Search Results (159)

Organoid and spheroid technologies have rapidly become pivotal in thyroid cancer research, offering models that are more physiologically relevant than traditional two-dimensional culture. In the study of papillary and anaplastic thyroid carcinomas, two subtypes that differ both histologically and clinically, three-dimensional (3D) models offer unparalleled insights into tumor biology, therapeutic vulnerabilities, and resistance mechanisms. These models maintain essential tumor characteristics such as cellular diversity, spatial structure, and interactions with the microenvironment, making them extremely valuable for disease modeling and drug testing. This review emphasizes recent progress in the development and use of thyroid cancer organoids and spheroids, focusing on their role in replicating disease features, evaluating targeted therapies, and investigating epithelial–mesenchymal transition (EMT), cancer stem cell behavior, and treatment resistance. Patient-derived organoids have shown potential in capturing individualized drug responses, supporting precision oncology strategies for both differentiated and aggressive subtypes. Additionally, new platforms, such as thyroid organoid-on-a-chip systems, provide dynamic, high-fidelity models for functional studies and assessments of endocrine disruption. Despite ongoing challenges, such as standardization, limited inclusion of immune and stromal components, and culture reproducibility, advancements in microfluidics, biomaterials, and machine learning have enhanced the clinical and translational potential of these systems. Organoids and spheroids are expected to become essential in the future of thyroid cancer research, particularly in bridging the gap between laboratory discoveries and patient-focused therapies. Full article

Thyroid cancer, the most frequently occurring endocrine neoplasm, comprises a heterogeneous group of histological subtypes, spanning from the indolent papillary thyroid carcinoma (PTC) to the rapidly progressive and lethal anaplastic thyroid carcinoma (ATC). Although conventional therapies, such as surgery and radioactive iodine (RAI), are effective for differentiated thyroid cancers, treatment resistance and poor prognosis remain major challenges in advanced and undifferentiated forms. In current times, growing attention has been directed toward the potential of Natural Killer (NK) cells as a promising immunotherapeutic avenue. These innate immune cells are capable of direct cytotoxicity against tumor cells, but their efficiency is frequently compromised by the immunosuppressive tumor microenvironment (TME), which inhibits NK cell activation, infiltration, and persistence. This review explores the dynamic interaction between NK cells and the TME in thyroid cancer, detailing key mechanisms of immune evasion, including the impact of suppressive cytokines, altered chemokine landscapes, and inhibitory ligand expression. We further discuss latest advancements in NK cell-based immunotherapies, including strategies for ex vivo expansion, genetic modification, and combinatorial approaches with checkpoint inhibitors or cytokines. Additionally, emerging modalities, such as NK cell-derived extracellular vesicles, are addressed. By combining mechanistic insights with advancing therapeutic techniques, this review provides a comprehensive perspective on NK cell-based interventions and their future potential in improving outcomes for patients with thyroid cancer. Full article

Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy with poor prognosis and limited treatment options. Precision oncology seeks personalized therapies that selectively modulate tumor behavior, which is critical for improving patient outcomes. In this study, we evaluated the therapeutic potential of human dental pulp stem cell-derived extracellular vesicles (hDPSC-EVs) in three ATC cell lines (8505C, HTH83, KTC-2). Fluorescence and confocal microscopy confirmed the efficient, time-dependent internalization of hDPSC-EVs by ATC cells, with increased fluorescence intensity over 48 h. Functional assays revealed the selective inhibition of migration and invasion in a cell line-dependent manner, without affecting cell proliferation, viability, or tumorigenic traits, indicating a non-cytotoxic, context-specific modulation of tumor behavior. After 72 h of EV treatment, targeted qPCR of 92 cancer-related genes showed the strongest response in 8505C cells (24 genes; 16 up, 8 down), moderate changes in KTC-2 (16 genes; 14 up, 2 down), and few alterations in HTH83 (6 genes; 4 up, 2 down). Across all lines, FN1 emerged as a context-dependent target, downregulated in 8505C but upregulated in the other two. No broad pathway enrichment was observed, indicating the fine-tuning of key networks rather than wholesale reprogramming. Despite variations across cell lines, hDPSC-EVs consistently demonstrated no impact on cell proliferation and no evidence of cytotoxicity or tumorigenic behavior, with no adverse outcomes. These findings provide preclinical evidence for hDPSC-EVs as a promising, safe, and targeted therapeutic platform in precision oncology, particularly for aggressive cancers, like ATC, warranting further exploration in preclinical and clinical studies. Full article

Thyroid cancer (TC) invariably remains the most prevalent endocrine cancer in the world. Major histological forms of TC include papillary (PTC), follicular (FTC), medullary (MTC), and anaplastic thyroid carcinoma (ATC), each of which has a unique clinical and molecular profile. The incidence rate of TC is higher in females, and unfortunately, it has tended to increase over the last several years. Yet the treatment of advanced or aggressive TC forms has improved recently because of developments in immunotherapy and targeted medicines, including PD-1 inhibitors and tyrosine kinase inhibitors (e.g., lenvatinib, sorafenib). Imaging, fine-needle aspiration biopsies, and molecular testing are implemented in the diagnostic process, e.g., in search of mutations that might affect prognosis and provide the most successful treatment option. Chemotherapy, immunotherapy, radioactive iodine therapy (RAI), surgery (such as a total thyroidectomy), and molecularly targeted therapies are currently standard treatment modalities in TC. Optimizing patient outcomes requires better diagnostic precision and individualized treatment regimens based on the genetic profile and tumor subtype. To improve survival and quality of life, it is critical to comprehend the complex etiology of TC and the changing therapeutic landscape. Full article

Thyroid cancer (TC) is a significant global health issue that exhibits notable heterogeneity in incidence and outcomes. In low-resource settings such as Africa, delayed diagnosis and limited healthcare access exacerbate mortality rates. Among follicular cell-derived thyroid cancers—including papillary (PTC), follicular (FTC), anaplastic (ATC), and poorly differentiated (PDTC) subtypes—the role of CD44 variants has emerged as a critical factor influencing tumor progression and multidrug resistance (MDR). CD44, a transmembrane glycoprotein, and its splice variants (CD44v) mediate cell adhesion, migration, and survival, contributing to cancer stem cell (CSC) maintenance and therapy resistance. Differential expression patterns of CD44 isoforms across TC subtypes have shown diagnostic, prognostic, and therapeutic implications. Specifically, CD44v6 expression in PTC has been correlated with metastasis and aggressive tumor behavior, while in FTC, its expression aids in distinguishing malignant from benign lesions. Furthermore, CD44 contributes to MDR through enhanced drug efflux via ABC transporters, apoptosis evasion, and CSC maintenance via the Wnt/β-catenin and PI3K/Akt pathways. Targeted therapies against CD44 such as monoclonal antibodies, hyaluronic acid-based nanocarriers, and gene-editing technologies hold promise in overcoming MDR. However, despite the mounting evidence supporting CD44-targeted strategies in various cancers, research on this therapeutic potential in TC remains limited. This review synthesizes existing knowledge on CD44 variant expression in follicular cell-derived thyroid cancers and highlights potential therapeutic strategies to mitigate MDR, particularly in high-burden regions, thereby improving patient outcomes and survival. Full article

Anaplastic thyroid carcinoma (ATC) is the rarest and most aggressive form of thyroid cancer, marked by a poor prognosis and resistance to conventional treatments. Like many malignancies, ATC has a complex genetic landscape, with numerous mutations driving tumor initiation, progression, and therapeutic resistance. However, recent advances in molecular research have expanded our understanding of these genetic alterations, paving the way for new targeted treatment strategies. Currently, therapies targeting specific genetic mutations, such as BRAF and MEK, show promise, but their effectiveness is limited to patients harboring these mutations. To explore broader therapeutic possibilities, we conducted a comprehensive literature review using the PubMed database and Google to identify studies on key genetic mutations in ATC. By leveraging these molecular insights, we aim to highlight potential therapeutic avenues that could enhance treatment options and improve patient outcomes. Full article

Thyroid carcinomas are driven by diverse molecular alterations, but the tumor suppressor gene folliculin (FLCN), best known for its role in Birt–Hogg–Dubé (BHD) syndrome, has received limited attention in thyroid tumors. Here, we describe two thyroid tumors with pathogenic FLCN alterations—one germline and one somatic—and analyze the broader prevalence and significance of FLCN in thyroid carcinomas using multiple large sequencing datasets, including ORIEN-AVATAR. Patient 1, with a germline FLCN mutation and a history of BHD syndrome, presented with a well-circumscribed oncocytic adenoma. Molecular testing confirmed biallelic FLCN inactivation, but no additional mutations or aggressive features were observed, and the patient remained disease-free post-thyroidectomy. Patient 2 harbored a somatic FLCN mutation in an oncocytic poorly differentiated thyroid carcinoma, which exhibited extensive angioinvasion, high proliferative activity, and concurrent TP53 and RB1 mutations. The tumor progressed with metastatic disease despite multimodal treatment. Thyroid carcinomas revealed FLCN alterations in 1.1% of cases. Pathogenic mutations were rare but associated with oncocytic morphology, while homozygous deletions occurred more frequently in genomically unstable tumors, including anaplastic thyroid carcinoma. These findings suggest FLCN mutations may act as early oncogenic drivers in oncocytic thyroid neoplasms, while deletions represent secondary events in aggressive tumor evolution. The lack of FLCN coverage in standard thyroid molecular panels likely underestimates its clinical relevance. Including FLCN in genetic testing could improve tumor detection and characterization, particularly in BHD patients who may benefit from routine thyroid screening. Further studies are needed to clarify FLCN’s role in thyroid cancer pathogenesis. Full article

Background/Objectives: Thyroid cancer is the most common cancer of the endocrine system worldwide. Despite many available therapeutic options, the mortality rate of some subtypes, including anaplastic thyroid cancer, is still significant. Photodynamic therapy brings hope, which, through local activation of cell death pathways, as well as its effect on the immune system and vessels feeding the tumor, brings effects incomparable to classical methods. Photosensitizers particularly used in the case of thyroid cancer are hypericin, porphyrin, photophrin, radachlorin, or 5-aminolevulinic acid. Even better effects are achieved by administering sulforaphene, carboplatin, or genistein before therapy. Methods: For this research, we review articles in regard to provide a critical summary of the existing literature on thyroid cancer to explain the current state of scientific evidence on this topic. Conclusions: Photodynamic therapy is undoubtedly a technique of the future; the main advantages of which are low invasiveness, the possibility of combining with other treatment methods, or the possibility of outpatient use. Full article

Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer. Tumor cells have been shown to activate alternative signaling pathways, making treatments less effective. One of the major proteins involved in the progression of ATC is the proto-oncogene KRAS that belongs to a group of small guanosine triphosphate (GTP)-binding proteins. Despite its recognized importance in cancer malignancy, KRAS is considered non-druggable and has never been studied in the field of ATC. In this context, a new synthetic molecule, BAY-293, has recently been developed that selectively inhibits the KRAS–SOS-1 interaction. Based on these findings, the aim of this study was to evaluate for the first time the antitumor effect of BAY-293 using in vitro and in vivo models of ATC. The in vitro model included different thyroid cancer (TC) cell lines used to study the effect of BAY-293 on the modulation of mitogen-activated protein kinase (MAPK) pathways, apoptosis, and cell migration. To confirm the in vitro findings and better mimic the complex tumor microenvironment, an in vivo orthotopic model of ATC was used. The results of the study indicate that BAY-293, both in vitro and in vivo, effectively blocked the KRAS/MAPK/ERK pathway and β-catenin, which act as downstream effectors essential for cell migration, and increased the apoptotic process by slowing the progression of ATC. In conclusion, this study demonstrated that KRAS/SOS-1 inhibition could be a promising therapeutic target for the treatment of ATC and highlighted BAY-293 as an innovative molecule that needs further research to fully evaluate its efficacy in the field of thyroid cancer. Full article

Background: Meta-analyses aimed to assess the effectiveness and safety of targeted and contemporary therapies utilised in locally advanced and metastatic anaplastic thyroid cancer (ATC). Methods: Employing PRISMA and MOOSE guidelines, PubMed, Scopus, Cochrane Library and Web of Science were explored from the inception of targeted therapy until December 2024. A meta-analysis was performed to evaluate the effectiveness, toxicity and survival outcomes of various mutationally directed agents, chemotherapy and radiotherapy in locally advanced/metastatic ATC cases. Results: A total of 47 studies (26 prospective phase II trials and 21 retrospective studies) involving 980 patients met the inclusion criteria. The pooled results showed an overall response rate (ORR) of 29.7% (95% CI: 25.4–34.2%; I² = 42.4%; p < 0.0001). A total of 49.9% deaths were reported, although a significant number remained alive compared to baseline (mean difference [MD]: 2.07, 95% CI: 1.90–2.24; I² = 88.6%; p < 0.0001). The pooled median progression-free survival (PFS) was 5.4 months (95% CI: 4.0–6.7 months; I² = 97.9%; p < 0.0001). Dabrafenib/trametinib (DT) with and without pembrolizumab and lenvatinib plus pembrolizumab (LP) were associated with higher ORR rates and improved OS and PFS. About 51.% of studies mentioned bio-marker analysis (BRAFV600 [14.7%], PDL1 [9.2%], RAS [1.1%], PIK3CA [1.0%] and NTRK1/3 [0.7%]). Toxicity was reported in 94.7% of patients. Conclusions: This meta-analysis found that DT could be a promising first-line treatment option for BRAFV600-mutated ATC, with or without immunotherapy. Alternatively, LP shows potential in BRAFV600 wild-type and PDL1-overexpressing cases. Routine biomarker analysis remains critical for optimising ATC management strategies. Full article

Background: In this study, we evaluated the changes in clinicopathological features and prognosis in patients with thyroid cancer in the last two decades using the Surveillance, Epidemiology, and End Results Database (SEER) data. Methods: Data from the SEER-12 registry (1992–2021) were analyzed, focusing on patients diagnosed with malignant thyroid cancer between 2001 and 2020. The study population was divided into Cohort 1 (2001–2010) and Cohort 2 (2011–2020). Cohorts 1 and 2 were compared regarding clinicopathological features and prognosis. Results: The study included 94,892 patients diagnosed with thyroid cancer between 2001 and 2020, with 39,265 patients in Cohort 1 and 55,627 in Cohort 2. Compared to Cohort 1, in Cohort 2 showed a statistically significant increase in the proportion of patients aged 60+ (+4.2%), male patients (+2.1%), and cases of papillary cancer (+5.3%) and regional disease (+3.7%) (all p < 0.001). Although Cohort 2 demonstrated an 8% improvement in survival compared to Cohort 1, this result was not statistically significant (p = 0.057). Prognostic factors were identified, such as disease stage at diagnosis, age, gender, and origin. Among pathological subtypes, the patients with papillary + FV had the best prognosis (HR: 0.78), compared to patients in the other group, mainly comprising anaplastic tumors and sarcomas, which had the worst prognosis (HR: 9.61). Conclusions: In this large-scale study of thyroid cancer patients, we found significant differences between the two cohorts. In Cohort 2, the proportion of patients aged ≥60 years, male, and with papillary thyroid cancer was increased. We found that age, sex, origin, histopathological subtype, and stage at diagnosis were prognostic factors in patients with thyroid cancer. Also, we observed a trend toward improved survival in Cohort 2. Full article

Background: Thyroid cancer (TC) is the most prevalent endocrine malignancy, and is categorized into well-differentiated and aggressive anaplastic types. Novel therapeutic modalities are needed for TC. Nanomedicine is a promising strategy for the development of precision medicine. In this context, we investigated the use of nanogels (NGs) to deliver agents with different physicochemical properties, specifically the hydrophilic agent doxorubicin (DOX) and the hydrophobic compound curcumin (CUR), in TC cell lines. Methods: Nα-9-fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) peptide-based NGs loaded with DOX and CUR were formulated using the solvent-switch method. DOX-loaded NGs were previously characterized. CUR-loaded NGs were characterized through rheology, scanning electron microscopy (SEM), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), and Fourier transform infrared (FT-IR) spectroscopy. Confocal microscopy, q-RT-PCR, and ATP lite assays were performed to evaluate the uptake and delivery of DOX- and CUR-loaded NGs on TC cell lines. Results: CUR-loaded NGs exhibited a mean diameter of approximately 204.3 nm and a zeta potential of −34.6 mV, indicative of a good stability. In vitro release studies revealed a sustained release profile of CUR over 72 h. Functional analyses demonstrated that Fmoc-FF-loaded NGs were internalized into TC cell lines. They were primarily localized in the cytoplasm rather than in early endosomes, thereby ensuring intracellular stability. Furthermore, Fmoc-FF NGs reduced the nuclear uptake kinetics of DOX in TC cells, suggesting a potential reduction in dose-limiting toxicity. Comparative studies with CUR-loaded NGs revealed similar internalization and delayed nuclear uptake, highlighting the efficacy of Fmoc-FF NGs in delivering hydrophobic agents. Conclusions: Overall, the data suggest that Fmoc-FF NGs represent a promising strategy for delivering agents with diverse physicochemical properties in TC, enhancing their efficacy and safety and warranting further investigation. Full article

Background/Objectives MC4R expression and its role in colorectal and anaplastic thyroid cancers, where resistance to therapy and lack of standard treatments remain significant challenges, are poorly understood. This study aimed to investigate MC4R as a potential therapeutic target in these cancers using the selective antagonist ML00253764 (ML), alone and in combination with vinorelbine (VNR) and irinotecan (or its active metabolite SN-38). Methods: Human colorectal adenocarcinoma HT-29, Caco-2, and anaplastic thyroid carcinoma 8305C cell lines were used. MC4R expression was assessed by Real-Time PCR with validated primers (Assay ID Hs00271877_s1), immunofluorescence, and Western blotting. Proliferation and apoptosis assays were conducted with ML, and synergy with VNR and SN-38 was evaluated by Combination Index and Loewe methods. ERK1/2 phosphorylation was measured using an ELISA assay. In vivo studies were conducted by injecting tumor cells into Athymic Nude-Foxn1nu mice, treated with ML, VNR, irinotecan, or their combinations. Results: MC4R expression was confirmed in all cell lines. ML treatment inhibited MC4R, producing antiproliferative and pro-apoptotic effects, with IC₅₀ values of 7667 ± 2144.6 nM (8305C), 806.4 ± 321.8 nM (HT-29), and 2993 ± 1135.2 nM (Caco-2). In combination with VNR and SN-38, ML exhibited significant synergy in vitro and reduced tumor volume in vivo without causing weight loss or adverse effects in mice. Conclusions This study identifies ML as a promising therapeutic agent that, when combined with chemotherapy, may offer a novel strategy for treating colorectal and anaplastic thyroid cancers. Full article

The p53 protein is a tumor-suppressing transcription factor that is critical in tumorigenesis. While TP53 mutations are rare in differentiated thyroid cancer (DTC), they are significantly more common in anaplastic thyroid cancer (ATC). This study presents original results and a meta-analysis reevaluating the prognostic value of TP53 mutations in thyroid cancer, including surrogate markers such as immunohistochemical p53 expression and serum p53-Abs levels. TP53 mutations were analyzed using SSSP and direct sequencing in a DTC group (15 patients), an ATC group (3 patients), and a control group (25 patients). The immunohistochemical p53 expression was assessed in tissue samples. A meta-analysis of 14 eligible studies identified through the PubMed, Scopus, Google Scholar, and Cochrane databases was conducted. Our results showed TP53 mutations in all ATC cases, 6.67% of DTC cases (1 out of 15), and none in the control group. Immunohistochemical p53 overexpression was observed in 4 out of 15 DTC (26.67%) and all ATC cases but absent in controls. A meta-analysis confirmed that TP53 mutations are significantly more frequent in ATC than controls (OR 8.95; 95% CI: 1.36–58.70; p = 0.02) but not in DTC vs. controls (OR 1.87; 95% CI: 0.53–6.58; p = 0.33). p53 overexpression was significantly higher in both DTC and ATC vs. controls (OR 7.99; 95% CI: 5.11–12.51; p < 0.01 and OR 64.37; 95% CI: 27.28–151.89; p < 0.01, respectively). The serum p53-Abs positivity was also elevated in patients with PTC vs. controls (OR 2.07; 95% CI: 1.24–3.47; p < 0.01). TP53 mutations are frequent events in the pathogenesis of ATC. In DTC, further prospective studies are needed to determine the prognostic value of TP53 mutations and related surrogate markers (immunohistochemical p53 expression, p53-Abs positivity). Full article