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16 pages, 2403 KiB

Open AccessArticle

Ouabain Effects on Human Anaplastic Thyroid Carcinoma 8505C Cells

by Mariana Pires Teixeira, Natalia Ferreira Haddad, Eliza Freitas Passos, Marcelle Novaes Andrade, Maria Luisa Arantes Campos, Joyle Moreira Carvalho da Silva, Camila Saggioro de Figueiredo, Elizabeth Giestal-de-Araujo, Denise Pires de Carvalho, Leandro Miranda-Alves and Luciana Souza de Paiva

Cancers 2022, 14(24), 6168; https://doi.org/10.3390/cancers14246168 - 14 Dec 2022

Cited by 1 | Viewed by 1383

Abstract

Anaplastic thyroid carcinoma (ATC) is a rare, but aggressive, carcinoma derived from follicular cells. While conventional treatments may improve patients’ survival, the lethality remains high. Therefore, there is an urgent need for more effective ATC treatments. Cardiotonic steroids, such as ouabain, have been [...] Read more.

Anaplastic thyroid carcinoma (ATC) is a rare, but aggressive, carcinoma derived from follicular cells. While conventional treatments may improve patients’ survival, the lethality remains high. Therefore, there is an urgent need for more effective ATC treatments. Cardiotonic steroids, such as ouabain, have been shown to have therapeutic potential in cancer treatment. Thus, we aimed to evaluate ouabain’s effects in human anaplastic thyroid cells. For this, 8505C cells were cultured in the presence or absence of ouabain. Viability, cell death, cell cycle, colony formation and migratory ability were evaluated in ouabain-treated and control 8505C cells. The expression of differentiation and epithelial-to-mesenchymal transition (EMT) markers, as well as IL-6, TGFb1 and their respective receptors were also quantified in these same cells. Our results showed that ouabain in vitro decreased the number of viable 8505C cells, possibly due to an inhibition of proliferation. A reduction in migration was also observed in ouabain-treated 8505C cells. In contrast, decreased mRNA levels of PAX8 and TTF1 differentiation markers and increased levels of the N-cadherin EMT marker, as well as IL-6 and TGFb1, were found in ouabain-treated 8505C cells. In short, ouabain may have anti-proliferative and anti-migratory effect on 8505C cells, but maintains an aggressive and undifferentiated profile. Full article

(This article belongs to the Special Issue New Insights in Neuroendocrine Neoplasms (NENs) and Thyroid Cancer: Focus on Basic, Translational, and Clinical Research)

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12 pages, 569 KiB

Open AccessArticle

Coexisting Molecular Alterations Increase the Risk of Malignancy in Thyroid Nodules with Copy Number Alterations

by Mohannad Rajab, Saruchi Bandargal, Marc Philippe Pusztaszeri, Véronique-Isabelle Forest, Sama Alohali, Sabrina Daniela da Silva, Michael Tamilia and Richard J. Payne

Cancers 2022, 14(24), 6149; https://doi.org/10.3390/cancers14246149 - 13 Dec 2022

Cited by 1 | Viewed by 1528

Abstract

Molecular mutations and alterations play a role in thyroid tumorigenesis. Different alterations are associated with different clinical and pathological characteristics. Copy number alterations (CNAs) are known to be present in some thyroid tumors; however, their idiosyncratic clinicopathological implications are not yet well elucidated. [...] Read more.

Molecular mutations and alterations play a role in thyroid tumorigenesis. Different alterations are associated with different clinical and pathological characteristics. Copy number alterations (CNAs) are known to be present in some thyroid tumors; however, their idiosyncratic clinicopathological implications are not yet well elucidated. A retrospective chart review was performed to identify patients with CNAs on pre-operative molecular testing results who subsequently underwent surgical treatment between January 2016 and April 2022 at McGill University teaching hospitals. Of the 316 patients with thyroid nodules who opted for molecular testing with ThyroSeqV3 followed by surgery, 67 (21.2%) nodules were positive for CNAs, including 23 Bethesda III, 31 Bethesda IV, 12 Bethesda V and 1 Bethesda VI nodules. On surgical pathology, 29.9% were benign and 70.1% were malignant or non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Among those that were malignant/NIFTP, 17.02% were considered to be aggressive cancers. The presence of other molecular alterations was found to be an independent predictor of malignancy in multivariate analysis (OR = 5.087, 95% C.I. = 1.12–23.04, p = 0.035). No unique factor was correlated with aggressiveness; however, CNA-positive thyroid nodules that were associated with high-risk mutations such as BRAF V600E, TP53, NTRK1/3 fusion, or PTEN mutation with high allele frequency (AF) ended up being aggressive cancers. Most of the CNA-positive thyroid nodules resulted in follicular patterned tumors in 41 (65.2%) cases and oncocytic tumors in 20 (29.9%) cases. This study demonstrates that 70.1% of surgically resected thyroid nodules with CNAs were malignant/NIFTP. Most CNA-positive thyroid nodules were either oncocytic patterned tumors or follicular patterned tumors. Furthermore, CNA-positive thyroid nodules were more likely to be malignant if they were associated with other molecular alterations or mutations. Full article

(This article belongs to the Special Issue New Insights in Neuroendocrine Neoplasms (NENs) and Thyroid Cancer: Focus on Basic, Translational, and Clinical Research)

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11 pages, 4393 KiB

Open AccessArticle

Thyroid Cancer Persistence in Patients with Unreliable Thyroglobulin Measurement: Circulating microRNA as Candidate Alternative Biomarkers

by Alfredo Campennì, M’hammed Aguennouz, Massimiliano Siracusa, Angela Alibrandi, Francesca Polito, Rosaria Oteri, Sergio Baldari, Rosaria Maddalena Ruggeri and Luca Giovanella

Cancers 2022, 14(22), 5620; https://doi.org/10.3390/cancers14225620 - 16 Nov 2022

Cited by 1 | Viewed by 1892

Abstract

Background: We aimed to evaluate the role of circulating miRNAs as a biomarker of the persistence of papillary thyroid cancer (PTC) in patients with an “uninformative” thyroglobulin (Tg) measurement. Methods: We prospectively enrolled 49 consecutive PTC patients with Tg-positive antibodies (TgAb) who had [...] Read more.

Background: We aimed to evaluate the role of circulating miRNAs as a biomarker of the persistence of papillary thyroid cancer (PTC) in patients with an “uninformative” thyroglobulin (Tg) measurement. Methods: We prospectively enrolled 49 consecutive PTC patients with Tg-positive antibodies (TgAb) who had undergone a (near)-total thyroidectomy and ¹³¹I therapy (RIT). The serum thyroid stimulating hormone (TSH), Tg, and TgAb levels were measured before and at 6 and 12 months after RIT, respectively. The serum miRNA (221, 222, 375, 155, and 146b) levels were measured simultaneously. Results: The response to the initial therapy was assessed according to the 2015 ATA criteria. A decrease in 50% or more of serum miRNA over time was observed in 41/49 PTC patients, who showed an excellent response (ER), but six and two patients were classified to have an indeterminate/incomplete biochemical or incomplete structural response to initial therapy. Conclusion: Serum miRNA kinetics emerge as a promising biomarker for the early detection of a persistent disease in PTC patients with uninformative Tg results. Full article

(This article belongs to the Special Issue New Insights in Neuroendocrine Neoplasms (NENs) and Thyroid Cancer: Focus on Basic, Translational, and Clinical Research)

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10 pages, 1181 KiB

Open AccessArticle

Persistent Thyroid Carcinoma and Pregnancy: Outcomes in an Italian Series and Review of the Literature

by Carla Colombo, Simone De Leo, Noemi Giancola, Matteo Trevisan, Daniele Ceruti, Francesco Frattini, Luca Persani and Laura Fugazzola

Cancers 2022, 14(22), 5515; https://doi.org/10.3390/cancers14225515 - 10 Nov 2022

Cited by 4 | Viewed by 1401

Abstract

Scanty data are available on the progression risk in patients with persistent thyroid cancer (TC) before pregnancy. We aimed to evaluate this topic in our series and to review available literature data. This was a retrospective study performed in a tertiary care Italian [...] Read more.

Scanty data are available on the progression risk in patients with persistent thyroid cancer (TC) before pregnancy. We aimed to evaluate this topic in our series and to review available literature data. This was a retrospective study performed in a tertiary care Italian TC center. We included 8 patients with persistent papillary TC who became pregnant after initial treatments (mean time interval of 62 months). Seven patients had the structural disease (lung and/or neck node metastases), while one patient had biochemical persistence. During a mean follow-up of 97 months, none of the patients showed disease progression either during pregnancy or during a follow-up of at least 12 months after delivery, and no additional treatments were needed. A sequential biochemical evaluation showed that thyroglobulin levels can significantly increase during pregnancy, returning to preconception levels after delivery. In conclusion, our data confirm that pregnancy is not associated with disease progression in patients with stable local and/or distant persistence before conception. Thus, pregnancy should not be contraindicated in metastatic women, although a precise clinical characterization, including the disease stage at diagnosis, the ATA risk class, and the dynamic risk stratification, should be conducted before conception. Full article

(This article belongs to the Special Issue New Insights in Neuroendocrine Neoplasms (NENs) and Thyroid Cancer: Focus on Basic, Translational, and Clinical Research)

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17 pages, 4584 KiB

Open AccessArticle

Preclinical Evaluation of Novel Tyrosine-Kinase Inhibitors in Medullary Thyroid Cancer

by Davide Saronni, Germano Gaudenzi, Alessandra Dicitore, Silvia Carra, Maria Celeste Cantone, Maria Orietta Borghi, Andrea Barbieri, Luca Mignani, Leo J. Hofland, Luca Persani and Giovanni Vitale

Cancers 2022, 14(18), 4442; https://doi.org/10.3390/cancers14184442 - 13 Sep 2022

Cited by 4 | Viewed by 2265

Abstract

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from parafollicular C cells of the thyroid gland. In this preclinical study, we tested three tyrosine-kinase inhibitors (TKIs): SU5402, a selective inhibitor of fibroblast growth factor receptor (FGFR)-1 and vascular endothelial growth factor receptor [...] Read more.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from parafollicular C cells of the thyroid gland. In this preclinical study, we tested three tyrosine-kinase inhibitors (TKIs): SU5402, a selective inhibitor of fibroblast growth factor receptor (FGFR)-1 and vascular endothelial growth factor receptor (VEGFR)-2; sulfatinib, an inhibitor of FGFR-1 and VEGFR-1, -2, -3; and SPP86, a RET-specific inhibitor. The effects of these compounds were evaluated in vitro in two human MTC cell lines (TT and MZ-CRC-1), and in vivo using xenografts of MTC cells in zebrafish embryos. SU5402, sulfatinib and SPP86 decreased cell viability. Sulfatinib and SPP86 significantly induced apoptosis in both cell lines. Sulfatinib and SPP86 inhibited the migration of TT and MZCRC-1 cells, while SU5402 was able to inhibit migration only in TT cells. In vivo we observed a significant reduction in TT cell-induced angiogenesis in zebrafish embryos after incubation with sulfatinib and SPP86. In conclusion, sulfatinib and SPP86 displayed a relevant antitumor activity both in vitro and in vivo. Moreover, this work suggests the potential utility of targeting FGFR and VEGFR signaling pathways as an alternative therapy for MTC. Full article

(This article belongs to the Special Issue New Insights in Neuroendocrine Neoplasms (NENs) and Thyroid Cancer: Focus on Basic, Translational, and Clinical Research)

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20 pages, 6654 KiB

Open AccessArticle

Characterisation of an Atrx Conditional Knockout Mouse Model: Atrx Loss Causes Endocrine Dysfunction Rather Than Pancreatic Neuroendocrine Tumour

by Tiago Bordeira Gaspar, Sofia Macedo, Ana Sá, Mariana Alves Soares, Daniela Ferreira Rodrigues, Mafalda Sousa, Nuno Mendes, Rui Sousa Martins, Luís Cardoso, Inês Borges, Sule Canberk, Fátima Gärtner, Leandro Miranda-Alves, Manuel Sobrinho-Simões, José Manuel Lopes, Paula Soares and João Vinagre

Cancers 2022, 14(16), 3865; https://doi.org/10.3390/cancers14163865 - 10 Aug 2022

Cited by 6 | Viewed by 2957

Abstract

ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss [...] Read more.

ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss (Atrx^KO) in pancreatic β cells, evaluating a large cohort of ageing mice (for up to 24 months (mo.)). Atrx loss did not cause PanNET formation but rather resulted in worsening of ageing-related pancreatic inflammation and endocrine dysfunction in the first year of life. Histopathological evaluation highlighted an exacerbated prevalence and intensity of pancreatic inflammation, ageing features, and hepatic steatosis in Atrx^KO mice. Homozygous floxed mice presented hyperglycaemia, increased weights, and glucose intolerance after 6 months, but alterations in insulinaemia were not detected. Floxed individuals presented an improper growth of their pancreatic endocrine fraction that may explain such an endocrine imbalance. A pilot study of BRACO-19 administration to Atrx^KO mice resulted in telomere instability, reinforcing the involvement of Atrx in the maintenance of β cell telomere homeostasis. Thereby, a non-obese dysglycaemic GEMM of disrupted Atrx is here presented as potentially useful for metabolic studies and putative candidate for inserting additional tumourigenic genetic events. Full article

(This article belongs to the Special Issue New Insights in Neuroendocrine Neoplasms (NENs) and Thyroid Cancer: Focus on Basic, Translational, and Clinical Research)

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Review

Jump to: Research

14 pages, 1223 KiB

Open AccessReview

The Effects of Radioligand Therapy on Quality of Life and Sexual Function in Patients with Neuroendocrine Neoplasms

by Pasqualino Malandrino, Rossella Mazzilli, Giulia Puliani, Sergio Di Molfetta, Gabriella Pugliese, Soraya Olana, Anna Maria Colao, Antongiulio Faggiano and on behalf of the NIKE Group

Cancers 2023, 15(1), 115; https://doi.org/10.3390/cancers15010115 - 24 Dec 2022

Cited by 1 | Viewed by 1281

Abstract

Peptide receptor radionuclide therapy (PRRT), also called radioligand therapy, is an effective antitumoral treatment in patients with neuroendocrine neoplasm (NEN). It improves the patient’s health-related quality of life (HRQoL), which is evaluated by self-assessment questionnaires. The aim of this narrative review was to [...] Read more.

Peptide receptor radionuclide therapy (PRRT), also called radioligand therapy, is an effective antitumoral treatment in patients with neuroendocrine neoplasm (NEN). It improves the patient’s health-related quality of life (HRQoL), which is evaluated by self-assessment questionnaires. The aim of this narrative review was to report the current knowledge on the changes of HRQoL and sexual function in patients with NEN treated with PRRT. We conducted a literature search of the PubMed, Embase, and APA PsycInfo databases. We selected 15 studies (12 for HRQoL and three for sexual function). After treatment with PRRT, patients with NEN experienced a significant improvement in their global health status, disease-related worries, social and emotional functioning, and cancer-related symptoms such as fatigue and diarrhea. Other symptoms, such as nausea/vomiting, dyspnea, and constipation, as well as the economic impact, were unchanged by radioligand therapy. Data on sexual function were not equally promising; only a few studies investigated this issue by using appropriate questionnaires in patients treated with radioligand therapy. Therefore, additional studies are needed to draw a conclusion about the benefits from PRRT on sexual function. Full article

(This article belongs to the Special Issue New Insights in Neuroendocrine Neoplasms (NENs) and Thyroid Cancer: Focus on Basic, Translational, and Clinical Research)

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18 pages, 847 KiB

Open AccessReview

Neuroendocrine Tumors: A Comprehensive Review on Nutritional Approaches

by Giovanna Muscogiuri, Luigi Barrea, Maria Celeste Cantone, Valentina Guarnotta, Rossella Mazzilli, Ludovica Verde, Claudia Vetrani, Annamaria Colao and Antongiulio Faggiano

Cancers 2022, 14(18), 4402; https://doi.org/10.3390/cancers14184402 - 10 Sep 2022

Cited by 2 | Viewed by 4332

Abstract

Neuroendocrine neoplasms are a heterogeneous group of neoplasms with increasing incidence, high prevalence, and survival worldwide. About 90% of cases are well differentiated forms, the so-called neuroendocrine tumors (NETs), with slow proliferation rates and prolonged survival but frequent development of liver metastases and [...] Read more.

Neuroendocrine neoplasms are a heterogeneous group of neoplasms with increasing incidence, high prevalence, and survival worldwide. About 90% of cases are well differentiated forms, the so-called neuroendocrine tumors (NETs), with slow proliferation rates and prolonged survival but frequent development of liver metastases and endocrine syndromes. Both the tumor itself and systemic therapy may have an impact on patient nutrition. Malnutrition has a negative impact on outcome in patients with NETs, as well as obesity. In addition, obesity and metabolic syndrome have been shown to be risk factors for both the development and prognosis of NET. Therefore, dietary assessment based on body composition and lifestyle modifications should be an integral part of the treatment of NET patients. Nutrition plans, properly formulated by a dietician, are an integral part of the multidisciplinary treatment team for patients with NETs because they allow an improvement in quality of life, providing a tailored approach based on nutritional needs and nutritional manageable signs and/or symptoms related to pharmacological treatment. The aim of this review is to condense the latest evidence on the role of the most used dietary models, the Mediterranean diet, the ketogenic diet, and intermittent fasting, in the context of NETs, while considering the clinical and molecular mechanisms by which these dietary models act. Full article

(This article belongs to the Special Issue New Insights in Neuroendocrine Neoplasms (NENs) and Thyroid Cancer: Focus on Basic, Translational, and Clinical Research)

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