International Journal of Molecular Sciences

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4 pages, 209 KiB

Open AccessEditorial

Recent Advances in Thyroid Cancer Research

by Daniela Grimm

Int. J. Mol. Sci. 2022, 23(9), 4631; https://doi.org/10.3390/ijms23094631 - 22 Apr 2022

Cited by 16 | Viewed by 3533

Abstract

This Special Issue (SI) “Recent Advances in Thyroid Cancer Research” covers research articles and reviews in the field of thyroid cancer research [...] Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)

Research

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13 pages, 3752 KiB

Open AccessArticle

Analogs of the Heat Shock Protein 70 Inhibitor MKT-077 Suppress Medullary Thyroid Carcinoma Cells

by Seung-Keun Hong, Dmytro Starenki, Oleta T. Johnson, Jason E. Gestwicki and Jong-In Park

Int. J. Mol. Sci. 2022, 23(3), 1063; https://doi.org/10.3390/ijms23031063 - 19 Jan 2022

Cited by 8 | Viewed by 1852

Abstract

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the RET proto-oncogene. We previously demonstrated that depletion of the mitochondrial molecular chaperone, mortalin, can effectively suppress human MTC cells in culture and in mouse xenografts, by disrupting mitochondrial bioenergetics [...] Read more.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the RET proto-oncogene. We previously demonstrated that depletion of the mitochondrial molecular chaperone, mortalin, can effectively suppress human MTC cells in culture and in mouse xenografts, by disrupting mitochondrial bioenergetics and subsequently inducing apoptosis and RET downregulation. Similar effects were induced by MKT-077, a water-soluble rhodocyanine dye analog known to inhibit mortalin, but with notable toxicity in animals. These observations led us to evaluate recently developed MKT-077 analogs that exhibited higher selectivity to HSP70 proteins and improved bioavailability. We validated the MTC cell-suppressive effects of mortalin depletion in three-dimensional cultures of the human MTC lines, TT, and MZ-CRC-1, and then evaluated different MKT-077 analogs in two- and three-dimensional cell cultures, to show that the MKT-077 analogs, JG-98 and JG-194, effectively and consistently inhibited propagation of TT and MZ-CRC-1 cells in these cultures. Of note, these compounds also effectively suppressed the viability of TT and MZ-CRC-1 progenies resistant to vandetanib and cabozantinib. Moreover, JG-231, an analog with improved microsomal stability, consistently suppressed TT and MZ-CRC-1 xenografts in mice. These data suggest that mortalin inhibition may have therapeutic potential for MTC. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)

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21 pages, 3010 KiB

Open AccessArticle

The CellBox-2 Mission to the International Space Station: Thyroid Cancer Cells in Space

by Daniela Melnik, Marcus Krüger, Herbert Schulz, Sascha Kopp, Markus Wehland, Johann Bauer, Bjorn Baselet, Randy Vermeesen, Sarah Baatout, Thomas J. Corydon, Manfred Infanger and Daniela Grimm

Int. J. Mol. Sci. 2021, 22(16), 8777; https://doi.org/10.3390/ijms22168777 - 16 Aug 2021

Cited by 12 | Viewed by 2566

Abstract

A spaceflight to the International Space Station (ISS) is a dream of many researchers. We had the chance to investigate the effect of real microgravity (CellBox-2 Space mission) on the transcriptome and proteome of FTC-133 human follicular thyroid cancer cells (TCC). The cells [...] Read more.

A spaceflight to the International Space Station (ISS) is a dream of many researchers. We had the chance to investigate the effect of real microgravity (CellBox-2 Space mission) on the transcriptome and proteome of FTC-133 human follicular thyroid cancer cells (TCC). The cells had been sent to the ISS by a Falcon 9 rocket of SpaceX CRS-13 from Cape Canaveral (United States) and cultured in six automated hardware units on the ISS before they were fixed and returned to Earth. Multicellular spheroids (MCS) were detectable in all spaceflight hardware units. The VCL, PXN, ITGB1, RELA, ERK1 and ERK2 mRNA levels were significantly downregulated after 5 days in space in adherently growing cells (AD) and MCS compared with ground controls (1g), whereas the MIK67 and SRC mRNA levels were both suppressed in MCS. By contrast, the ICAM1, COL1A1 and IL6 mRNA levels were significantly upregulated in AD cells compared with 1g and MCS. The protein secretion measured by multianalyte profiling technology and enzyme-linked immunosorbent assay (AngiogenesisMAP^®, extracellular matrix proteins) was not significantly altered, with the exception of elevated angiopoietin 2. TCC in space formed MCS, and the response to microgravity was mainly anti-proliferative. We identified ERK/RELA as a major microgravity regulatory pathway. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)

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16 pages, 6502 KiB

Open AccessArticle

Loss of ZNF677 Expression Is an Independent Predictor for Distant Metastasis in Middle Eastern Papillary Thyroid Carcinoma Patients

by Abdul K. Siraj, Pratheesh Kumar Poyil, Sandeep Kumar Parvathareddy, Khadija Alobaisi, Saeeda O. Ahmed, Saif S. Al-Sobhi, Fouad Al-Dayel and Khawla S. Al-Kuraya

Int. J. Mol. Sci. 2021, 22(15), 7833; https://doi.org/10.3390/ijms22157833 - 22 Jul 2021

Cited by 6 | Viewed by 1715

Abstract

Thyroid cancer incidence has increased in recent decades. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Approximately 30% of PTC patients develop recurrence or distant metastasis and tend to have poor prognosis. Therefore, the identification of targetable biomarkers in [...] Read more.

Thyroid cancer incidence has increased in recent decades. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Approximately 30% of PTC patients develop recurrence or distant metastasis and tend to have poor prognosis. Therefore, the identification of targetable biomarkers in this subset of patients is of great importance. Accumulating evidence indicates that zinc finger protein 677 (ZNF677), which belongs to the zinc finger protein family, is an important effector during the progression of multiple malignancies. However, its role in Middle Eastern PTC patients has not been fully illustrated. Here, we uncovered the molecular mechanism and the clinical impact of ZNF677 expression in a large cohort of more than 1200 Middle Eastern PTC and 15 metastatic tissues. We demonstrated that ZNF677 is frequently downregulated in primary PTC (13.6%, 168/1235) and showed that complete loss of expression of ZNF677 is significantly associated with aggressive clinico-pathological markers such as extrathyroidal extension (p = 0.0008) and distant metastases (p < 0.0001). We also found a significantly higher incidence of ZNF677 loss in primary tumors with distant metastases (33.3%; p < 0.0001) as well as in distant metastatic tissues (46.7%; p = 0.0002) compared to the overall cohort (13.6%). More importantly, PTC with loss of ZNF677 expression showed significantly lower metastasis-free survival (p = 0.0090). Interestingly, on multivariate logistic regression analysis, ZNF677 loss was an independent predictor of distant metastasis in PTC (Odds ratio = 2.60, 95% Confidence interval = 1.20–5.62, p = 0.0155). In addition, we found a significant association between ZNF677 loss and phospho-AKT expression (p < 0.0001). Our functional molecular results suggest that ZNF677 acts as a tumor suppressor, mediating its effect by inhibiting AKT phosphorylation. Taken together, our results highlight the pivotal role played by ZNF677 during carcinogenesis and metastasis formation in Middle Eastern PTC patients. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)

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13 pages, 4153 KiB

Open AccessArticle

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

by Sara C. Credendino, Marta De Menna, Irene Cantone, Carmen Moccia, Matteo Esposito, Luigi Di Guida, Mario De Felice and Gabriella De Vita

Int. J. Mol. Sci. 2021, 22(14), 7666; https://doi.org/10.3390/ijms22147666 - 17 Jul 2021

Cited by 2 | Viewed by 2317

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)

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17 pages, 2383 KiB

Open AccessArticle

^V600EBRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells

by Eva Jiménez-Mora, Beatriz Gallego, Sergio Díaz-Gago, Marina Lasa, Pablo Baquero and Antonio Chiloeches

Int. J. Mol. Sci. 2021, 22(11), 6033; https://doi.org/10.3390/ijms22116033 - 03 Jun 2021

Cited by 9 | Viewed by 2680

Abstract

The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where ^V600EBRAF is a main oncogene. Here, we analyse the effect of ^V600EBRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of [...] Read more.

The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where ^V600EBRAF is a main oncogene. Here, we analyse the effect of ^V600EBRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of autophagy in cell survival of thyroid cancer cells. We reveal that the inhibition of ^V600EBRAF activity with its specific inhibitor PLX4720 or the depletion of its expression by siRNA induces autophagy in thyroid tumour cells. We show that ^V600EBRAF downregulation increases LKB1-AMPK signalling and decreases mTOR activity through a MEK/ERK-dependent mechanism. Moreover, we demonstrate that PLX4720 activates ULK1 and increases autophagy through the activation of the AMPK-ULK1 pathway, but not by the inhibition of mTOR. In addition, we find that autophagy blockade decreases cell viability and sensitize thyroid cancer cells to ^V600EBRAF inhibition by PLX4720 treatment. Finally, we generate a thyroid xenograft model to demonstrate that autophagy inhibition synergistically enhances the anti-proliferative and pro-apoptotic effects of ^V600EBRAF inhibition in vivo. Collectively, we uncover a new role of AMPK in mediating the induction of cytoprotective autophagy by ^V600EBRAF inhibition. In addition, these data establish a rationale for designing an integrated therapy targeting ^V600EBRAF and the LKB1-AMPK-ULK1-autophagy axis for the treatment of ^V600EBRAF-positive thyroid tumours. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)

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Review

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25 pages, 915 KiB

Open AccessReview

Clinicopathological and Molecular Features of Secondary Cancer (Metastasis) to the Thyroid and Advances in Management

by Marie Nguyen, George He and Alfred King-Yin Lam

Int. J. Mol. Sci. 2022, 23(6), 3242; https://doi.org/10.3390/ijms23063242 - 17 Mar 2022

Cited by 10 | Viewed by 3026

Abstract

Secondary tumours to the thyroid gland are uncommon and often incidentally discovered on imaging. Symptomatic patients often present with a neck mass. Collision tumours of secondary tumours and primary thyroid neoplasms do occur. Ultrasound-guided fine-needle aspiration, core-needle biopsy, and surgical resection with histological [...] Read more.

Secondary tumours to the thyroid gland are uncommon and often incidentally discovered on imaging. Symptomatic patients often present with a neck mass. Collision tumours of secondary tumours and primary thyroid neoplasms do occur. Ultrasound-guided fine-needle aspiration, core-needle biopsy, and surgical resection with histological and immunohistochemical analysis are employed to confirm diagnosis as well as for applying molecular studies to identify candidates for targeted therapy. Biopsy at the metastatic site can identify mutations (such as EGFR, K-Ras, VHL) and translocations (such as EML4-ALK fusion) important in planning target therapies. Patients with advanced-stage primary cancers, widespread dissemination, or unknown primary origin often have a poor prognosis. Those with isolated metastasis to the thyroid have better survival outcomes and are more likely to undergo thyroid resection. Systemic therapies, such as chemotherapy and hormonal therapy, are often used as adjuvant treatment post-operatively or in patients with disseminated disease. New targeted therapies, such as tyrosine kinase inhibitors and immune checkpoint inhibitors, have shown success in reported cases. A tailored treatment plan based on primary tumour features, overall cancer burden, and co-morbidities is imperative. To conclude, secondary cancer to the thyroid is uncommon, and awareness of the updates on diagnosis and management is needed. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)

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23 pages, 1818 KiB

Open AccessReview

Kinase-Inhibitors in Iodine-Refractory Differentiated Thyroid Cancer—Focus on Occurrence, Mechanisms, and Management of Treatment-Related Hypertension

by Anne Christine Kaae, Michael C. Kreissl, Marcus Krüger, Manfred Infanger, Daniela Grimm and Markus Wehland

Int. J. Mol. Sci. 2021, 22(22), 12217; https://doi.org/10.3390/ijms222212217 - 12 Nov 2021

Cited by 5 | Viewed by 2784

Abstract

Differentiated thyroid cancer (DTC) usually has a good prognosis when treated conventionally with thyroidectomy, radioactive iodine (RAI) and thyroid-stimulating hormone suppression, but some tumors develop a resistance to RAI therapy, requiring alternative treatments. Sorafenib, lenvatinib and cabozantinib are multikinase inhibitors (MKIs) approved for [...] Read more.

Differentiated thyroid cancer (DTC) usually has a good prognosis when treated conventionally with thyroidectomy, radioactive iodine (RAI) and thyroid-stimulating hormone suppression, but some tumors develop a resistance to RAI therapy, requiring alternative treatments. Sorafenib, lenvatinib and cabozantinib are multikinase inhibitors (MKIs) approved for the treatment of RAI-refractory DTC. The drugs have been shown to improve progression-free survival (PFS) and overall survival (OS) via the inhibition of different receptor tyrosine kinases (RTKs) that are involved in tumorigenesis and angiogenesis. Both sorafenib and lenvatinib have been approved irrespective of the line of therapy for the treatment of RAI-refractory DTC, whereas cabozantinib has only been approved as a second-line treatment. Adverse effects (AEs) such as hypertension are often seen with MKI treatment, but are generally well manageable. In this review, current clinical studies will be discussed, and the toxicity and safety of sorafenib, lenvatinib and cabozantinib treatment will be evaluated, with a focus on AE hypertension and its treatment options. In short, treatment-emergent hypertension (TE-HTN) occurs with all three drugs, but is usually well manageable and leads only to a few dose modifications or even discontinuations. This is emphasized by the fact that lenvatinib is widely considered the first-line drug of choice, despite its higher rate of TE-HTN. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)

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