Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Cell and Molecular Biology of Thyroid Disorders 2.0

Special Issue Editors
Special Issue Information
Keywords
Related Special Issue
Published Papers

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 (30 November 2020) | Viewed by 54439

Share This Special Issue

Special Issue Editor

Dr. Daniela Grimm

E-Mail Website
Guest Editor

1. Institute of Biomedicine, Aarhus University, Ole Worms Allé 4, 8000 Aarhus, Denmark
2. Department of Microgravity and Translational Regenerative Medicine, Otto von Guericke University Magdeburg, Pfälzerplatz 2, 39106 Magdeburg, Germany
Interests: breast cancer; thyroid cancer; prostate cancer; cell biology; gravitational biology; space medicine; tissue engineering; pharmacology; apoptosis; SOX transcription factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second volume of our previous Special Issue, “Cell and Molecular Biology of Thyroid Disorders”. The proper function of the thyroid gland and its cells is of the highest importance for our health. Very often, an iodine deficiency causes a malfunction of the thyroid and plays a role in carcinogenesis. Both hyperthyroidism and hypothyroidism have detrimental effects on our bodies.

The main topic of this Special Issue is the cell and molecular biology of thyroid disorders. There has been exciting progress in understanding the molecular mechanisms of thyroid diseases.

A special focus of volume 2 will be thyroid cancer. Molecular alterations represent novel diagnostic and prognostic molecular markers and therapeutic targets for thyroid cancer. Specific biomarkers and cancer-specific changes in gene expression patterns and alterations of the protein content have been identified. Original studies on the pathophysiology, diagnosis, and therapy of thyroid cancer, including genetics, proteomics, metabolomics, molecular, and cell biology, are welcome.

It will also cover clinical studies, providing novel mechanistic insights into the underlying pathogenesis or new aspects that may impact clinical therapy, as well as recent study results in order to review the current status of new therapy options in thyroid cancer.

Dr. Daniela Grimm
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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 semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 diseases
Thyroid Cancer
Cell Biology
Cell Signaling
Iodine deficiency
Apoptosis
Biomarker
Proteomics

Related Special Issue

Cell and Molecular Biology of Thyroid Disorders in International Journal of Molecular Sciences (19 articles)

Published Papers (13 papers)

Download All Papers

Editorial

Jump to: Research, Review

6 pages, 232 KiB

Open AccessEditorial

Cell and Molecular Biology of Thyroid Disorders 2.0

by Daniela Grimm

Int. J. Mol. Sci. 2021, 22(4), 1990; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041990 - 17 Feb 2021

Cited by 2 | Viewed by 1760

Abstract

This issue is the second volume of the previous Special Issue, “Cell and Molecular Biology of Thyroid Disorders” [...] Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

Research

Jump to: Editorial, Review

9 pages, 11378 KiB

Open AccessArticle

FOXE1 Gene Dosage Affects Thyroid Cancer Histology and Differentiation In Vivo

by Sara C. Credendino, Carmen Moccia, Elena Amendola, Giuliana D’Avino, Luigi Di Guida, Eduardo Clery, Adelaide Greco, Claudio Bellevicine, Arturo Brunetti, Mario De Felice and Gabriella De Vita

Int. J. Mol. Sci. 2021, 22(1), 25; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010025 - 22 Dec 2020

Cited by 11 | Viewed by 2182

Abstract

The transcription factor Forkhead box E1 (FOXE1) is a key player in thyroid development and function and has been identified by genome-wide association studies as a susceptibility gene for papillary thyroid cancer. Several cancer-associated polymorphisms fall into gene regulatory regions and are likely to affect FOXE1 expression levels. However, the possibility that changes in FOXE1 expression modulate thyroid cancer development has not been investigated. Here, we describe the effects of FOXE1 gene dosage reduction on cancer phenotype in vivo. Mice heterozygous for FOXE1 null allele (FOXE1^+/−) were crossed with a BRAF^V600E-inducible cancer model to develop thyroid cancer in either a FOXE1^+/+ or FOXE1^+/− genetic background. In FOXE1^+/+ mice, cancer histological features are quite similar to that of human high-grade papillary thyroid carcinomas, while cancers developed with reduced FOXE1 gene dosage maintain morphological features resembling less malignant thyroid cancers, showing reduced proliferation index and increased apoptosis as well. Such cancers, however, appear severely undifferentiated, indicating that FOXE1 levels affect thyroid differentiation during neoplastic transformation. These results show that FOXE1 dosage exerts pleiotropic effects on thyroid cancer phenotype by affecting histology and regulating key markers of tumor differentiation and progression, thus suggesting the possibility that FOXE1 could behave as lineage-specific oncogene in follicular cell-derived thyroid cancer. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Figure 1

22 pages, 523 KiB

Open AccessArticle

Differences in Gene Expression Profile of Primary Tumors in Metastatic and Non-Metastatic Papillary Thyroid Carcinoma—Do They Exist?

by Sylwia Szpak-Ulczok, Aleksandra Pfeifer, Dagmara Rusinek, Malgorzata Oczko-Wojciechowska, Malgorzata Kowalska, Tomasz Tyszkiewicz, Marta Cieslicka, Daria Handkiewicz-Junak, Krzysztof Fujarewicz, Dariusz Lange, Ewa Chmielik, Ewa Zembala-Nozynska, Sebastian Student, Agnieszka Kotecka-Blicharz, Aneta Kluczewska-Galka, Barbara Jarzab, Agnieszka Czarniecka, Michal Jarzab and Jolanta Krajewska

Int. J. Mol. Sci. 2020, 21(13), 4629; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134629 - 29 Jun 2020

Cited by 5 | Viewed by 2618

Abstract

Molecular mechanisms of distant metastases (M1) in papillary thyroid cancer (PTC) are poorly understood. We attempted to analyze the gene expression profile in PTC primary tumors to seek the genes associated with M1 status and characterize their molecular function. One hundred and twenty-three patients, including 36 M1 cases, were subjected to transcriptome oligonucleotide microarray analyses: (set A—U133, set B—HG 1.0 ST) at transcript and gene group level (limma, gene set enrichment analysis (GSEA)). An additional independent set of 63 PTCs, including 9 M1 cases, was used to validate results by qPCR. The analysis on dataset A detected eleven transcripts showing significant differences in expression between metastatic and non-metastatic PTC. These genes were validated on microarray dataset B. The differential expression was positively confirmed for only two genes: IGFBP3, (most significant) and ECM1. However, when analyzed on an independent dataset by qPCR, the IGFBP3 gene showed no differences in expression. Gene group analysis showed differences mainly among immune-related transcripts, indicating the potential influence of tumor immune infiltration or signal within the primary tumor. The differences in gene expression profile between metastatic and non-metastatic PTC, if they exist, are subtle and potentially detectable only in large datasets. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Figure 1

18 pages, 5865 KiB

Open AccessArticle

The TUSC2 Tumour Suppressor Inhibits the Malignant Phenotype of Human Thyroid Cancer Cells via SMAC/DIABLO Protein

by Raffaela Mariarosaria Mariniello, Francesca Maria Orlandella, Anna Elisa De Stefano, Paola Lucia Chiara Iervolino, Giovanni Smaldone, Neila Luciano, Nara Cervone, Francesco Munciguerra, Silvia Esposito, Peppino Mirabelli and Giuliana Salvatore

Int. J. Mol. Sci. 2020, 21(3), 702; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030702 - 21 Jan 2020

Cited by 13 | Viewed by 3126

Abstract

Thyroid carcinoma is the most common endocrine cancer and includes different forms. Among these, anaplastic thyroid carcinoma (ATC) is the rarest but the most lethal subtype, compared to papillary thyroid carcinoma (PTC) which shows an overall good prognosis. We have previously showed that Tumor Suppressor Candidate 2 (TUSC2), a known tumour suppressor gene, is downregulated in human PTC and ATC compared to normal thyroid samples. The aim of this study was to gain insight into the molecular mechanisms induced by TUSC2 in thyroid cancer cells. Here, we stably transfected TUSC2 in papillary (TPC-1) and in anaplastic (8505C) thyroid cancer cell lines and studied its effects on several biological processes, demonstrating that TUSC2 overexpression decreased thyroid cancer cell proliferation, migration and invasion. Through the proteome profiler apoptosis array, we observed that TUSC2 increased sensitivity to apoptosis by increasing the SMAC/DIABLO and CYTOCHROME C proteins. On the other hand, transient silencing of TUSC2, by siRNA, in an immortalized thyroid follicular epithelial cell line (Nthy-ori 3-1) showed the opposite effect. Finally modulation of SMAC/DIABLO partially rescued the biological effects of TUSC2. Thus, our data highlight a tumour suppressor role of TUSC2 in thyroid carcinogenesis, suggesting that it could be a promising target and biomarker for thyroid carcinoma. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Graphical abstract

18 pages, 2994 KiB

Open AccessArticle

Transcription Factor Prospero Homeobox 1 (PROX1) as a Potential Angiogenic Regulator of Follicular Thyroid Cancer Dissemination

by Magdalena Rudzińska, Michał Mikula, Katarzyna D. Arczewska, Ewa Gajda, Stanisława Sabalińska, Tomasz Stępień, Jerzy Ostrowski and Barbara Czarnocka

Int. J. Mol. Sci. 2019, 20(22), 5619; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225619 - 10 Nov 2019

Cited by 15 | Viewed by 3451

Abstract

It is well known that Prospero homeobox 1 (PROX1) is a crucial regulator of lymphangiogenesis, that reprograms blood endothelial cells to lymphatic phenotype. However, the role of PROX1 in tumor progression, especially in angiogenesis remains controversial. Herein, we studied the role of PROX1 in angiogenesis in cell lines derived from follicular thyroid cancer (FTC: FTC-133) and squamous cell carcinoma of the thyroid gland (SCT: CGTH-W-1) upon PROX1 knockdown. The genes involved in angiogenesis were selected by RNA-seq, and the impact of PROX1 on vascularization potential was investigated using human umbilical vein endothelial cells (HUVECs) cultured in conditioned medium collected from FTC- or SCT-derived cancer cell lines after PROX1 silencing. The angiogenic phenotype was examined in connection with the analysis of focal adhesion and correlated with fibroblast growth factor 2 (FGF2) levels. Additionally, the expression of selected genes involved in angiogenesis was detected in human FTC tissues. As a result, we demonstrated that PROX1 knockdown resulted in upregulation of factors associated with vascularization, such as metalloproteinases (MMP1 and 3), FGF2, vascular endothelial growth factors C (VEGFC), BAI1 associated protein 2 (BAIAP2), nudix hydrolase 6 (NUDT6), angiopoietin 1 (ANGPT1), and vascular endothelial growth factor receptor 2 (KDR). The observed molecular changes resulted in the enhanced formation of capillary-like structures by HUVECs and upregulated focal adhesion in FTC-133 and CGTH-W-1 cells. The signature of selected angiogenic genes’ expression in a series of FTC specimens varied depending on the case. Interestingly, PROX1 and FGF2 showed opposing expression levels in FTC tissues and seven thyroid tumor-derived cell lines. In summary, our data revealed that PROX1 is involved in the spreading of thyroid cancer cells by regulation of angiogenesis. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Figure 1

20 pages, 7495 KiB

Open AccessArticle

The Pathogenic TSH β-Subunit Variant C105Vfs114X Causes a Modified Signaling Profile at TSHR

by Laura Kalveram, Gunnar Kleinau, Kamila Szymańska, Patrick Scheerer, Adolfo Rivero-Müller, Annette Grüters-Kieslich and Heike Biebermann

Int. J. Mol. Sci. 2019, 20(22), 5564; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225564 - 07 Nov 2019

Cited by 4 | Viewed by 2809

Abstract

(1) Background: Central congenital hypothyroidism (CCH) is a rare endocrine disorder that can be caused by mutations in the β-subunit of thyrotropin (TSHB). The TSHB mutation C105Vfs114X leads to isolated thyroid-stimulating-hormone-(TSH)-deficiency and results in a severe phenotype. The aim of this study was to gain more insight into the underlying molecular mechanism and the functional effects of this mutation based on two assumptions: a) the three-dimensional (3D) structure of TSH should be modified with the C105V substitution, and/or b) whether the C-terminal modifications lead to signaling differences. (2) Methods: wild-type (WT) and different mutants of hTSH were generated in human embryonic kidney 293 cells (HEK293 cells) and TSH preparations were used to stimulate thyrotropin receptor (TSHR) stably transfected into follicular thyroid cancer cells (FTC133-TSHR cells) and transiently transfected into HEK293 cells. Functional characterization was performed by determination of Gs, mitogen activated protein kinase (MAPK) and Gq/11 activation. (3) Results: The patient mutation C105Vfs114X and further designed TSH mutants diminished cyclic adenosine monophosphate (cAMP) signaling activity. Surprisingly, MAPK signaling for all mutants was comparable to WT, while none of the mutants induced PLC activation. (4) Conclusion: We characterized the patient mutation C105Vfs114X concerning different signaling pathways. We identified a strong decrease of cAMP signaling induction and speculate that this could, in combination with diverse signaling regarding the other pathways, accounting for the patient’s severe phenotype. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Figure 1

23 pages, 3473 KiB

Open AccessArticle

Toll-Like Receptors-2 and -4 in Graves’ Disease—Key Players or Bystanders?

by Agnieszka Polak, Ewelina Grywalska, Janusz Klatka, Jacek Roliński, Beata Matyjaszek-Matuszek and Maria Klatka

Int. J. Mol. Sci. 2019, 20(19), 4732; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194732 - 24 Sep 2019

Cited by 9 | Viewed by 2688

Abstract

Graves’ disease (GD) is an autoimmune disease that affects the thyroid. The development of autoimmunity is associated with innate immune responses where the prominent role plays Toll-like receptors (TLRs). The aim of our study was to assess the relationship between the expression levels of TLR-2 and TLR-4 on CD4+ and CD8+ T as well as CD19+ B lymphocytes in patients with GD and selected clinical parameters. The study group consisted of 32 women with GD, the control group consisted of 20 healthy women. Immunophenotyping was performed using the flow cytometry and cytokines concentrations were assessed using ELISA assay. The mean percentage of CD4+/TLR-2+ and CD8+/TLR-2+ T cells in patients with GD was higher than in the control group (p < 0.0001). After obtaining euthyroidism, the mean percentage of CD4+/TLR-2+ T cells in patients with GD decreased (p < 0.0001). The expression level of TLR-2 on CD4+ T lymphocytes correlated with serum FT3 concentration in patients with GD (r = 0.47, p = 0.007). The mean percentage of CD8+/TLR-2+ T cells in patients with GD before treatment compared to patients with GD after obtaining euthyroidism was higher (p = 0.0163). Similar findings were found for TLR-4. Thus the TLR-2 and TLR-4 can be a prognostic marker for Graves’ disease. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Figure 1

22 pages, 4522 KiB

Open AccessArticle

Identification of Human Enzymes Oxidizing the Anti-Thyroid-Cancer Drug Vandetanib and Explanation of the High Efficiency of Cytochrome P450 3A4 in its Oxidation

by Radek Indra, Petr Pompach, Václav Martínek, Paulína Takácsová, Katarína Vavrová, Zbyněk Heger, Vojtěch Adam, Tomáš Eckschlager, Kateřina Kopečková, Volker Manfred Arlt and Marie Stiborová

Int. J. Mol. Sci. 2019, 20(14), 3392; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143392 - 10 Jul 2019

Cited by 13 | Viewed by 3839

Abstract

The metabolism of vandetanib, a tyrosine kinase inhibitor used for treatment of symptomatic/progressive medullary thyroid cancer, was studied using human hepatic microsomes, recombinant cytochromes P450 (CYPs) and flavin-containing monooxygenases (FMOs). The role of CYPs and FMOs in the microsomal metabolism of vandetanib to N-desmethylvandetanib and vandetanib-N-oxide was investigated by examining the effects of CYP/FMO inhibitors and by correlating CYP-/FMO-catalytic activities in each microsomal sample with the amounts of N-desmethylvandetanib/vandetanib-N-oxide formed by these samples. CYP3A4/FMO-activities significantly correlated with the formation of N-desmethylvandetanib/ vandetanib-N-oxide. Based on these studies, most of the vandetanib metabolism was attributed to N-desmethylvandetanib/vandetanib-N-oxide to CYP3A4/FMO3. Recombinant CYP3A4 was most efficient to form N-desmethylvandetanib, while FMO1/FMO3 generated N-oxide. Cytochrome b₅ stimulated the CYP3A4-catalyzed formation of N-desmethylvandetanib, which is of great importance because CYP3A4 is not only most efficient in generating N-desmethylvandetanib, but also most significant due to its high expression in human liver. Molecular modeling indicated that binding of more than one molecule of vandetanib into the CYP3A4-active center can be responsible for the high efficiency of CYP3A4 N-demethylating vandetanib. Indeed, the CYP3A4-mediated reaction exhibits kinetics of positive cooperativity and this corresponded to the in silico model, where two vandetanib molecules were found in CYP3A4-active center. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Figure 1

12 pages, 506 KiB

Open AccessArticle

Does the Epstein–Barr Virus Play a Role in the Pathogenesis of Graves’ Disease?

by Aleksandra Pyzik, Ewelina Grywalska, Beata Matyjaszek-Matuszek, Jarosław Ludian, Ewa Kiszczak-Bochyńska, Agata Smoleń, Jacek Roliński and Dawid Pyzik

Int. J. Mol. Sci. 2019, 20(13), 3145; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133145 - 27 Jun 2019

Cited by 11 | Viewed by 6630

Abstract

Graves’ disease (GD) it the most common chronic organ-specific thyroid disorder without a fully recognized etiology. The pathogenesis of the disease accounts for an interaction between genetic, environmental, and immunological factors. The most important environmental factors include viral and bacterial infections. The Epstein-Barr virus (EBV) is one of the most common latent human viruses. Literature has suggested its role in the development of certain allergic and autoimmune diseases. EBV also exhibits oncogenic properties. The aim of the study was to analyze and compare the presence of EBV DNA in peripheral blood mononuclear cells (PBMCs) in patients with newly recognized GD and to find a correlation between EBV infection and the clinical picture of GD. The study included 39 untreated patients with newly diagnosed GD and a control group of 20 healthy volunteers who were gender and age matched. EBV DNA was detected with reverse transcription polymerase chain reaction (RT PCR) assay. The studies showed a significantly higher incidence of EBV copies in PBMCs among GD patients compared to the control group. Whereas, no significant correlations were found between the incidence of EBV copies and the evaluated clinical parameters. Our results suggest a probable role of EBV in GD development. EBV infection does not affect the clinical picture of Graves’ disease. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

23 pages, 3536 KiB

Open AccessReview

The Impact of Transcription Factor Prospero Homeobox 1 on the Regulation of Thyroid Cancer Malignancy

by Magdalena Rudzińska and Barbara Czarnocka

Int. J. Mol. Sci. 2020, 21(9), 3220; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093220 - 02 May 2020

Cited by 8 | Viewed by 3212

Abstract

Transcription factor Prospero homeobox 1 (PROX1) is continuously expressed in the lymphatic endothelial cells, playing an essential role in their differentiation. Many reports have shown that PROX1 is implicated in cancer development and acts as an oncoprotein or suppressor in a tissue-dependent manner. Additionally, the PROX1 expression in many types of tumors has prognostic significance and is associated with patient outcomes. In our previous experimental studies, we showed that PROX1 is present in the thyroid cancer (THC) cells of different origins and has a high impact on follicular thyroid cancer (FTC) phenotypes, regulating migration, invasion, focal adhesion, cytoskeleton reorganization, and angiogenesis. Herein, we discuss the PROX1 transcript and protein structures, the expression pattern of PROX1 in THC specimens, and its epigenetic regulation. Next, we emphasize the biological processes and genes regulated by PROX1 in CGTH-W-1 cells, derived from squamous cell carcinoma of the thyroid gland. Finally, we discuss the interaction of PROX1 with other lymphatic factors. In our review, we aimed to highlight the importance of vascular molecules in cancer development and provide an update on the functionality of PROX1 in THC biology regulation. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Figure 1

19 pages, 1327 KiB

Open AccessReview

Multikinase Inhibitor Treatment in Thyroid Cancer

by Ole Vincent Ancker, Marcus Krüger, Markus Wehland, Manfred Infanger and Daniela Grimm

Int. J. Mol. Sci. 2020, 21(1), 10; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010010 - 18 Dec 2019

Cited by 66 | Viewed by 8903

Abstract

Thyroid cancer is the most common endocrine malignancy. Most thyroid cancer types respond well to conventional treatment consisting of surgery and radioactive iodine (RAI) therapy. Unfortunately, some thyroid cancer types are resistant to surgical and RAI therapy. Multikinase inhibitors (MKIs) can be used in the treatment of advanced refractory thyroid cancers. The objective of this review is to give an update on MKI treatment (lenvatinib, sorafenib, sunitinib, cabozantinib, pazopanib, vandetanib) of thyroid cancer, regarding its efficacy and safety profile. We evaluated 212 articles through a PubMed search. A total of 20 articles met the inclusion and none the exclusion criteria. The studies showed promising progression-free survival rates compared to placebo treatment from earlier studies and similar or better results compared to the SELECT and DECISION trials. Adverse effects (AEs) are substantial in the treatment with MKIs. Almost all patients treated with these novel drugs experienced AEs. It is therefore crucial to focus on the management of AEs for a decent long-term outcome. The AEs are often more severe in patients with high efficacy of MKIs, which could indicate a correlation. Taken together, the novel therapeutic regimen with MKIs has shown favorable results in otherwise treatment-resistant thyroid cancer. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Graphical abstract

31 pages, 1136 KiB

Open AccessReview

The Immune Landscape of Thyroid Cancer in the Context of Immune Checkpoint Inhibition

by Gilda Varricchi, Stefania Loffredo, Giancarlo Marone, Luca Modestino, Poupak Fallahi, Silvia Martina Ferrari, Amato de Paulis, Alessandro Antonelli and Maria Rosaria Galdiero

Int. J. Mol. Sci. 2019, 20(16), 3934; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20163934 - 13 Aug 2019

Cited by 69 | Viewed by 8390

Abstract

Immune cells play critical roles in tumor prevention as well as initiation and progression. However, immune-resistant cancer cells can evade the immune system and proceed to form tumors. The normal microenvironment (immune cells, fibroblasts, blood and lymphatic vessels, and interstitial extracellular matrix (ECM)) maintains tissue homeostasis and prevents tumor initiation. Inflammatory mediators, reactive oxygen species, cytokines, and chemokines from an altered microenvironment promote tumor growth. During the last decade, thyroid cancer, the most frequent cancer of the endocrine system, has emerged as the fifth most incident cancer in the United States (USA), and its incidence is steadily growing. Inflammation has long been associated with thyroid cancer, raising critical questions about the role of immune cells in its pathogenesis. A plethora of immune cells and their mediators are present in the thyroid cancer ecosystem. Monoclonal antibodies (mAbs) targeting immune checkpoints, such as mAbs anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed cell death protein-1/programmed cell death ligand-1 (anti-PD-1/PD-L1), have revolutionized the treatment of many malignancies, but they induce thyroid dysfunction in up to 10% of patients, presumably by enhancing autoimmunity. Combination strategies involving immune checkpoint inhibitors (ICIs) with tyrosine kinase (TK) or serine/threonine protein kinase B-raf (BRAF) inhibitors are showing considerable promise in the treatment of advanced thyroid cancer. This review illustrates how different immune cells contribute to thyroid cancer development and the rationale for the antitumor effects of ICIs in combination with BRAF/TK inhibitors. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Figure 1

19 pages, 1648 KiB

Open AccessReview

Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment

by Livia Manzella, Michele Massimino, Stefania Stella, Elena Tirrò, Maria Stella Pennisi, Federica Martorana, Gianmarco Motta, Silvia Rita Vitale, Adriana Puma, Chiara Romano, Sandra Di Gregorio, Marco Russo, Pasqualino Malandrino and Paolo Vigneri

Int. J. Mol. Sci. 2019, 20(13), 3258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133258 - 02 Jul 2019

Cited by 37 | Viewed by 3923

Abstract

The Insulin-like growth factor (IGF) axis is one of the best-established drivers of thyroid transformation, as thyroid cancer cells overexpress both IGF ligands and their receptors. Thyroid neoplasms encompass distinct clinical and biological entities as differentiated thyroid carcinomas (DTC)—comprising papillary (PTC) and follicular (FTC) tumors—respond to radioiodine therapy, while undifferentiated tumors—including poorly-differentiated (PDTC) or anaplastic thyroid carcinomas (ATCs)—are refractory to radioactive iodine and exhibit limited responses to chemotherapy. Thus, safe and effective treatments for the latter aggressive thyroid tumors are urgently needed. Despite a strong preclinical rationale for targeting the IGF axis in thyroid cancer, the results of the available clinical studies have been disappointing, possibly because of the crosstalk between IGF signaling and other pathways that may result in resistance to targeted agents aimed against individual components of these complex signaling networks. Based on these observations, the combinations between IGF-signaling inhibitors and other anti-tumor drugs, such as DNA damaging agents or kinase inhibitors, may represent a promising therapeutic strategy for undifferentiated thyroid carcinomas. In this review, we discuss the role of the IGF axis in thyroid tumorigenesis and also provide an update on the current knowledge of IGF-targeted combination therapies for thyroid cancer. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Cell and Molecular Biology of Thyroid Disorders 2.0

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Related Special Issue

Published Papers (13 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI