Search Results (55)

Background: Radioiodine (Na[¹³¹I]I) therapy is the cornerstone of systemic treatment for differentiated thyroid cancer (DTC), exploiting sodium–iodide symporter (NIS) expression for durable control. Up to 30–40% of advanced cases develop radioiodine-refractory disease (RAI-R DTC), marked by impaired iodine uptake, aggressive behavior, and poor response to Na[¹³¹I]I. Locoregional treatments, multikinase inhibitors (MKIs), and selective targeted agents improve progression-free survival but are not curative and carry cumulative toxicity, motivating precision-based alternatives. The primary objective of this review is to clarify the evolving theranostic paradigm in RAI-R DTC; the secondary objectives are to appraise redifferentiation and iodine-based theranostics for restoring or exploiting iodine avidity and to evaluate non-iodine theranostic strategies for cases where iodine biology is absent, impaired, or unreliable. Methods: This narrative review synthesizes contemporary evidence on theranostic strategies in RAI-R DTC, drawn from available studies, clinical trials, and current guidelines, with an emphasis on redifferentiation and non-iodine approaches; a systematic search protocol was not applied. Results: Theranostics couples target-specific molecular imaging with matched radionuclide therapy and response-adapted sequencing. Its most transformative application is redifferentiation, in which pharmacologic modulation of oncogenic signaling can restore iodine avidity and enable renewed, dosimetry-guided Na[¹³¹I]I treatment. Beyond iodine, somatostatin receptor (SSTR) imaging and peptide receptor radionuclide therapy (PRRT) have re-emerged in very selected cases, whereas alpha emitters remain investigational. Refractoriness is increasingly viewed as a reversible continuum rather than a fixed state. Conclusions: Theranostics can individualize RAI-R DTC treatment, restoring or exploiting iodine biology where possible and shifting to non-iodine targets where it is unreliable. Patient selection, timing, and integration with systemic therapy are central, and prospective validation is needed. Full article

The Na⁺/I⁻ symporter (NIS) is the plasma membrane (PM) protein that actively mediates iodide (I⁻) transport into the thyroid gland. Pathogenic variants in the SLC5A5 gene cause iodide transport defects (ITDs). A heterozygous G288S NIS variant was identified in a Spanish family in which female carriers developed thyroid dysfunction during pregnancy. Here, we characterized the functional significance of the G288S variant and other substitutions at residue 288 of human NIS. Human NIS (hNIS) expression and maturation were analyzed by immunoblotting, its subcellular localization was analyzed by immunofluorescence and flow cytometry, and its activity was analyzed by radioiodide uptake assays. The G288S variant does not affect hNIS maturation, membrane trafficking, or I⁻ uptake capacity, but significantly reduces I⁻ affinity while preserving substantial transport activity. In contrast, substitutions introducing charged residues (arginine, aspartic acid, or glutamic acid) or proline severely disrupted NIS maturation, plasma membrane targeting, and iodide transport. Because the variant was identified in heterozygosity, we evaluated residue 288 substitutions under heterozygous-like conditions. Co-expression of the patient-derived G288S variant with WT NIS produced an intermediate apparent K_m without reducing V_max compared with WT, consistent with a modest co-expression-dependent kinetic effect rather than a strong dominant-negative mechanism. In contrast, the severely disruptive G288E substitution reduced cell-surface NIS expression under co-expression conditions, providing proof-of-principle evidence that severe alteration of residue 288 can impair NIS plasma membrane delivery. These findings highlight residue 288 as a key determinant of hNIS functionality and underscore the need to carefully evaluate heterozygous SLC5A5/NIS variants, as they may become clinically relevant under conditions of increased physiological iodine demand and contribute to partial iodide transport impairment. Full article

Cell-based immunotherapies require noninvasive tools that can quantify the migration, biodistribution, and persistence of administered immune cells. This review focuses primarily on oncologic immune cell therapy, while also considering selected inflammatory disease models in which immune-cell trafficking is biologically relevant. We critically compare direct radionuclide labeling, sodium iodide symporter (NIS)-based reporter gene imaging, radionuclide-integrated nanoplatforms, and Cerenkov-based hybrid optical conversion strategies. Direct labeling with agents such as [⁸⁹Zr]Zr-oxine, [¹¹¹In]In-oxine, and [⁹⁹ᵐTc]Tc-HMPAO enables early positron emission tomography (PET)/single-photon emission computed tomography (SPECT) biodistribution assessment, usually within hours to several days after cell administration. NIS reporter imaging with [¹²⁴I]NaI, [¹²³I]NaI, [⁹⁹ᵐTc]TcO₄⁻, or [¹⁸F]TFB supports repeated viability-dependent imaging, because signal generation depends on active transporter expression in living engineered cells. Radionuclide-integrated gold nanoplatforms can improve intracellular retention and offer theranostic potential through combined imaging, photothermal, radiotherapeutic, or immunomodulatory functions. We further discuss PET/SPECT balance, radiopharmaceutical nomenclature, nanoparticle stabilization, ethical aspects of genetic modification, tumor-on-a-chip systems for preclinical testing, and limitations of narrative evidence synthesis. Together, these platforms provide complementary strategies for image-guided immune cell therapy, with translational relevance for patient selection, treatment optimization, safety monitoring, and oncology practice. In conclusion, NIS-centered nuclear imaging and radionuclide-integrated nanoplatforms represent complementary, clinically actionable tools for quantitative immune-cell tracking, therapeutic optimization, and safety monitoring in translational oncology and inflammatory disease research. Full article

The sodium/iodide symporter (NIS/SLC5A5) is a major determinant of radioiodine therapy efficacy in differentiated thyroid cancer (DTC). This narrative review examines the molecular mechanisms underlying NIS dysregulation and radioiodine refractoriness in DTC. Reduced NIS expression or function in radioiodine-refractory DTC is associated with multiple mechanisms, including transcriptional suppression linked to MAPK/ERK and PI3K/AKT pathway activation and disruption of thyroid differentiation programs; epigenetic silencing involving SLC5A5 regulatory regions; impaired protein trafficking and membrane localization; and post-transcriptional regulation by microRNAs such as miR-221-3p, miR-222-3p, miR-146b-3p, and miR-204-5p. Genetic alterations including BRAF V600E and TERT promoter mutations are associated with dedifferentiated tumor phenotypes and poor radioiodine response. Redifferentiation approaches using MAPK pathway inhibitors such as selumetinib and dabrafenib can restore iodine uptake in selected patients, although the overall clinical applicability of these strategies remains under evaluation. A better understanding of these mechanisms may support improved biologic stratification and more selective therapeutic decision-making in radioiodine-refractory DTC. Full article

The sodium iodide symporter (NIS) is a key protein in thyroid function responsible for iodine uptake, and it may be involved in the pathogenesis of autoimmune thyroiditis. However, it is also expressed in the salivary glands, the primary target of autoreactive cells in Sjögren’s syndrome (SS). Given the common link between the two diseases, we computationally investigated whether the epitopes of NIS can trigger an immune response leading to SS in Hashimoto’s thyroiditis (HT) patients genetically predisposed to both diseases. The TepiTool 2016, ABCpred 2006, and DiscoTope 2.0 servers were used to predict T-cell and B-cell epitopes by inputting the FASTA sequences and 3D structures of NIS, thyroid peroxidase (TPO) and Ro60 Y RNA-binding protein (Ro60), which served as reference antigens for HT and SS, respectively. T-cell epitopes were selected based on their binding to a panel of human leukocyte antigen (HLA) alleles associated with both SS and HT. We identified a total of 376 linear T-cell epitopes, 64 linear B-cell epitopes and 68 conformational B-cell epitopes of NIS. Compared to TPO, NIS T-cell epitopes showed significantly lower affinity for HLA alleles (p < 0.0001), while no significant difference was found compared to Ro60. While linear B-cell epitopes of NIS, TPO, and Ro60 showed similar binding affinity, conformational epitopes of NIS were predicted to have higher immunogenicity than Ro60 (p = 0.04), while no significant difference was found compared to TPO. These pivotal findings, discovered by the methods of computer modeling, suggest that NIS can potentially activate T cells and B cells in patients with genetic predisposition to SS and HT and need to be confirmed by further laboratory studies. Full article

Background: Sodium/iodide symporter (NIS) is a membrane protein involved in iodide transport into cells, making it a key component of thyroid physiology and radioiodine therapy for thyroid cancer. Although NIS is expressed in many extrathyroidal tissues, including breast tumors, its functional role and prognostic significance in these contexts remain a subject of active investigation. Understanding the mechanisms regulating NIS, its influence on cellular processes such as migration and metastasis, and its connection with transcription factors like FOXA1 could contribute to the development of new therapeutic strategies for breast cancer treatment. This study aims to investigate the correlation between sodium/iodide symporter (NIS) expression and response to neoadjuvant chemotherapy in patients with triple-negative breast cancer (TNBC). Methods: The current retrospective study included 161 TNBC patients who received neoadjuvant chemotherapy followed by mastectomy. NIS expression was assessed via immunohistochemistry, graded semi-quantitatively from 0 to 3+. The Residual Cancer Burden (RCB) scale was used to evaluate the response to chemotherapy. Statistical analysis included Lilliefors tests and Kendall’s tau correlation coefficient. Publicly available Cancer Genome Atlas datasets were analyzed to assess the relationship between NIS and FOXA1 expression. Results: NIS immunopositivity was observed in 69.5% of TNBC samples compared to 63.3% GATA-3-positive and 31.0% of Mammaglobin-positive samples. While no significant correlation was found between NIS expression and age, TNM stage, or Ki-67, a statistically significant moderate positive correlation (τ = 0.481, p < 0.01) was identified between NIS expression and RCB index, indicating that higher NIS expression was associated with a poorer response to neoadjuvant chemotherapy. TCGA data analysis revealed a statistically significant increase in NIS mRNA expression in FOXA1-mutated TNBC samples compared to FOXA1-wild-type samples (p < 0.05). Younger patients exhibited higher Ki-67 levels (τ = −0.416, p < 0.05). Conclusions: Higher NIS expression correlates with chemoresistance to neoadjuvant chemotherapy in TNBC patients. This phenomenon may be linked to FOXA1 activity, suggesting that NIS may represent a potential biomarker for chemoresistance in TNBC. The inverse correlation between patient age and Ki-67 levels may be associated with a different mutational landscape in younger patients. Full article

Breast cancer is one of the most common malignancies worldwide, affecting 2.3 million and causing 670,000 deaths in women annually. However, data indicate that the risk of developing breast cancer decreases with pregnancy at a young age, and each subsequent pregnancy further reduces the risk by approximately 10%. One of the characteristics inherent in both the mammary gland epithelium in pregnant women and luminal epithelial adenocarcinomas is the increased expression of NIS—the sodium/iodide symporter, whose defective cytoplasmic forms possess pro-oncogenic properties. Therefore, the analysis of the degree of influence of pregnancy on NIS expression in breast cancer cells is of medical interest. The aim of this study is to conduct a comparative morphological analysis of NIS expression in breast cancer cells according to the number of pregnancies of each patient. This study included 161 patients with triple-negative breast cancer who visited the P.A. Herzen Moscow Oncology Research Institute from 2020 to 2023. Immunohistochemical examination was performed using antibodies to NIS. The gravidity status of women was determined based on provided medical documentation. The degree of NIS expression was assessed using a modified Gainor scale. Statistical analysis was performed using mean and standard deviation (SD) depending on the normality of the distribution (Lilliefors test: p > 0.20); a p-value ≤ 0.05 was considered statistically significant. The degree of correlation between variables was assessed using Kendall’s tau rank correlation coefficient. A weak to moderate negative correlation (τ: −0.369) was found between the number of pregnancies and the degree of NIS expression in triple-negative breast cancer cells. In patients with triple-negative breast cancer, a weak to moderate negative correlation was found between the degree of NIS expression and gravidity status. The discovered phenomenon is likely due to the terminal differentiation of the mammary gland epithelium that occurs during pregnancy. This may potentially indicate the suppression of pro-oncogenic properties of atypical cells developed from the epithelium that has undergone terminal differentiation. Full article

Background: Thyroid hormone synthesis requires the normal function of thyroid follicular cells and adequate nutritional intake of iodine. For in vitro studies on thyroid cell pathophysiology, the immortalized FRTL5 rat thyroid cell line and a derivative thereof, the PCCL3 cell line, are widely used. However, a permanent human thyroid cell line is currently lacking. A recent report described a cell line obtained from human thyroid cells designated as Cl-huThyrEC. Methods: Four clones of Cl-huThyrEC cells were obtained and cultured in the presence of thyroid stimulating hormone (TSH). The expression of key genes defining the thyroid follicular cell phenotype was determined by reverse-transcription PCR (RT-PCR) in FRTL5, PCCL3, and Cl-huThyrEC cells. The latter were cultured as monolayers and as organoids in Matrigel. Iodide uptake was measured and compared among the cell lines. Results: Gene expression analysis reveals that Cl-huThyrEC cells express the thyroid-restricted transcription factors (PAX8, NKX2.1, FOXE1), the TSH receptor (TSHR), and thyroglobulin (TG), but they do not express the sodium-iodide symporter (NIS), thyroid peroxidase (TPO), and pendrin (SLC26A4). In functional studies, Cl-huThyrEC cells are unable to concentrate iodide. Conclusions: Despite the expression of certain key genes that are limited or restricted to thyroid follicular cells, Cl-huThyrEC cells lack some of the essential characteristics of thyroid follicular cells, in particular, NIS. Hence, their utility as a model system for thyroid follicular cells is limited. Full article

Since the 1940s, 131-I radioiodine therapy (RIT) has been the primary treatment for metastatic differentiated thyroid cancer (DTC). Approximately half of these patients respond favorably to RIT, achieving partial or complete remission or maintaining long-term stable disease, while the other half develop radioiodine-refractory DTC (RAI-R DTC). The main genomic alteration involved in radioiodine resistance is the activated mitogen-activated protein kinase (MAPK) pathway, which results in the loss of sodium iodide symporters (NIS). Therefore, RAI-R DTC requires alternative treatment options such as tyrosine kinase inhibitors. Over the past decade, several studies have investigated pharmacological induction or enhancement of NIS expression through “redifferentiation” therapies, mainly targeting the MAPK pathway. These novel approaches can restore radioiodine sensitivity in previously refractory patients and, therefore, potentially reestablish the efficacy of RIT. This review discusses various redifferentiation strategies, including their molecular mechanisms and clinical implications. Full article

Hashimoto’s thyroiditis (HT) is a prevalent autoimmune disorder marked by chronic inflammation of the thyroid gland, predominantly affecting children and adolescents. In a previous study, we developed a “maximal” mathematical model of thyroid physiology to simulate the complex interactions within the thyroid gland. The present research introduces an enhanced version of the “maximal” model, integrating the pathophysiological impacts of HT. It specifically models the adverse effects of thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies (TPOAb and TgAb) on TPO, Tg, sodium iodide symporter (NIS), albeit indirectly, and thyroid volume. Additionally, we present a new “minimal” model offering a streamlined interpretation of thyroid physiology and pathophysiology, designed for faster computational analysis while maintaining essential physiological interactions. Both models were fitted against longitudinal clinical data from patients with HT, assessing the concentrations of Thyroid Stimulating Hormone (TSH), Thyroxine (T4), and thyroid volume over 36 months, in both untreated patients and those receiving levothyroxine (LT4) treatment. The adaptation of the models to data shows that both of them accurately reproduce the available observed clinical outcomes, with the “maximal” model providing more detailed physiological insights but requiring extensive data and longer computation times. In contrast, the “minimal” model, despite exhibiting less realistic TSH oscillations, offers rapid parameter estimation and may be more feasible in clinical settings. These models hold significant potential as tools for detailed study and management of HT, enabling simulations of disease progression and therapeutic responses, thus paving the way for personalized treatment strategies. Full article

Approximately 90% of thyroid cancers are differentiated thyroid cancers (DTCs), originating from follicular epithelial cells. Out of these, 90% are papillary thyroid cancer (PTC), and 10% are follicular thyroid cancer (FTC). The standard care procedure for PTC includes surgery, followed by radioiodine (RAI) ablation and thyroid-stimulating hormone (TSH) suppressive therapy. Globally, treating radioiodine-refractory DTC poses a challenge. During malignant transformation, thyroid epithelial cells often lose their ability to absorb radioiodine due to impaired membrane targeting or lack of NIS (sodium/iodide symporter) expression. Recent reports show an increase in PD-L1 (programmed death ligand 1) expression in thyroid cancer cells during dedifferentiation. However, no research exists wherein NIS and PD-L1 expression are analyzed together in thyroid cancer. Therefore, we aimed to investigate and correlate PD-L1 and NIS expression within primary tumor samples of lymph node metastatic PTC. We analyzed the expression of hNIS (human sodium/iodide symporter) and PD-L1 in primary tumor samples from metastatic PTC patients using immunohistochemistry. Immunohistochemistry analysis of PD-L1 and NIS was conducted in 89 and 86 PTC cases, respectively. Any subcellular NIS localization was counted as a positive result. PD-L1 expression was absent in 25 tumors, while 58 tumors displayed PD-L1 expression in 1–50% of their cells; in 6 tumors, over 50% of the cells tested positive for PD-L1. NIS immunohistochemistry was performed for 86 primary papillary carcinomas, with 51 out of 86 tumors showcasing NIS expression. Only in seven cases was NIS localized in the plasma membrane; in most tumors, NIS was primarily found in the intracytoplasmic membrane compartments. In the case of PD-L1 staining, cells showing linear membrane positivity of any intensity were counted as positive. The evaluation of NIS immunostaining was simpler: cells showing staining of any intensity of cytoplasmic or membranous fashion were counted as positive. The number of NIS positive cells can be further divided into cytoplasmic and membrane positive compartments. There was no observed correlation between PD-L1 and NIS expression. We can speculate that the manipulation of the PD-1/PD-L1 axis using anti-PD-L1 or anti-PD-1 antibodies could reinstate the functional expression of NIS. However, based on our study, the only conclusion that can be drawn is that there is no correlation between the percentage of NIS- or PD-L1-expressing tumor cells in the primary tumor of lymph node metastatic PTC. Full article

Background: Glioblastoma (GBM) is a highly aggressive, invasive, and growth factor-independent grade IV glioma. Survival following the diagnosis is generally poor, with a median survival of approximately 15 months, and it is considered the most aggressive and lethal central nervous system tumor. Conventional treatments based on surgery, chemotherapy, and radiation therapy only delay progression, and death is inevitable. Malignant glioma cells are resistant to traditional therapies, potentially due to a subpopulation of glioma stem cells that are invasive and capable of rapid regrowth. Methods: This is a literature review. The systematic retrieval of information was performed on PubMed, Embase, and Google Scholar. Specified keywords were used in PubMed and the articles retrieved were published in peer-reviewed scientific journals and were associated with brain GBM cancer and the sodium iodide symporter (NIS). Additionally, the words ‘radionuclide therapy OR mesenchyma, OR radioiodine OR iodine-131 OR molecular imaging OR gene therapy OR translational imaging OR targeted OR theranostic OR symporter OR virus OR solid tumor OR combined therapy OR pituitary OR plasmid AND glioblastoma OR GBM OR GB OR glioma’ were also used in the appropriate literature databases of PubMed and Google Scholar. A total of 68,244 articles were found in this search on Mesenchymal Stem Cell Sodium Iodide Symporter and GBM. These articles were found till 2024. To study recent advances, a filter was added to include articles only from 2014 to 2024, duplicates were removed, and articles not related to the title were excluded. These came out to be 78 articles. From these, nine were not retrieved and only seven were selected after the removal of keyword mismatched articles. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. Results: As a result of their natural capacity to identify malignancies, MSCs are employed as tumor therapy vehicles. Because MSCs may be transplanted using several methods, they have been proposed as the ideal vehicles for NIS gene transfer. MSCs have been used as a delivery vector for anticancer drugs in many tumor models due to their capacity to move precisely to malignancies. Also, by directly injecting radiolabeled MSCs into malignant tumors, a therapeutic dosage of beta radiation may be deposited, with the added benefit that the tumor would only localize and not spread to the surrounding healthy tissues. Conclusion: The non-invasive imaging-based detection of glioma stem cells presents an alternate means to monitor the tumor and diagnose and evaluate recurrence. The sodium iodide symporter gene is a specific gene in a variety of human thyroid diseases that functions to move iodine into the cell. In recent years, an increasing number of studies related to the sodium iodide symporter gene have been reported in a variety of tumors and as therapeutic vectors for imaging and therapy. Gene therapy and nuclear medicine therapy for GBM provide a new direction. In all the preclinical studies reviewed, image-guided cell therapy led to greater survival benefits and, therefore, has the potential to be translated into techniques in glioblastoma treatment trials. Full article

Adjuvant systemic therapies effectively reduce the risk of breast cancer recurrence and metastasis, but therapy resistance can develop in some patients due to breast cancer stem cells (BCSCs). Oncolytic adenovirus (OAd) represents a promising therapeutic approach as it can specifically target cancer cells. However, its potential to target BCSCs remains unclear. Here, we evaluated a Cox-2 promoter-controlled, Ad5/3 fiber-modified OAd designed to encode the human sodium iodide symporter (hNIS) in breast cancer models. To confirm the potential of OAds to target BCSCs, we employed BCSC-enriched estrogen receptor-positive (ER+) paclitaxel-resistant (TaxR) cells and tumorsphere assays. OAd-hNIS demonstrated significantly enhanced binding and superior oncolysis in breast cancer cells, including ER+ cells, while exhibiting no activity in normal mammary epithelial cells. We observed improved NIS expression as the result of adenovirus death protein deletion. OAd-hNIS demonstrated efficacy in targeting TaxR BCSCs, exhibiting superior killing and hNIS expression compared to the parental cells. Our vector was capable of inhibiting tumorsphere formation upon early infection and reversing paclitaxel resistance in TaxR cells. Importantly, OAd-hNIS also destroyed already formed tumorspheres seven days after their initiation. Overall, our findings highlight the promise of OAd-hNIS as a potential tool for studying and targeting ER+ breast cancer recurrence and metastasis. Full article

In targeted radionuclide therapy, determining the absorbed dose of the ligand distributed to the whole body is vital due to its direct influence on therapeutic and adverse effects. However, many targeted alpha therapy drugs present challenges for in vivo quantitative imaging. To address this issue, we developed a planar imaging system equipped with a cadmium telluride semiconductor detector that offers high energy resolution. This system also comprised a 3D-printed tungsten collimator optimized for high sensitivity to astatine-211, an alpha-emitting radionuclide, and adequate spatial resolution for mouse imaging. The imager revealed a spectrum with a distinct peak for X-rays from astatine-211 owing to the high energy resolution, clearly distinguishing these X-rays from the fluorescent X-rays of tungsten. High collimator efficiency (4.5 × 10⁻⁴) was achieved, with the maintenance of the spatial resolution required for discerning mouse tissues. Using this system, the activity of astatine-211 in thyroid cancer tumors with and without the expression of the sodium iodide symporter (K1-NIS/K1, respectively) was evaluated through in vivo imaging. The K1-NIS tumors had significantly higher astatine-211 activity (sign test, p = 0.031, n = 6) and significantly decreased post-treatment tumor volume (Student’s t-test, p = 0.005, n = 6). The concurrent examination of intratumor drug distribution and treatment outcome could be performed with the same mice. Full article

Leiomyosarcoma (LMS) has been challenging to diagnose because of limitations in clinical and radiographic predictors, as well as the lack of reliable serum or urinary biomarkers. Most uterine masses consist of benign leiomyoma (LM). However, it is currently a significant challenge in gynecology practice to differentiate LMS from LM. This inability poses grave consequences for patients, leading to a high number of unnecessary hysterectomies, infertility, and other major morbidities and possible mortalities. This study aimed to evaluate the use of Survivin-Sodium iodide symporter (Ad-Sur-NIS) as a reporter gene biomarker to differentiate malignant LMS from benign LM by using an F18-NaBF₄ PET/CT scan. The PET/CT scan images showed a significantly increased radiotracer uptake and a decreased radiotracer decay attributable to the higher abundance of Ad-Sur-NIS in the LMS tumors compared to LM (p < 0.05). An excellent safety profile was observed, with no pathological or metabolic differences detected in Ad-Sur-NIS-treated animal versus the vehicle control. Ad-Sur-NIS as a PET scan reporter is a promising imaging biomarker that can differentiate uterine LMS from LM using F18-NaBF₄ as a radiotracer. As a new diagnostic method, the F18 NaBF₄ PET/CT scan can provide a much-needed tool in clinical practices to effectively triage women with suspicious uterine masses and avoid unnecessary invasive interventions. Full article