search for in cytological material to refine FNAC diagnosis and avoid unnecessary surgeries. Nowadays, several “home-made” methods as well as commercial tests are available to investigate the molecular signature of an aspirate. Moreover, other markers (i.e., microRNA, and circulating tumor cells) have been proposed to discriminate benign from malignant thyroid lesions. Here, we review the literature and provide data from our laboratory on mutational analysis of FNAC material and circulating microRNA expression obtained in the last 6 years. Full article
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Open AccessReview The Adverse Effect of Hypertension in the Treatment of Thyroid Cancer with Multi-Kinase Inhibitors
Int. J. Mol. Sci. 2017, 18(3), 625; doi:10.3390/ijms18030625
Received: 16 January 2017 / Revised: 7 March 2017 / Accepted: 9 March 2017 / Published: 14 March 2017
Cited by 4 | PDF Full-text (1050 KB) | HTML Full-text | XML Full-text
Abstract
The treatment of thyroid cancer has promising prospects, mostly through the use of surgical or radioactive iodine therapy. However, some thyroid cancers, such as progressive radioactive iodine-refractory differentiated thyroid carcinoma, are not remediable with conventional types of treatment. In these cases, a treatment
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The treatment of thyroid cancer has promising prospects, mostly through the use of surgical or radioactive iodine therapy. However, some thyroid cancers, such as progressive radioactive iodine-refractory differentiated thyroid carcinoma, are not remediable with conventional types of treatment. In these cases, a treatment regimen with multi-kinase inhibitors is advisable. Unfortunately, clinical trials have shown a large number of patients, treated with multi-kinase inhibitors, being adversely affected by hypertension. This means that treatment of thyroid cancer with multi-kinase inhibitors prolongs progression-free and overall survival of patients, but a large number of patients experience hypertension as an adverse effect of the treatment. Whether the prolonged lifetime is sufficient to develop sequelae from hypertension is unclear, but late-stage cancer patients often have additional diseases, which can be complicated by the presence of hypertension. Since the exact mechanisms of the rise of hypertension in these patients are still unknown, the only available strategy is treating the symptoms. More studies determining the pathogenesis of hypertension as a side effect to cancer treatment as well as outcomes of dose management of cancer drugs are necessary to improve future therapy options for hypertension as an adverse effect to cancer therapy with multi-kinase inhibitors. Full article
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