tretinoin and Thyroid-Neoplasms

The purpose of this study was to evaluate the response of retinoic acid (RA) in radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC).. Systematic searches of MEDLINE (from inception to December 2016) and of EMBASE (from inception to December 2016) were performed for English-language publications on thyroid cancer treated with RA. Studies were classified according to the response criteria used: (1) 123I or 131I whole body scintigraphy (WBS), (2) serum thyroglobulin (Tg) level, (3) the response evaluation criteria in solid tumors (RECIST) version 1.0, and (4) World Health Organization (WHO) criteria.. Disease response rates as determined by WBS ranged widely between 6.2% and 46.1% with a pooled disease response rate of 27.6% (95% confidence interval: 21.7-34.0%). Response rates as determined by Tg level ranged from 56.6% to 83.3% (pooled response rate 61.3% (51.0-70.9%)), RECIST response rates from 0% to 45.5% (pooled response rate 17.0% (1.4-44.5%)), and according to WHO criteria, the pooled response rate was 30.8% (12.7-52.7%).. A minority of patients with RAI-refractory DTC respond to RA treatment.

Topics: Humans; Iodine Radioisotopes; Thyroglobulin; Thyroid Neoplasms; Tretinoin; Whole Body Imaging

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; 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Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; 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Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; 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STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Although well-differentiated thyroid carcinomas are usually curable by the combined effects of surgery, radioiodine ablation and thyroid stimulating hormone (TSH) suppressive therapy, recurrence develops in 20-40% of patients. During tumour progression, cellular de-differentiation occurs in up to 30% of cases and is usually accompanied by more aggressive growth, metastasis spread and loss of iodide uptake. The therapeutic options for de-differentiated thyroid cancer are limited and generally not efficient. Retinoic acids (RA) are biologically active metabolites of vitamin A that regulate growth and differentiation of many cell types, by binding to specific nuclear receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Recent studies have shown that RA can induce in vitro re-differentiation of thyroid carcinoma cell lines, as suggested by increased expression of the sodium/iodide symporter (NIS), type I iodothyronine deiodinase, alkaline phosphatase and by the increment of cellular (131)I uptake. In addition to re-differentiating effects, RA also exert anti-proliferative actions, as the inhibition of mitosis and the induction of apoptosis. Previous clinical studies have shown that iodide uptake may be re-stimulated after RA in about 20-50% of patients with radioiodine non-responsive thyroid carcinoma. Longer follow-up of patients demonstrated that, besides iodide uptake increment, RA can induce tumour regression or at least tumour growth stabilisation. The therapy is generally well tolerated and the most frequent side effects are dryness of skin and mucosa, and hypertriglyceridemia. This paper describes the recent advances in the field of thyroid cancer therapy and reviews the use of RA as a promising novel therapeutic tool.

Topics: Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Proliferation; Humans; Technology, Pharmaceutical; Thyroid Neoplasms; Tretinoin

The sodium iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates the active transport of iodide in the thyroid gland and a number of extrathyroidal tissues, in particular lactating mammary gland. Because of its crucial role in the ability of thyroid follicular cells to trap iodide, cloning of NIS opened an exciting and extensive new field of thyroid-related research. Cloning and molecular characterization of NIS allowed investigation of its expression and regulation in thyroidal and nonthyroidal tissues, and its potential pathophysiological and therapeutic implications in benign and malignant thyroid disease. In addition to its key function in thyroid physiology, NIS-mediated iodide accumulation allows diagnostic thyroid scintigraphy as well as effective therapeutic application of radioiodine in benign and malignant thyroid disease. Characterization and application of NIS as a novel therapeutic gene and the presence of high native NIS expression in the majority of breast cancers further suggest a promising role of NIS in diagnosis and therapy of cancer outside the thyroid gland.

Topics: Biological Transport, Active; Breast; Breast Neoplasms; Carcinoma, Papillary; Carcinoma, Papillary, Follicular; Female; Genetic Therapy; Humans; Iodine; Lactation; Male; Mutation; Prostatic Neoplasms; Symporters; Thyroid Diseases; Thyroid Gland; Thyroid Neoplasms; Thyroiditis, Autoimmune; Tretinoin

Thyroid cancer is relatively rare, accounting for 0.5 - 10 cases per 100,000 individuals per year. Despite their generally favourable prognosis, patients with differentiated thyroid cancer are at risk of tumour recurrence for decades after diagnosis. The optimal management remains controversial even in the low-risk patients because of the high cure rates, long natural history and rarity of these tumours. Therapeutic interventions in recurrent and metastatic differentiated thyroid cancer depend on the type of initial treatment, the site and the extent of disease. Surgical excision of the amenable-to-surgery lesions and radioiodine administration remain the first approach. External radiotherapy may be given to patients with inoperable lesions or those not concentrating radioiodine. Chemotherapy has not provided consistently successful results. Various therapeutic approaches for anaplastic carcinoma give poor results, making the development of novel treatments necessary. Innovative strategies, including recombinant human thyroid stimulating hormone, retinoic acid redifferentiation therapy and gene therapy, may lead to further improvement in the management of thyroid cancer arising from follicular cells.

Topics: Adenocarcinoma, Follicular; Adenocarcinoma, Papillary; Antineoplastic Agents; General Surgery; Genetic Therapy; Humans; Iodine Radioisotopes; Neoplasm Metastasis; Neoplasm Recurrence, Local; Recombinant Proteins; Thyroid Neoplasms; Thyrotropin; Tretinoin

For the treatment of differentiated thyroid cancer, surgery, radioiodide therapy, and thyrotropin-suppressive thyroxine application represent established therapeutic measures of proven efficiency, affording a good prognosis for this disease. However, in up to 30% of the cases, dedifferentiation is observed, giving rise to tumors that are refractory to conventional treatment. Eventually, this may lead to the most malignant human tumor, anaplastic thyroid carcinoma, with a life expectancy of only a few months after diagnosis. Among novel approaches for the treatment of dedifferentiated thyroid carcinomas, retinoic acid redifferentiation therapy was evaluated in several in vitro and in vivo studies. Cell culture experiments in thyroid carcinoma lines show that RA treatment affects thyroid specific functions (type I 5'-deiodinase, sodium/iodide-symporter), cell-cell or cell-matrix interaction (intercellular adhesion molecule-1, E-cadherin), differentiation markers (alkaline phosphatase, CD97), growth, and tumorigenicity. The observed changes, which involve multiple parameters that characterize a mature, functional thyrocyte, may be interpreted as partial redifferentiation. In clinical pilot studies, about 40% of the patients responded to RA application with an increased radioiodide uptake. In an evaluation of 20 RA-treated patients with well-documented data sets, 8 exhibited a decrease (4) or stabilization (4) in tumor size and/or in serum thyroglobulin levels in addition to enhanced radioiodide transport. This indicates that these patients with a long history of unresponsiveness to other treatment may have experienced an actual therapeutic benefit. These data suggest that RA redifferentiation therapy, considering especially its comparatively mild side effects, may soon represent an alternative therapeutic approach to otherwise untreatable thyroid tumors.

Topics: Cell Line; Clinical Trials as Topic; Humans; Pilot Projects; Thyroid Gland; Thyroid Neoplasms; Tretinoin

Topics: Animals; Cell Transformation, Neoplastic; Cytokines; Female; Gene Expression Regulation; Humans; Iodides; Mammary Glands, Animal; Pregnancy; Promoter Regions, Genetic; Symporters; Thyroglobulin; Thyroid Neoplasms; Thyrotropin; Tissue Distribution; Tretinoin

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; 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Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; 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STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Retinoic acid (RA) treatment has been used for redifferentiation of metastatic thyroid cancer with loss of radioiodine uptake. The aim of this study was to improve the understanding of RA resistance and investigate the role of bexarotene in thyroid cancer cells.. A model of thyroid cancer cell lines with differential response to RA was used to evaluate the biological effects of retinoid and rexinoid and to correlate this with RA receptor levels. Subsequently, thyroid cancer patients were treated with 13-cis RA and bexarotene and response evaluated on radioiodine uptake reinduction on posttherapy scan and conventional imaging.. In thyroid cancer patients, 13-cis RA resistance can be bypassed in some tumors by bexarotene. A decreased tumor growth without differentiation was observed confirming our in vitro data. Indeed, we show that ligands of RARs or RXRs exert different effects in thyroid cancer cell lines through either differentiation or inhibition of cell growth and invasion. These effects are associated with restoration of RARβ and RXRγ levels and downregulation of NF-κB targets genes. We show that bexarotene inhibits the transactivation potential of NF-κB in an RXR-dependent manner through decreased promoter permissiveness without interfering with NF-κB nuclear translocation and binding to its responsive elements. Inhibition of transcription results from the release of p300 coactivator from NF-κB target gene promoters and subsequent histone deacetylation.. This study highlights dual mechanisms by which retinoids and rexinoids may target cell tumorigenicity, not only via RARs and RXRs, as expected, but also via NF-κB pathway.

Topics: Antigens, Differentiation; Antineoplastic Agents; Bexarotene; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; E1A-Associated p300 Protein; Female; Gene Expression Regulation, Neoplastic; Humans; Isotretinoin; Male; Middle Aged; Neoplasm Invasiveness; NF-kappa B; Receptors, Retinoic Acid; Retinoid X Receptor gamma; Tetrahydronaphthalenes; Thyroid Neoplasms; Transcription, Genetic; Transcriptional Activation; Treatment Outcome; Tretinoin

To evaluate the changes in differentiation markers and therapeutic effects in all-trans-retinoic acid (ATRA)-treated patients with dedifferentiated thyroid cancer.. Between September 2001 and July 2004 eleven patients were analysed retrospectively. They had dedifferentiated thyroid cancers (DTC) (four follicular, five papillary, two oxyphilic) and were selected for treatment with ATRA (1.00+/-0.09 mg x kg x d) for 30 or 60 days. All patients had advanced stage tumours with prior operative and radioiodine treatment. Extensive tumour invasion, distant metastatic spread, and insufficient or non-existent uptake of radioiodine precluded conventional therapeutic options. Changes in I uptake, response of target lesions, and serum thyroglobulin (Tg) levels were measured and compared in these patients before and after ATRA therapy.. In 11 patients with DTC, iodine uptake was increased in four and there was a partial response (PR) of target lesions in five patients as well as two patients with stable disease. Tg was assessed in eight patients, in whom two responders showed increased radioiodine uptake or no change and decreased Tg level, as well as PR after ATRA-induced differentiation therapy.. ATRA has an effect on the differentiation status of DTC and deserves further investigation.

Topics: Adult; Antineoplastic Agents; Cell Transformation, Neoplastic; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Radionuclide Imaging; Radiopharmaceuticals; Thyroglobulin; Thyroid Gland; Thyroid Neoplasms; Treatment Outcome; Tretinoin

We sought to evaluate the efficacy, biochemical effects, safety and outcome of recombinant human thyroid-stimulating hormone (rhTSH) as an adjunct to radioiodine treatment of advanced differentiated thyroid carcinoma (DTC). We also sought to determine whether rhTSH is useful as an adjunct to radioiodine treatment following isotretinoin re-differentiation therapy of DTC metastases that have lost function. Therefore, in 54 consecutive patients who had retained bulky metastatic and/or locoregional lesions of DTC despite the exhaustion of other therapeutic options, we gave one to four courses of two consecutive daily intramuscular injections of rhTSH, 0.9 mg, followed by a therapeutic activity of (131)I per os on day 3. Fifty patients had received prior radioiodine treatment aided by l-thyroxine (T(4)) withdrawal. We included in the study 23 patients who had received a trial of isotretinoin therapy for re-differentiation of confirmed de-differentiated metastases. In a blinded, within-patient comparison of post-therapy whole-body scans after the first rhTSH-aided and latest withdrawal-aided treatments in patients with functional metastases at baseline, 18 of 27 (67%) scan pairs were concordant, four (15%) were discordant in favour of the rhTSH-aided scan and five (19%) were discordant in favour of the withdrawal-aided scan. In total, 37 (74%) of 50 paired scans were concordant, eight (16%) favoured rhTSH and five (10%) favoured withdrawal. All differences appeared to be attributable to clinical causes, not to any difference between endogenous and exogenous TSH stimulation. Reflecting the biochemical activity of rhTSH and the release of thyroglobulin (Tg) due to tumour destruction, median serum Tg concentration rose approximately fourfold between baseline and day 6 of the rhTSH-aided treatment course. rhTSH was well tolerated, with mostly minor, transient toxicity, except for neck oedema in three patients with neck infiltrates and pathological spine fracture in one patient with a large vertebral metastasis. At 6 months, complete response occurred in one (2%), partial response in 12 (26%) and disease stabilisation in 19 (40%) of 47 evaluable patients. The rate of complete + partial response was 41% and that of disease stabilisation, 30%, in the 27 evaluable patients with functional metastases at baseline; the corresponding rates were 10% and 55% in the 20 evaluable patients with non-functional metastases at baseline. Although within-patient comparison of early o

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Chemotherapy, Adjuvant; Female; Humans; Injections, Intramuscular; Iodine Radioisotopes; Male; Middle Aged; Neoplasm Recurrence, Local; Recombinant Proteins; Thyroid Neoplasms; Thyrotropin; Treatment Outcome; Tretinoin

Cellular retinoic acid-binding protein 2 (CRABP2) participates in retinoid partitioning between different nuclear receptors. Recently, we identified that CRABP2 is one of the progression-associated genes in thyroid cancer. To explore the prognostic and functional significance of CRABP2, immunohistochemical analysis was performed in thyroid tissues and neoplasms. Overexpression of CRABP2 was observed in malignant thyroid neoplasms but not in benign thyroid lesions. CRABP2 expression was an independent predictive factor for recurrence-free survival in patients with differentiated thyroid cancer. Knockdown of CRABP2 reduced the sensitivity of thyroid cancer cells to retinoic acid. Importantly, CRABP2 expression in thyroid cancer cells was associated with epithelial-mesenchymal transition properties, including anoikis resistance, migration, and invasion capacity. Furthermore, invasion promoted by CRABP2 was mediated at least partly by the integrin/focal adhesion kinase/AKT pathway. In summary, CRABP2 expression is upregulated in thyroid cancer with adverse prognostic implications. The invasion-stimulating effects appear independent of canonical retinoic acid signaling and may serve as a potential therapeutic target.

Topics: Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Integrins; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Proto-Oncogene Proteins c-akt; Receptors, Retinoic Acid; Recurrence; Thyroid Neoplasms; Tretinoin

Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Resveratrol; Stilbenes; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tretinoin; Up-Regulation

Recently, diagnoses of radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) have become more common; prognosis is poor. It has been suggested that cancer stem cells account for radiotherapy resistance. By flow cytometry, different expression percents of CD133 and OCT4 in thyroid cancer cell lines were detected. By real-time quantitative PCR, different mRNA expression of CD133, OCT4, GLUT1, thyroglobulin (TG), thyroperoxidase (TPO) and sodium iodine symporter (NIS) was analyzed; the localization of CD133, OCT4, and NIS expression was examined using immunofluorescence confocal microscopy. Different expression of CD133, OCT4, and NIS in 21 human thyroid cancer and nodule tissues was investigated using immunohistochemistry. CD133-positive cells were isolated by magnetic sorting. Stronger colony formation ability of CD133-positive and weaker ability of CD133-negative cells in vivo were examined by colony formation. The effects of all-trans retinoic acid (ATRA) on CD133-positive cells in vivo were explored with Cell Counting Kit-8, colony formation, apoptosis, cell cycle, and ethynyl deoxyuridine assays. The ARO cell line and RAI-R DTC tissue specimens had more CD133-positive cells. NIS expression was significantly lower in RAI-R DTC tissue compared to radioiodine-sensitive DTC (RAI-DTC) tissue and specimens from patients with thyroid nodule. ATRA inhibited the stem cell characteristics of CD133-positive cells and induced CD133-positive cell differentiation to CD133-negative cells, and promoted CD133-positive cell apoptosis.

Topics: AC133 Antigen; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Glucose Transporter Type 1; Humans; Neoplastic Stem Cells; Octamer Transcription Factor-3; Thyroglobulin; Thyroid Neoplasms; Tretinoin

All-trans retinoic acid (ATRA) is an anti-tumor compound, exerting different anti-cancer effects on different types of cancer cells. Unfortunately, retinoids are also characterized by certain side effects following systemic administration, such as the burning of skin and general malaise. The highly variable degree of bioavailability of ATRA plus its tendency to induce its own destruction through metabolic degradation following oral treatment necessitate the development of alternative formulations. The aim of this work is to evaluate the physico-chemical properties of unilamellar, ATRA-containing liposomes and to investigate the cytotoxic activity of this potential nanomedicine on human thyroid carcinoma cells. Liposomes made up of DPPC/Chol/DSPE-mPEG2000 (6:3:1 molar ratio), characterized by a mean diameter of ∼200nm, a polydispersity index of 0.1 and a negative surface charge, were used as ATRA-carriers and their antiproliferative efficacy was investigated in comparison with the free drug on three different human thyroid carcinoma cell lines (PTC-1, B-CPAP, and FRO) through MTT-testing. The liposomes protected the ATRA against photodegradation and increased its antiproliferative properties due to the improvement of its cellular uptake. ATRA-loaded liposomes could be a novel formulation useful for the treatment of anaplastic thyroid carcinoma.

Topics: Administration, Oral; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Carriers; Humans; Kinetics; Light; Liposomes; Microscopy, Confocal; Nanoparticles; Skin; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tretinoin

To determine whether all-trans retinoic acid (ATRA) could improve iodine uptake via repressing transcriptional activity of β-catenin in thyroid cancer cells.. Three kinds of treatment models were firstly established with alcohol, ATRA, and transfection of β-catenin shRNA in undifferentiated human thyroid cancer cell line-SW1736.Then the expressions of sodium iodide symporter (NIS), β-catenin and its regulating factors, epithelial-mensechymal transition (EMT)-phenotype, invasion and metastasis associated proteins were further measured in above three cell models.After that, the influence of ATRA on the functional expression of NIS, iodine uptake potency, tumor growth curve and treatment effect inducing by radioactive iodine was comparatively analyzed in vitro and in vivo trials.. After treated with ATRA, transcriptional activity of β-catenin decreased by downregulating phosphorylation of β-catenin Ser45, Y654 and GSK-3β Ser9. Additionally, ATRA effectively upregulated the protein level of NIS, and reversed EMT phenotype in alcohol treated cells, with absence in epithelial expression of E-cadherin and cytokeratin 18, as well as abnormal expression of Vimentin, urinary plasminogen activator (uPA), uPAR and Fibronectin.Compared with alcohol-treated group, both in vitro proliferation and invasion potential of ATRA treated cells markedly decreased (all P<0.05), and iodine uptake in vitro increased about 3.5-folds (P=0.007). In ATRA-treated animal model, tumor growth potential and tumor mass were significantly inhibited by radio-iodine ((131)I) treatment (all P<0.05).. ATRA can increase functional expression of NIS via downregulating transcriptional activity of β-catenin and promote isotope sensitivity to radio-iodine in human undifferentiated thyroid cancer.

Topics: beta Catenin; Blotting, Western; Cadherins; Cell Line, Tumor; Humans; Iodine; Phosphorylation; Symporters; Thyroid Neoplasms; Transcription, Genetic; Tretinoin; Urokinase-Type Plasminogen Activator

Recently, the main therapy of medullary thyroid cancer (MTC) is surgical, but by which way there is a poor prognosis with a mean survival of only 5 years. In some cases, some researchers found that it is the medullary thyroid cancer stem cells (MTCSCs) that cause metastasis and recurrence. This study aimed to eradicate MTCSCs through administration of all-trans-retinoic acid (ATRA). Here we demonstrate that MTCSCs possess stem- like properties in serum-free medium. The ABCG2, OCT4 and sodium iodide symporter (NIS) were changed by ATRA. Additionally, we found that ATRA can increase the expression of NIS in vivo. All the data suggested that ATRA could increase the iodine uptake of MTCSCs through NIS.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Carcinoma, Neuroendocrine; Humans; Iodine; Iodine Radioisotopes; Mice; Mice, Nude; Neoplasm Proteins; Neoplastic Stem Cells; Octamer Transcription Factor-3; Spheroids, Cellular; Symporters; Thyroid Gland; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

Retinoids have shown potential for the inhibition of tumour growth and progression. The objective of this study was to investigate retinoic acid nuclear receptor subtypes RAR/RXR and iodothyronine 5'-deiodinase, type I expression pattern in papillary thyroid tumour tissue of 26 patients in order to compare with those of the non-neoplastic thyroid tissue of the corresponding patients. The expression of selected parameters mRNA was examined by semi-quantitative RT-PCR. Papillary thyroid carcinoma (PTC) expressed RXRγ, when compared to non-neoplastic thyroid tissues of the corresponding patients that were lacking expression of RXRγ or its expression was very low. Moreover, we found significantly increased expression of RARα and RARγ in the overall group of PTC. This increase was detected in cases with positive lymph node metastasis (LNM), but not in cases with negative LNM. RARβ was significantly reduced in the subgroup of classic variant (CV). We also detected absence or significantly lower expression of hDIO1 mRNA in tumour tissue when compared to non-neoplastic tissue in both overall PTC cases and in the CV subgroup. However, the significantly decreased levels of hDIO1 mRNA were detected in cases with negative LNM but not in cases with positive LNM when compared to corresponding non-tumour tissue in both overall PTC cases and in the CV subgroup. Differences in RAR and RXR subtype mRNA expression patterns in various PTCs may contribute to the immunochemistry data available, and may thus find exploitation in clinical oncology, particularly in the differential diagnosis of thyroid neoplasms.

Topics: Adult; Aged; Carcinoma; Carcinoma, Papillary; Diagnosis, Differential; DNA-Binding Proteins; Female; Gene Expression Regulation, Neoplastic; Humans; Lymph Nodes; Male; Middle Aged; Neoplasm Metastasis; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoid X Receptor gamma; Retinoid X Receptors; RNA, Messenger; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tretinoin

Since all-trans retinoic acid (ATRA) has shown promising results in differentiation therapy, the present study was designed to investigate the effects of ATRA on thyroid carcinoma and to evaluate the effectiveness of ATRA in redifferentiation induction of thyroid carcinoma. Therefore, we investigated cell growth rate, morphological and nuclear: cytoplasmic ratio, adherent-dependent growth, response to chemotherapy drug following differentiation, T3 and T4 measurement, and critical genes expression pattern. Papillary cell line showed more growth inhibition by ATRA, in addition, mesenchymal and spindle-shape of 8305C cells changed to polygonal. Additionally, high nuclear: cytoplasmic ratio of anaplastic decreased significantly. Redifferentiation significantly suppressed the anchorage-dependent growth in the both cell lines in a dose-dependent manner, potentiated the arsenic trioxide (ATO) effects in anaplastic and papillary cell lines. Furthermore, reduction in the expression of stemness, and invasion related genes was observed in the both cell lines. Altogether, ATRA treatment could hold the aggressive behavior of thyroid carcinoma in restraint and/or potentiate the effect of chemotherapy drug ATO.

Topics: Antigens, Differentiation; Antineoplastic Agents; Carcinoma; Cell Dedifferentiation; Cell Differentiation; Cell Line, Tumor; Cell Nucleus Size; Cell Proliferation; Cell Shape; Cell Size; Cell Survival; Gene Expression; Humans; Thyroid Neoplasms; Thyroxine; Tretinoin; Triiodothyronine

Radioiodine ablation is ineffective in patients with radioiodine nonresponsive thyroid carcinoma. We investigated the effects of all-trans retinoic acid (ATRA) combined with histone deacetylase inhibitor, tributyrin on sodium-iodide symporter (NIS) expression, radioiodine uptake, and inhibition of cell proliferation in a poorly differentiated follicular thyroid carcinoma (FTC-133) in vitro.. FTC-133 cells were cultured in the presence of ATRA and tributyrin either as a single agent or in combinations for 48 h. The expression of NIS mRNA and protein was, respectively, detected by quantitative real-time polymerase chain reaction and western blot. The radioiodine uptake was determined after incubation of FTC-133 cells with 125I-iodide. Finally, the cell proliferation test of FTC-133 was performed after treatment.. Enhanced expression of NIS mRNA and protein was observed in FTC-133 cells treated with ATRA and tributyrin, which further resulted in significant higher levels of radioiodine uptake than that of untreated control cells and cells treated with ATRA alone. Additive inhibition of the proliferation of FTC-133 cells was also observed with the combination of ATRA and tributyrin.. The combination of ATRA and tributyrin induced a synergistic effect on radioiodine uptake and inhibition of FTC-133 cells proliferation in vitro. However, further in-vivo studies and additional molecular research will be needed to determine the absolute efficiency of radioiodine therapy.

Topics: Adenocarcinoma, Follicular; Biological Transport; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Iodine Radioisotopes; Symporters; Thyroid Neoplasms; Tretinoin; Triglycerides

The aim of this study was to assess the clinical outcome of redifferentiation therapy using retinoic acid (RA) in combination with 131I therapy, and to identify biological parameters that predict therapeutic response in Korean patients with radioiodine-refractory papillary thyroid carcinoma (PTC).. A total of 47 patients (13 men, 34 women; age 54.2±13.6 years) with radioiodine-refractory PTC underwent therapy consisting of consecutive treatment with 131I and RA. Each 131I/RA treatment cycle involved the administration of oral isotretinoin for 6 weeks at 1-1.5 mg/kg daily followed by a single oral dose of 131I (range 5.5-16.7 GBq). Therapeutic responses were determined using serum thyroglobulin (Tg) levels and the change in tumour size 6 months after completing the 131I/RA therapy. Biological parameters and pathological parameters before and after combined therapy were compared.. After completing 131I/RA therapy, 1 patient showed a complete response, 9 partial response, 9 stable disease, and 28 progressive disease, representing an overall response rate of 21.3%. Univariate analysis revealed that an age of <45 years and a persistently high serum Tg level were related to a good response. No clinical response was achieved when metastases showing no iodine uptake were present. Multivariate regression analysis showed that an age of <45 years was significantly associated with a good response. Of the 24 patients with well-differentiated carcinoma, 5 (20.8%) responded to 131I/RA therapy, whereas all 6 patients with poorly differentiated carcinoma failed to respond.. 131I/RA therapy was found to elicit a response rate of 21.3% among patients with radioiodine-refractory PTC, and an age of <45 years was found to be significantly associated with a good response.

Topics: Carcinoma; Carcinoma, Papillary; Combined Modality Therapy; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Republic of Korea; Retrospective Studies; Thyroid Cancer, Papillary; Thyroid Neoplasms; Treatment Failure; Tretinoin

The effectiveness rate of all-trans-retinoic acid (RA) is only about 30% in the clinical application of inducing thyroid carcinoma differentiation. In addition, there are severe toxic side effects, which limit its clinical application. Phase I-III clinical studies have been conducted on the combined application of two or more kinds of inductors in tumors. Nevertheless, the combination of RA with histone deacetylase inhibitors is rarely reported. This article studied the effects of differentiation for papillary thyroid carcinoma and follicular thyroid carcinoma cell lines induced by RA combined with trichostatin A (TSA), enhancing the effect of induction, while reducing the toxic side effects of a single drug, to provide a theoretical basis for preclinical trials.. After incubation with RA combined with TSA, K1 and FTC-133 were grouped into Group 1 (RA 10(-4) mol/L plus TSA 1.65 x 10(-7) mol/L), Group 2 (RA 1 x 10(-4) mol/L plus TSA 3.31 x 10(-7) mol/L), Group 3 (RA 10(-5) mol/L plus TSA 1.65 x 10(-7) mol/L), Group 4 (RA 1 x10(-5) mol/L plus TSA 3.31 x 10(-7) mol/L) by four varied concentrations and three time points (12 h, 24 h, and 48 h). The cell proliferation, conformation, toxic effect, and induced differentiation on K1 and FTC-133 cell lines were studied microscopically with hematoxylin-eosin (HE) to observe cell quantity and morphology, methyl-thiazolyl-tetrazolium (MTT) to calculate cell survival rates, and electrochemiluminescence analysis measuring in vitro thyroglobulin (Tg) levels.. The research showed that K1 and FTC-133 cells had cell spacing increases, with an outer edge of smooth, nuclear chromatin condensation after RA combined TSA. Survival rate were assessed by an analysis of variance (ANOVA) by concentration and time point, F values of K1 and FTC-133 were 23.52 and 170.14, and 57.09 and 224.35, respectively. There were significant differences for both cells (P < 0.01). The SNK analysis indicated that survival rates were in the order of Group 2 < Group 1 < Group 4 < Group 3. Tg was also assessed by ANOVA, F values of K1 were 69.63 and 101.07, and F values of FTC-133 were 79.77 and 81.72 (P < 0.01). Group 1 was compared with Group 3 of K1 and FTC-133 by the least significant difference (LSD) method, and there was no statistical difference between the two group (P = 0.06, 0.2, respectively; P > 0.05), yet a significant difference was seen between the other Groups.. Lower concentrations of RA combined with lower concentrations of TSA have both inhibited cell proliferation, decreased toxicity of the drugs, and increased the effect of K1 and FTC-133 cell differentiation. The mechanism of action may be that TSA has pretranscription DNA regulation and that RA has posttranscriptional signal regulation to enhance the effects of inhibited proliferation and differentiation of cells by transcription systems.

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Apoptosis; Carcinoma; Carcinoma, Papillary; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Thyroglobulin; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tretinoin

Our previous studies demonstrated that retinoic acid (RA)-induced reduction of both, the key glycolytic enzyme ENO1 and proliferation-promoting c-Myc, resulted in decreased vitality and invasiveness of the follicular thyroid carcinoma cell lines FTC-133 and FTC-238. By employing two-dimensional electrophoresis and mass spectrometry, we identified proteins affected by RA treatment. In addition to previously reported decrease in ENO1 expression, we found that RA led to significantly reduced levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase isoenzymes M1/M2 (PKM1/M2), peptidyl-prolyl cis-trans isomerase A (PPIA), transketolase (TKT), annexin A2 (ANXA2), glutathione S-transferase P (GSTP1) and peroxiredoxin 2 (PRDX2) as compared to untreated control. The same proteins investigated on thyroid tissues were found to be significantly up-regulated in follicular, papillary and undifferentiated thyroid carcinomas when compared with goiter and adenoma tissues. These findings identify new target proteins for RA-mediated anti-tumor and re-differentiation therapies and provide novel insights into treatments for thyroid carcinoma.

Topics: Adolescent; Adult; Aged; Biomarkers, Pharmacological; Biomarkers, Tumor; Carcinoma; Cell Line, Tumor; Female; Humans; Male; Metabolome; Middle Aged; Proteomics; Thyroid Neoplasms; Tretinoin; Young Adult

To investigate the anti metastatic potential of retinoic acid as an important determinant of metastatic behavior in thyroid carcinoma and understand the role of invasion associated proteins.. Differentiated thyroid carcinoma cell lines FTC-133 and XTC.UC1, anaplastic thyroid cancer cell lines C643 and HTH74 were studied. All cell lines were cultured with all-trans-RA (ATRA) or solvent ethanol. The in vitro invasion and adhesion potency were studied by transwell experiment and short-term adhesion assay. The functions of invasion associated proteins, urokinase type plasminogen activator (uPA), uPA receptor (uPAR), MMP2 and E-cadherin were investigated by semi-quantitative RT-PCR and Western blot.. In vitro invasion assay revealed that ATRA treatment could reduce the invasive potency in all the thyroid cancer cell lines. On Day 5 of ATRA treatment, the numbers of cells that migrated through extracellular matrix were as follows, in contrast to control group, FTC-133: 91±9 vs 118±10, C643: 92±17 vs 164±21, HTH74: 87±18 vs 169±15, and XTC.UC1: 95±23 vs 136±15, respectively (all P<0.05). Short term adhesion assay suggested that ATRA increases cancer cell adhesion to extracellular matrix (ECM) in C643, HTH74 and XTC.UC1. RT-PCR and Western blot both revealed diminished expression of uPAR in all four carcinoma cell lines. In C643 and HTH74 cell lines, the expression of uPA was reduced and the expression of E-Cadherin was increased; whereas the MMP2 expression was not significantly down-regulated in ATRA treated group. In ATRA treated FTC-133 and XTC.UC1 cell lines, MMP2 expression was decreased, but no significant changes in uPA and E-Cadherin expression were observed.. The present study demonstrates the influence of ATRA on two important determinants of metastatic behavior ("de adhesion" and proteolysis) in thyroid carcinoma cell lines.

Topics: Cadherins; Cell Adhesion; Cell Division; Cell Line, Tumor; Humans; Matrix Metalloproteinase 2; Neoplasm Invasiveness; Neoplasm Metastasis; Receptors, Retinoic Acid; Thyroid Neoplasms; Tretinoin; Urokinase-Type Plasminogen Activator

Retinoic acid (RA) acts as an anti-proliferative and redifferentiation agent in the therapy of thyroid carcinoma. Our previous studies demonstrated that pretreatment of follicular thyroid carcinoma cell lines FTC-133 and FTC-238 resulted in decreased in vitro proliferation rates and reduced tumor cell growth of xenotransplants. In addition to the previous results, we found that RA led to decreased vitality and invasiveness of FTC-133 and FTC-238 cells as they reacted with reduction of intracellular ATP levels and number of migrated cells respectively. However, the molecular mechanisms by which RA mediates these effects are not well understood. Two-dimensional (2D) screening of the proteins related to ATP metabolism and western blot analysis revealed alpha-enolase (ENO1) to be down-regulated in FTC-133 and FTC-238 cells after RA treatment. 2D gel detection and mass spectrometric analysis revealed that ENO1 existed as three separate protein spots of distinct pIs (ENO1-A1-A3). Comparative 2D difference gel electrophoresis analysis of fluorescently labeled protein samples of RA-treated and untreated FTC-133 demonstrated a selective down-regulation of ENO1-A1 which we identified as a phosphoprotein. RA caused the dephosphorylation of ENO1-A1. Both, RA-mediated and specific knock-down of ENO1/MBP-1 resulted in the reduction of MYC oncoprotein, and simultaneously decreased proliferation rates of FTC-133 and FTC-238 cell lines. In summary, the RA-mediated down-regulation of the ENO1 gene products and MYC oncoprotein provides a novel molecular mechanism facilitating the anti-proliferative effect of RA in human thyroid carcinoma cells and suggests new pathways for supportive RA therapies.

Topics: Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Line, Tumor; Cell Movement; Cell Proliferation; DNA-Binding Proteins; Electrophoresis, Gel, Two-Dimensional; Gene Expression Regulation, Neoplastic; Humans; Phosphopyruvate Hydratase; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Thyroid Neoplasms; Tretinoin; Tumor Suppressor Proteins

Retinoic acid presently is the most advanced agent able to improve the efficacy of radioiodine therapy in differentiated thyroid carcinoma. In order to identify compounds with higher efficacy a panel of pharmacologically well-characterized compounds with antitumour action in solid cancer cell lines was screened.. The effects of the compounds on iodide uptake, cell number, proliferation and apoptosis were evaluated.. In general, compounds were more effective in cell lines derived from more aggressive tumours. The effectiveness in terms of number of responsive cell lines and maximal increase in iodide uptake achieved decreased in the order: APHA > valproic acid approximately sirolimus approximately arsenic trioxide > retinoic acid approximately lovastatin > apicidine approximately azacytidine approximately retinol approximately rosiglitazone approximately bortezomib.. We hypothesize that testing of cells from primary tumours or metastases in patients may be a way to identify compounds with optimum therapeutic efficacy for individualized treatment.

Topics: Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Boronic Acids; Bortezomib; Carcinoma; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Iodides; Lovastatin; Neoplasm Metastasis; Oxides; Pyrazines; Sirolimus; Thymus Gland; Thyroid Neoplasms; Tretinoin

The prognosis of patients with metastasized thyroid carcinoma is not optimistic, necessitating the search for new treatment options.. Beneficial effects of retinoic acid (RA) have been suggested in thyroid cancer differentiation and the present study was performed to investigate the anti-metastatic potential of RA in respect of important determinants of metastatic behavior in thyroid carcinoma, focusing on the role of invasion-associated proteins.. Differentiated thyroid carcinoma cell lines FTC- 133 and XTC.UC1, and anaplastic thyroid cancer cell lines C643 and HTH74 were studied. All cell lines were cultured with alltrans- RA (ATRA) or the solvent ethanol. Invasion and adhesion potency in vitro was studied by transwell experiment and short-term adhesion assay. The involvement of invasion-associated proteins, urokinase type plasminogen activator (uPA), uPA receptor (uPAR), matrix metalloproteinase-2 (MMP-2) and E-cadherin, were investigated by semi-quantitative RT-PCR and Western blot.. In vitro invasion assay revealed that ATRA treatment could reduce the invasive potency in all the thyroid cancer cell lines, with the most significant effect in anaplastic cancer cells. Short-term adhesion assay suggested that ATRA increases cancer cell adhesion to extracellular matrix (ECM) in C643, HTH74 and XTC.UC1, probably through a transcriptional and translational regulation of some attachment molecules. RT-PCR andWestern blot both revealed diminished expression of uPAR in all four carcinoma cell lines. In C643 and HTH74 cell lines, the expression of uPA was reduced and the expression of E-cadherin was increased, whereas the MMP-2 expression was not significantly down-regulated in ATRA-treated group. In ATRA-treated FTC-133 and XTC.UC1 cell lines, MMP-2 expression was decreased, but no significant changes in uPA and E-cadherin expression were observed.. The present study demonstrates the influence of ATRA on both important determinants of metastatic behavior ("de-adhesion" and proteolysis) in thyroid carcinoma cell lines, especially in anaplastic cancer cells. These findings may add to the explanations for beneficial effects of RA in the treatment of metastatic thyroid carcinomas.

Topics: Adenocarcinoma, Follicular; Adult; Cadherins; Cell Adhesion; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Male; Matrix Metalloproteinase 2; Neoplasm Invasiveness; Thyroid Neoplasms; Tretinoin; Urokinase-Type Plasminogen Activator

We studied cell growth rate, mechanisms of growth inhibition, phenotype re-differentiation, expression of RARalpha, beta, gamma and differentiation thyroid genes before and after combined treatment with 5-Aza-CdR and RA (5-Aza/RA) of human thyroid carcinoma cell lines (FRO, WRO, TT). Furthermore, the activity and localization of the re-expressed sodium-iodide-symporter (NIS) protein was analyzed. After 5-Aza/RA treatment, all cell lines showed a significant reduction in cell growth. This was associated with apoptosis in the TT, with inhibition of cell proliferation in the WRO, and with cell cycle impairment in FRO and WRO. FRO and WRO treated with 5-Aza/RA lost the ability to grow in soft agar. FRO re-expressed thyroid transcription factor-1 and thyroglobulin, TT and WRO re-expressed PAX-8 and FRO and TT re-expressed RARbeta and NIS mRNA. Despite this expression, they were unable to take up iodine: a cytoplasmic localization of NIS protein was demonstrated in FRO. In conclusion, besides a significant reduction in cell growth rate and in the ability to grow in soft agar, treatment with 5-Aza/RA partially re-differentiated FRO and induced expression of NIS mRNA and protein in FRO and TT, but this treatment was unable to restore the functional activity of NIS, likely because it was located into the cytoplasm without reaching the plasma membrane.

Topics: Azacitidine; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Colony-Forming Units Assay; Decitabine; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Humans; Organ Specificity; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Symporters; Thyroid Neoplasms; Tretinoin

The anti-proliferative effect of retinoic acid (RA) has been documented for various tumors. Some 40% of patients with advanced and poorly differentiated thyroid cancer have been shown to respond to RA with increased uptake of radioiodine. It has been suggested that these effects may be caused by redifferentiation. Presently, little is known about the effects of RA on tumor angiogenesis, a prerequisite for growth and metastatic spread. The aim of the current study was to determine, whether tumor-induced angiogenesis of thyroid cancer is affected by RA. In vitro, the effect of 0.1/10 microM 13-cis RA on tumor cell number (MTT assay) and secretion of VEGF (ELISA) was analyzed in three thyroid cancer cell lines (FTC 236, C634 and XTC), as well as in endothelial cells (HUVEC) over several passages. In vivo, tumor growth, VEGF-expression and microvessel density (VSD) of RA treated thyroid cancer cells after xenotransplantation to nude mice was evaluated by morphometric analysis. In vitro, thyroid cancer cell lines responded to RA with reduced proliferation, ranging from 26 to 34% after 2 weeks of treatment and with up to 80% reduced secretion of VEGF. In vivo, tumor volumes of animals receiving RA were reduced by 33% (FTC 236), 27% (C643) and 6% (XTC), respectively. VSD of experimental tumors was diminished in the FTC 236 (25%) and the C643 cell line (15%), and almost unchanged in XTC tumors (7%). In vivo, VEGF-expression and apoptosis were not significantly affected by RA. In vitro, proliferation of HUVEC was inhibited by conditioned medium of C643 cells pretreated with RA (0.1/10 microM), as well as by administration of RA (0.1/10 microM). This study confirms thyroid tumor cell growth to be inhibited by RA. It demonstrates a decrease of in vitro VEGF accumulation and reduction of VSD in experimental undifferentiated thyroid carcinoma, suggesting that reduced angiogenesis may be an important mechanism responsible for the therapeutic effect of RA in thyroid cancer. Moreover, a direct anti-proliferative effect of RA on human endothelial cells is suggested.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Endothelial Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Thyroid Neoplasms; Transplantation, Heterologous; Tretinoin; Vascular Endothelial Growth Factor A

We report the characteristics of three cell lines (designated, SNU-80, SNU-373 and SNU-790), which were established from two papillary carcinomas and one anaplastic carcinoma obtained from three Korean thyroid carcinoma patients. All cell lines grow as adherent cells. Electron microscopy characteristically showed cytoplasmic invaginations of nuclei and intranuclear cytoplasmic inclusions. SNU-80 and SNU-790 cells showed a positive reaction to anti-cytokeratin antibody, and SNU-790 cells positivity for CK-19. All lines were free of mycoplasma or bacteria and were proven unique by DNA fingerprinting analysis. The p15 and p16 genes are deleted in the SNU-790 line. Mutations of the p53 gene were found in two lines (SNU-80 and SNU-373), but no mutations in the RET or MEN1 genes were observed. Mutations of the BRAF gene were found in the SNU-80 (G468R) and the SNU-790 (V599E) cell lines, but no mutations in the K-ras gene were present. SNU-80 and SNU-790 cells showed a positive reaction to anti-cytokeratin antibody, and no evidence of the production of thyroglobulin or calcitonin was observed. The cell lines were unable to trap radioactive iodine but did not contain TSH receptor. In addition, we investigated the mRNA expression levels of Tg, TSHR, TTF-1, PAX-8, NIS, IL-6, and LIF, and of the alpha, beta and gamma retinoic acid receptors in these cell lines. IL-6 was down-regulated in all three cell lines by all-trans-retinoic acid treatment. RAR-alpha was expressed but RAR-beta was not expressed in the three cell lines, and RAR-gamma was not expressed in SNU-790. Interestingly, RAR-beta (SNU-80 and SNU-373) and RAR-gamma (SNU-790) was up-regulated by all-trans-retinoic acid treatment. We believe that these well-characterized thyroid carcinoma cell lines may be useful tools for investigations on the biological characteristics of thyroid carcinoma, particularly for investigations related to gene alterations, especially of the BRAF gene. These cell lines may also be useful for redifferentiation therapy studies on thyroid carcinoma using all-trans-retinoic acid.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Humans; Mutation; Neoplasm Proteins; Proto-Oncogene Proteins B-raf; Thyroid Neoplasms; Tretinoin

Treatment with retinoic acid (RA) is effective to restore radioactive iodine uptake in metastases of a small fraction of thyroid cancer patients. In order to find predictive markers of response, we took advantage of two thyroid cancer cell lines, FTC133 and FTC238, with low RA-receptor (RAR)beta expression but differing in their response to RA. We report that in both cell lines, RA signalling pathways are functional, as transactivation of an exogenous RARbeta2 promoter is effective in the presence of pharmacological concentrations of all-trans RA, and enhanced in RA-resistant FTC238 cells after ectopical expression of RARbeta, suggesting a defective endogenous RARbeta2 promoter in these cells. Further analyses show that whereas the RARbeta2 promoter is in an unmethylated permissive status in both FTC133 and FTC238 cells, it failed to be associated with acetylated forms of histones H3 or H4 in FTC238 cells upon RA treatment. Incubation with a histone deacetylase inhibitor, alone or in combination with RA, restored histone acetylation levels and reactivated RARbeta and differentiation marker Na+/I- symporter gene expression. Thus, histone modification patterns may explain RA-refractoriness in differentiated thyroid cancer patients and suggest a potential benefit of combined transcriptional and differentiation therapies.

Topics: Acetylation; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; DNA Methylation; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Promoter Regions, Genetic; Receptors, Retinoic Acid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroid Neoplasms; Transcriptional Activation; Tretinoin

The aim of this study was to comparatively investigate the effects of 5-azacytidine-C (5-Aza), trichostatin-A (TSA), and all-trans retinoic acid (ATRA) on mRNA expressions of Na/I symporter (NIS), thyroglobulin (Tg), thyroid peroxidase (TPO), and thyroid stimulating hormone receptor (TSH-R), and radioiodine (RAI) uptake in cancer (B-CPAP) and normal (Nthy-ori 3-1) thyroid cell lines. Cell lines were treated with 10 ng/mL of TSA, 5 microM of 5-Aza, and 1 microM of ATRA, according to the MTT (methyl-thiazol-tetrazolium) test results. Additionally, recombinant thyroid stimulating hormone (rTSH) was also applied, with a selected dose of 100 ng/mL. Following the treatment, NIS, Tg, TPO, and TSH-R mRNA levels were detected by real-time-polymerase chain reaction (RT-PCR) and RAI uptakes were measured by using a well counter as the counts/cell number. 5-Aza increased TSH-R mRNA expression in both of the cell lines and decreased TPO, NIS, and Tg mRNA levels in the cancer cell line. In the normal thyroid cell line, 5-Aza increased TPO mRNA levels 2-fold and made no differences in NIS and Tg mRNA levels. TSA treatment repressed NIS and Tg mRNA levels, and made no differences on other thyroid specific genes investigated in the cancer cell line. In the normal thyroid cell line, TSA increased TSH-R mRNA levels in 72 hours and created no important differences in other genes. ATRA repressed the TSH-R mRNA levels in the normal thyroid cell line and increased the TPO and Tg mRNA levels slightly in both cell lines. Furthermore, in short-term treatment, ATRA repressed NIS gene expression slightly, but in the long term, this repression turned to basal levels. 5-Aza, TSA, and ATRA did not make any differences in RAI uptake in the cancer cell line, but rTSH increased RAI uptake significantly. In the normal thyroid cell line, TSA and ATRA decreased RAI uptake (to 1/10 and 1/2, respectively), but 5-Aza and rTSH increased RAI uptake significantly (2- and 4-fold, respectively). We have shown an increase in TSH-R gene expression and radioiodine uptake with 5-Aza. Further in vitro and in vivo studies are needed to support our findings and the potential clinical use of this agent.

Topics: Aged; Apoptosis; Azacitidine; Cell Line, Tumor; Gene Expression Regulation; Humans; Hydroxamic Acids; Iodine Radioisotopes; Proteins; RNA, Messenger; Thyroid Gland; Thyroid Neoplasms; Time Factors; Tretinoin

The aim of this study was to comparatively investigate the effects of 5-azacytidine-C (5-Aza), trichostatin-A (TSA), and all-trans retinoic acid (ATRA) on the mRNA expressions of the sodium and iodine (Na/I) symporter (NIS), thyroglobulin (Tg), thyroid peroxidase (TPO), and the thyroid-stimulating hormone receptor (TSH-R), as well as radioiodine (RAI) uptake in cancer (B-CPAP) and normal (Nthy-ori 3-1) thyroid cell lines. Cell lines were treated with 10 ng/mL of TSA, 5 microM of 5-AZA, and 1 microM of ATRA, according to the MTT (methyl-thiazol-tetrazolium) test results. Additionally, recombinant thyroid-stimulating hormone (rTSH) was also applied, with a selected dose of 100 ng/mL. Following the treatment, NIS, Tg, TPO, and TSH-R mRNA levels were detected by real-time-polymerase chain reaction (RT-PCR) and RAI uptakes were measured by using a well counter as counts/cell number. 5-Aza increased TSH-R mRNA expression in both of the cell lines and decreased TPO, NIS, and Tg mRNA levels in the cancer cell line. In the normal thyroid cell line, 5-AZA increased TPO mRNA levels by 2-fold and made no differences in NIS and Tg mRNA levels. TSA treatment repressed NIS and Tg mRNA levels and made no change on other thyroid-specific genes that were investigated in the cancer cell line. In the normal thyroid cell line, TSA increased TSH-R mRNA levels in 72 hours and created no important difference in the other genes. ATRA repressed the TSH-R mRNA levels in the normal thyroid cell line and increased the TPO and Tg mRNA levels slightly in both the cell lines. Furthermore, in short-term treatment, ATRA repressed the NIS gene expression slightly, but in the long term, this repression turned to basal levels. 5-Aza, TSA, and ATRA did not make any changes in RAI uptake in the cancer cell line, but rTSH increased RAI uptake significantly. In the normal thyroid cell line, TSA and ATRA decreased RAI uptake (to 1/10 and 1/2, respectively), but 5-Aza and rTSH increased RAI uptake significantly (2- and 4-fold, respectively). In our study, we showed an increase in TSH-R gene expression and radioiodine uptake with 5-Aza. Further in vitro and in vivo studies are needed to support our findings and the potential clinical use of this agent.

Topics: Aged; Apoptosis; Azacitidine; Cell Line, Tumor; Gene Expression Regulation; Humans; Hydroxamic Acids; Iodine Radioisotopes; Proteins; RNA, Messenger; Thyroid Gland; Thyroid Neoplasms; Time Factors; Tretinoin

Histone deacetylase (HDAC) inhibitors have been shown to reverse repression of some genes, including retinoic acid (RA) receptor beta2. In this work, we studied the effects of RA alone or combined with the HDAC inhibitor sodium butyrate (NaB) in a poorly differentiated thyroid carcinoma cell line (FTC-133) cultured in vitro or transplanted into nude mice. In vitro, the action of the xenobiotics on cell differentiation was evaluated by the measurement of alkaline phosphatase (ALP) activity. In vivo, FTC cells were injected in nude mice divided into four groups: controls, RA (1 mg/kg), NaB (50 mg/kg) in two daily injections or both RA plus NaB. Body weight, tumoral volume (TV), doubling time of the tumor, specific growth delay and inhibition of tumoral growth at day 35 were determined in each group. In vitro, RA increased the NaB-induced increase in ALP activity. In vivo, body weight and TV decreased with RA or NaB. Specific growth delay significantly increased with RA (72.5%; P < 0.001) and with NaB (31.3%; 0.02

Topics: Alkaline Phosphatase; Animals; Body Weight; Butyrates; Cell Differentiation; Cell Proliferation; Drug Synergism; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Thyroid Neoplasms; Tretinoin

Radioiodine (I-131) therapy is of proven efficacy for differentiated thyroid carcinoma. However, its efficacy relies on specific uptake mechanisms, which may be lost during the evolution of the disease. Attempts to increase the iodine uptake of such tumors have been made using retinoic acid because it exerts redifferentiating effects on thyrocytes. This study aims to assess the capability of the retinoic acid (RA) treatment to reinforce iodine 131-irradiation efficacy for metastatic and progressive multi-irradiated thyroid cancer. In this clinical prospective study, 11 patients (mean age +/- 1 SD = 61 +/- 12 years, sex ratio M/F = 5/6) with a progressive disease despite iterative surgery and iodine irradiations were treated with 13-cis-retinoic acid (1.5 mg/kg day) over 8 weeks prior to I-131 irradiation. The redifferentiating effect of RA was evaluated by serum thyroglobulin (Tg) monitoring during RA treatment and qualitative analysis of iodine uptake on the post-therapeutic whole body scan. The clinical usefulness of RA treatment was assessed by clinical follow-up, Tg monitoring, and tumor size. No serious event that could possibly be related to the treatment was reported. The mean follow up time was 24.2 +/- 12 months (range 3-46 months). Iodine uptake was only slightly improved in two patients. Nevertheless, the clinical benefits of RA seem to be very poor. Five patients died of a metastatic disease. Five others presented new clinical evidences of a progressive disease. In conclusion, this prospective study demonstrates the absence of efficacy of I-131 irradiation combined with RA for the treatment of patients with aggressive, rapidly growing metastatic thyroid cancer. Thus, patients with highly aggressive disease, rapidly growing in a short period from 2 to 6 months, should not be considered for RA therapy.

Topics: Adult; Aged; Combined Modality Therapy; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prospective Studies; Reproducibility of Results; Thyroid Neoplasms; Tretinoin

The plasma membrane glycoprotein sodium/iodide symporter (NIS) is crucial for thyroid hormone biosynthesis and mediates the iodide uptake of thyrocytes. It has been shown that retinoic acid (RA) alters NIS gene expression in thyroid carcinoma lines and stimulates their iodide uptake. Here, we generated an ARO human thyroidal cancer cell line that expresses the NIS gene (ARO-NIS) and found that its baseline 125I uptake was threefold higher than that of its parental ARO cells. However, a 1-microM all-trans retinoic acid (tRA) treatment significantly increased this 125I uptake up to approximately approximately 6.5-fold on Day 3. tRA also elevated NIS mRNA expression in ARO-NIS cells, with peaks of expression being observed on Day 3. To investigate the underlying genomic mechanisms involved in these tRA-induced phenotypic changes, we subjected tRA-treated and untreated ARO-NIS cells to cDNA microarray analysis. Of 1152, genes spotted onto the microarray membrane, 18 were up-regulated (z ratio>2.0) and 33 were down-regulated (z ratio<-2.0) in ARO-NIS cells after 3 days of tRA treatment. More specifically, tRA increased the expression of BCL3, CSRP3, v-fos, and CDK5 genes and decreased the expression of the FGF12 and IGFBP6 genes. Thus, tRA treatment of human anaplastic thyroid carcinoma cells stably expressing the NIS gene significantly elevates their NIS-mediated radioiodine uptake and alters the expression of many genes involved in cell growth and cellular differentiation. Therefore, tRA treatment and NIS gene transfection are potential tools for the diagnosis and treatment of thyroid cancer.

Topics: Carcinoma; Cell Line, Tumor; Dose-Response Relationship, Drug; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Iodine Radioisotopes; Metabolic Clearance Rate; Neoplasm Proteins; Radiopharmaceuticals; Symporters; Thyroid Neoplasms; Tretinoin

Conventional chemotherapy and radiotherapy are ineffective for the treatment of advanced thyroid tumors like poorly differentiated papillary, anaplastic, and medullary thyroid cancer. In the attempt to evaluate the possibility of using retinoic acid (RA) in the treatment of thyroid cancer refractory to conventional therapy, we studied the effect of all-trans-RA treatment on five human thyroid cancer cell lines. We found that WRO and NPA, derived from follicular and poorly differentiated human thyroid carcinoma, respectively, showed a growth inhibition after 25 and 21 d of RA treatment. Both apoptosis and a decrease in DNA synthesis were observed as mechanisms of growth inhibition. In the NPA cell line, a delay of cell-cycle progression has also been observed. On the contrary, we did not observe any recovery of mRNA expression of thyroid-specific genes and in particular of the sodium iodide symporter gene. The lack of recovery of radioiodide uptake after all-trans-RA treatment confirmed the inability to reexpress sodium iodide symporter mRNA. The main difference between the all-trans-RA responding cells (WRO and NPA) and the nonresponding cells [ARO, FRO (derived from human anaplastic thyroid tumors) and TT (derived from human medullary thyroid tumor)] was the basal and all-trans-RA induced RA receptor (RAR)beta mRNA expression. Interestingly, 14 thyroid tumors (10 papillary and four anaplastic) showed a significant lower expression of RARbeta mRNA when compared with normal thyroid tissues. In agreement with this result, only 30% of papillary thyroid carcinomas analyzed were positive for RARbeta protein expression with a degree of expression that was much lower than that found in normal thyroid tissue. In conclusion we found that all-trans-RA treatment can determine a significant in vitro growth inhibition especially in differentiated thyroid tumor-derived cell lines but it seems unable to reinduce the expression of thyroid-specific genes and in particular to reinduce the ability to take up iodine. The growth inhibition is likely due to apoptosis in an early phase and to a decrease of DNA synthesis later. In some cases, a delay of the cell-cycle progression also may be responsible for the growth inhibition. The finding of a basal and RA-induced RARbeta mRNA expression only in cell lines responding to all-trans-RA suggests that the growth inhibition might be mediated by RARbeta.

Topics: Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Receptors, Retinoic Acid; RNA, Messenger; Thyroid Gland; Thyroid Neoplasms; Tretinoin

Disturbed expression of retinoic acid (RA) receptors (RAR/RXR) contributes to the pathogenesis and tumor progression of epithelial carcinomas.. To examine whether altered responses to retinoids may correlate with differences in RA receptor equipment, retinoid effects were examined in human thyroid carcinoma cell lines of various differentiation stages in culture and after xenotransplantation onto rodent models.. Cell growth was assessed by the MTT test, mRNA expression was examined by Northern blot and quantitative competitive RT-PCR, and type I 5'-deiodinase (5'DI) activity was measured by in vitro deiodination assay. Nude rats and mice were used for xenotransplantation experiments.. All-trans-RA and RAR-selective synthetic retinoids stimulated activity and mRNA expression of the thyroid differentiation marker 5'DI in the follicular thyroid carcinoma cell line FTC-133. In the less differentiated FTC-238 cells, stimulation of 5'DI activity was less pronounced than in FTC-133 cells, and a reduced level of RAR beta mRNA was detected. In the anaplastic thyroid carcinoma cell lines HTh 74 and C 643, the activity of 5'DI was not increased by retinoids, and expression of RAR alpha mRNA was reduced. Proliferation of FTC-133 and FTC-238 cells was decreased by all-trans-RA. Pretreatment of FTC-133 with RA resulted in a reduced tumor growth in xenotransplantation experiments as compared with untreated control cells. This reduction was less pronounced in the case of FTC-238 cells. Thus, retinoid therapy might be applied to treat follicular thyroid carcinomas. However, tumor-specific RAR repertoires need to be analyzed as a prerequisite for successful intervention with appropriate, probably receptor-selective retinoids.

Topics: Adenocarcinoma, Follicular; Animals; Antineoplastic Agents; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Rats; Rats, Nude; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; RNA, Messenger; Thyroid Neoplasms; Tretinoin; Xenograft Model Antitumor Assays

It was shown previously that hNIS mRNA expression is stimulated by retinoic acid (RA) in human follicular thyroid carcinoma cell lines FTC-133 and FTC-238, and patients with thyroid carcinomas lacking iodide uptake respond to RA treatment with increased radioiodide transport. Here, in transient transfection experiments using FTC-238 cells, hNIS promoter/luciferase reporter constructs showed an up to 2.5-fold increase in transcriptional activity after incubation with 1 microM RA. Stimulation by 10 nM T3 was up to 2.4-fold. Deletion or block mutation of a putative nuclear receptor recognition site, 'DR10', abolished RA and T3 responses. Four copies of the DR10 cloned 5' to the thymidine kinase promoter gave a 2.6-fold and a 1.4-fold increase in transcriptional activity after RA and T3 stimulation, respectively. In electrophoretic mobility shifts, a wildtype DR10 oligonucleotide, but not block mutants of either DR10 halfsite, interacted with nuclear receptors. Thus, RA redifferentiation of advanced thyroid carcinomas may reinduce iodide uptake by stimulating hNIS expression and thereby make tumours accessible for radioiodide therapy again.

Topics: Adenocarcinoma, Follicular; Animals; Genes, Reporter; Humans; Iodine Radioisotopes; Oligonucleotides; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear; Response Elements; Symporters; Thyroid Neoplasms; Transfection; Tretinoin; Triiodothyronine; Tumor Cells, Cultured

Retinoic acid (RA) has antiproliferative as well as redifferentiating effects in thyroid cancers. Similar effects have been seen with phenylacetate (PA) therapy. These observations prompted us to evaluate the potential antiproliferative effects of the combination of RA and PA in follicular thyroid cancer.. Three follicular cell lines were treated in vitro with varying concentrations of all-trans RA or PA alone or in combination. Growth was measured by dimethyl-thiazol-diphenyltetrazolium bromide assays.. RA (1-2.5 micromol/L) and PA (1-10 mmol/L) alone inhibited cell growth in a time- and dose-dependent manner, with maximum effect at 5 days. The combination of RA and PA had synergistic antiproliferative effects. In the FTC-133 cell line, RA alone (2.5 micromol/L) inhibited growth 16% and PA alone (10 mmol/L) inhibited growth 35% versus controls, whereas the combination of the 2 inhibited growth by 60% at 5 days (P < .005). Similar results were seen with FTC-236 and FTC-238 cell lines.. Our results support that RA and PA have antiproliferative effects in follicular thyroid cancer and are synergistic. The combination of RA and PA may be beneficial in the treatment of advanced thyroid cancers for which conventional therapy fails or as an adjuvant to radioactive iodine therapy in aggressive tumors.

Topics: Antineoplastic Agents; Cell Division; Dose-Response Relationship, Drug; Drug Synergism; Humans; Phenylacetates; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

A new human thyroid carcinoma cell line, KTC-1, was established from the malignant pleural effusion of a recurrent thyroid carcinoma patient. Cytogenetic analysis revealed a normal karyotype, and no p53 mutation in exons 5-9 was detected. This cell line is tumorigenic in athymic nude mice. Histological findings by light and electron microscopy, such as the absence of follicular structures and the existence of intranuclear cytoplasmic inclusions and psammoma bodies, indicated transplanted tumors to be a poorly differentiated papillary thyroid carcinoma. A low expression level of thyroglobulin was detected by immunocytochemistry and RT-PCR. Messenger ribonucleic acid (mRNA) expression of thyroid transcription factor-1 and PAX-8 was also detected. No mRNA expression of TSH receptors, thyroid peroxidase, or Na+/I- symporter was detected. Interleukin-6 and leukemia inhibitory factor were secreted into the medium. These findings suggest this cell line to be functionally poorly differentiated. Moreover, all-trans-retinoic acid increased the mRNA expression of thyroglobulin and decreased both the mRNA expression and secretion of interleukin-6 and leukemia inhibitory factor while significantly stimulating growth. RT-PCR analysis of retinoic acid receptors (RARs) revealed that KTC-1 cells express a moderate level of RARalpha and -gamma, but a low level of RARbeta. This cell line may be useful for studying redifferentiation therapy for thyroid carcinoma.

Topics: Animals; Carcinoma, Papillary; Cell Differentiation; Cell Division; Cytokines; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Genes, p53; Growth Inhibitors; Humans; Interleukin-6; Leukemia Inhibitory Factor; Lymphokines; Mice; Mice, Nude; Nuclear Proteins; Paired Box Transcription Factors; PAX8 Transcription Factor; Polymorphism, Single-Stranded Conformational; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroglobulin; Thyroid Gland; Thyroid Neoplasms; Thyroid Nuclear Factor 1; Trans-Activators; Transcription Factors; Transcription, Genetic; Transplantation, Heterologous; Tretinoin; Tumor Cells, Cultured

NGF has anti-proliferative and anti-invasive effects in neuroendocrine tumors. In the present work we examined the effects of NGF and retinoic acid on cell proliferation and invasion in thyroid carcinoma cells. We found that NGF and retinoic acid do not affect cell proliferation on their own but in combination they produce a strong inhibition. We also found that retinoic acid regulates the matrix metalloproteinase 2 activity and invasion. In contrast, NGF inhibited invasion and reverted the effect of retinoic acid. This effect of NGF is likely mediated by an increase in adhesion to laminin and collagen IV and the inhibition of cell migration. NGF also induced the expression of the p75 NGF receptor. In conclusion, NGF and retinoic acid in combination inhibit proliferation and invasion of thyroid papillary carcinoma cells. These data open the possibility of a potential combined therapy for thyroid papillary carcinomas.

Topics: Antineoplastic Agents; Carcinoma, Papillary; Cell Adhesion; Cell Division; Cell Movement; Humans; Matrix Metalloproteinase 2; Neoplasm Invasiveness; Nerve Growth Factor; Receptor, Nerve Growth Factor; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

CD97 is a dimeric glycoprotein belonging to the secretin receptor superfamily and is abundantly expressed in cells of hematopoietic origin. The aim of this study was to analyze the expression of the CD97 protein in thyroid carcinomas and the role of all-trans-retinoic acid (RA) in the regulation of CD97 protein in monolayer culture of the human follicular thyroid carcinoma cell line FTC-133. In normal thyroid tissue, no immunoreactivity of CD97 could be found, whereas in differentiated thyroid carcinomas, CD97 expression was either lacking or low. Undifferentiated anaplastic thyroid carcinomas revealed high CD97 expression. The expression of CD97 protein seems to be correlated to the postoperative histopathological classification staging. Approximately 50% of FTC-133 cells expressed the CD97 protein under basal culture conditions. No differences were found in the number of CD97-positive cells after TSH, forskolin, and insulin treatment compared to control values. Epidermal growth factor treatment led to an increase in CD97 immunostaining (up to 90%), whereas phorbol 12-myristate 13-acetate slightly decreased the immunoreactivity of CD97 (from 50% to 30%). Under basal conditions, RA treatment for 72 h led to a decrease in total cell number by 33% and in CD97-positive cells from 50% to 30%. TSH, forskolin, phorbol 12-myristate 13-acetate, and insulin showed no effect after 72-h pretreatment with RA, whereas epidermal growth factor treatment led to a slight increase in the number of the CD97-positive cells (from 30% to 40%) compared to the control value. These data suggest that CD97 expression may play an important role in the dedifferentiation of thyroid tumors, and RA might interfere with this process in thyroid carcinoma by suppressing the dedifferentiation marker CD97.

Topics: Adult; Aged; Antigens, CD; Carcinoma; Cell Count; Cell Division; Child; Female; Humans; Male; Membrane Glycoproteins; Middle Aged; Receptors, G-Protein-Coupled; Stimulation, Chemical; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

Thyroid carcinomas no longer accessible to radio-iodide or TSH-suppressive T4 therapy, due to loss of thyroid-specific functions, might be sufficiently re-differentiated by retinoic acid (RA) to be treated by conventional methods again. To help evaluate the feasibility of RA re-differentiation therapy in thyroid carcinomas, we examined the functionality of RA receptors (RARs/RXRs), central RA signal mediators, in human thyroid-carcinoma cell lines as model systems. [3H]-RA binding assays with nuclear extracts from follicular thyroid-carcinoma cell lines FTC-133 and -238 revealed high-affinity binding sites for RA. Electrophoretic mobility shift and super-shift assays using a DR2 ("direct repeat" 2) RA response element demonstrated DNA-binding of RARalpha, RARgamma, RXRalpha and RXRbeta in nuclear extracts of FTC-133 and anaplastic HTh74 cells. Use of a DR5 RA response element revealed no difference in DNA binding. In supershift assays with a DR4 T3 response element, we found DNA-binding by TRalpha1, TRalpha2, and TRbeta. Northern-blot analysis showed low expression of RXRbeta mRNA in FTC-133 and of TRalpha1 mRNA in FTC-133 and FTC-238 cells. Using RT-PCR, we detected mRNA for RARalpha, RARbeta, RARgamma, RXRalpha, and RXRbeta in the 4 cell lines and in human thyroid-carcinoma samples. RARbeta mRNA was reduced in FTC-238 cells and RXRbeta mRNA was decreased in anaplastic C643 cells and 9 of 12 tumor samples. Differential RA regulation of RA-receptor-mRNA expression was observed in the various cell lines. Thus, RA and T3 nuclear receptors are present in thyroid-carcinoma cell lines or tissues, albeit with cell-line and tumor-dependent variations; in the cell lines, they were shown to be functional with respect to DNA and/or ligand binding.

Topics: Carcinoma; Feasibility Studies; Humans; Neoplasm Proteins; Polymerase Chain Reaction; Receptors, Retinoic Acid; Receptors, Thyroid Hormone; RNA, Messenger; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

The purpose of this study was to investigate the effects of cytokines and retinoic acid in human thyroid cancer cell growth. Cellular proliferation studies of the CGTH W-1 and SW 579 cell lines were performed with various cytokines and all-trans retinoic acid (RA). Cell number was determined by cell counting and incorporation of [3H]thymidine into DNA. Inhibitory effects of tumour necrosis factor alpha (TNF-alpha) were found in both cell lines. SW 579 was more sensitive to TNF-alpha. The SW 579 cell line revealed gradually decreased cell proliferation in [3H]thymidine incorporation studies as TNF-alpha concentration increased. In contrast, the CGTH W-1 cell line revealed prominent suppressive effects when the TNF-alpha concentrations increased over 1 ng/ml. An inhibitory effect of interleukin 1 beta (IL-1 beta) on CGTH W-1 cells was noted at the concentration of 1 ng/ml, however, IL-1 beta failed to demonstrate an inhibitory effect in SW 579 cells.

Topics: Adenocarcinoma, Follicular; Cytokines; Humans; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

We report on a patient with a follicular Hurthle cell carcinoma in whom distant metastases were initially radioiodine negative or only weakly positive. Redifferentiation therapy with 13-cis retinoic acid induced a significant radioiodine uptake in metastatic tissue. Thyroglobulin (Tg) immunostaining and autoradiography of a bone metastasis in the right femur, which was initially radioiodine negative, proved Tg synthesis, combined with iodine incorporation into tumor cells. Glucose metabolism in metastases was partially increased and partially unchanged after redifferentiation therapy. The distinct increase of serum Tg after retinoic acid treatment was interpreted as a functional sign of redifferentiation.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Female; Femoral Neoplasms; Femur; Humans; Thyroglobulin; Thyroid Gland; Thyroid Neoplasms; Tomography, Emission-Computed; Tretinoin

This study examined the action of 9-cis retinoic acid and 1,25-dihydroxyvitamin D3 analogues (KH 1060, EB 1089 and MC 903) on the release of calcitonin (CT) and calcitonin gene-related peptide (CGRP) in the rat C cell line CA-77. This cell line mainly secretes CGRP. Using radioimmunoassays (RIAs) for CT and CGRP, we measured the release of both peptides in the culture medium as well as the amount of these proteins contained in the CA-77 C cells. 9-cis retinoic acid decreased the release of both CGRP and CT dose-dependently in the range between 1 nM and 1 microM. The half-effective dose was 10 nM. The treatment of CA-77 C cells with 0.1 microM calcitriol alone only slightly decreased the release of both CT and CGRP. The increase in the amount of CT and CGRP released by the action of 1 microM dexamethasone was reduced by 1 microM 9-cis retinoic acid, and this effect was enhanced by the addition of 0.1 microM calcitriol or KH 1060, EB 1089 and MC 903. When the C cells were continuously stimulated by dexamethasone, after 6 days of exposure to the combined treatment with calcitriol analogues + 9-cis retinoic acid, there was a greater decrease in the amount of CGRP contained in the C cells than after treatment with 9-cis retinoic alone. Our data suggested that combined treatment with retinoic acid and calcitriol analogues exerted a stronger inhibition on the amounts of the two peptides either contained in the cells or released in the medium than each hormone alone.

Topics: Alitretinoin; Animals; Calcitonin; Calcitonin Gene-Related Peptide; Calcitriol; Carcinoma, Medullary; Dexamethasone; Dose-Response Relationship, Drug; Drug Interactions; Kinetics; Rats; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

Decreased iodide uptake in de-differentiated thyroid carcinomas impedes radioiodide therapy. RTPCR analysis revealed reduced expression of Na+/I- symporter (NIS) mRNA in human thyroid carcinomas as compared to normal thyroid. However, in follicular thyroid carcinoma cell lines FTC-133 and FTC-238, treatment with 1 microM all-trans retinoic acid (RA) markedly increased NIS mRNA levels. Anaplastic thyroid carcinoma cell lines HTh74 and C643 showed basal expression of NIS mRNA, but no RA-stimulation. All four cell lines contained the approximately 80 kD NIS protein as judged by Western blot, although they did not accumulate iodide. In contrast, in nontransformed rat FRTL-5 cells, 1 microM RA downregulated NIS mRNA levels, inhibited the TSH- or forskolin-triggered induction of NIS message after TSH-depletion, and reduced iodide uptake to 38% after 5 d. This divergent RA-responsivity of NIS may provide the means to target radioiodide to thyroid carcinomas by upregulating iodide transport into tumor tissue while simultaneously inhibiting iodide accumulation in normal thyrocytes and may thus re-establish the potential for radioiodide therapy.

Topics: Animals; Blotting, Northern; Blotting, Western; Carrier Proteins; Colforsin; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Iodides; Membrane Proteins; Polymerase Chain Reaction; Rats; RNA, Messenger; Symporters; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Tretinoin; Tumor Cells, Cultured

This study was aimed to establish TSH dependent, transplantable thyroid tumor (TT) in B6C3F1 (BCF1) mice. In addition, transplanted TT was examined for its growth in mice given 17 beta-estradiol (E2), retinoic acid (RA), tamoxifen (TAM), T3 and T4. Both sexes of BCF1 mice were observed for 12 months under IDD and distilled water (DW), starting at 4 weeks of age. Groups of mice received an i.p. injection of radioactive iodine (131I) once at a dose of 60 mu Ci/head and/or given 0.25 mg E2 pellet s.c. One piece of induced pituitary or thyroid tumor was individually dissected aseptically and s.c. grafted under the fat pad of one site of the neck in the same strain of mice at 5 weeks of age. All mice were sacrificed between 7.5 to 13.5 months after grafting the tumors depending on the experiments. The transplantability of both pituitary and thyroid tumor was 100% in IDD mice, but TT was about 50% with a combined treatment of IDD plus E2. A supplement of thyroid hormones of T3 or T4 in mice with IDD completely inhibited the growth of in situ or grafted thyroid tumors. The growth of in situ thyroid gland was significantly promoted by the oral administration of RA in both sexes, whereas the growth of transplanted TT was significantly increased by RA in the female, but not in the male. Oral administration of TAM proved inhibitory upon in in situ and transplanted TT in the male, but not in the female. Thyroid tumor induced by IDD could grow only in mice with IDD and was partially regulated of its growth by RA and TAM.

Topics: Animals; Estradiol; Female; Iodine; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Pituitary Neoplasms; Tamoxifen; Thyroid Neoplasms; Thyroxine; Tretinoin; Triiodothyronine

Retinoic acids (RAs), well characterized regulators of proliferation and differentiation, partly re-differentiate follicular thyroid carcinoma cell lines (FTC-133, FTC-238, and HTC-TSHr) as well as SV40-transfected immortalized thyroid cell lines (ori3 and 7751). This is indicated by the stimulation of type I 5'-deiodinase and other differentiation markers. As demonstrated by RT-PCR, electrophoretic mobility shift, and [3H]-retinoic acid binding assays, thyroid carcinoma cell lines express RA receptor mRNAs and functional ligand- and DNA-binding receptor proteins able to mediate RA-dependent signal transduction. Together, these properties make these thyroid-derived cell lines useful in vitro models for studying the effects of an RA re-differentiation therapy of thyroid cancer.

Topics: Animals; Cell Differentiation; Cell Division; Cell Line, Transformed; Humans; Iodide Peroxidase; Rats; Receptors, Retinoic Acid; Retinoids; RNA, Messenger; Simian virus 40; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

The expression of intercellular adhesion molecule-1 (ICAM-1) in tumoral tissues may promote their interaction with the immune system and cytotoxic effect on tumoral cells. This observation led to the investigation of ICAM-1 expression and modulation in different tumoral cell systems in vitro. Recently, retinoic acid-responsive elements have been found in the 5'-regulatory region of the human ICAM-1 gene. In the present study, we investigated, by flow cytometry, the effect of retinoic acid on the surface expression of ICAM-1 in human thyroid carcinoma cell lines. Two papillary (NPA and TPC-1), one follicular (WRO), one anaplastic (ARO) and one immortalized fetal (TAD-2) cell line have been studied. All of them produced constitutively ICAM-1; its surface expression and specific messenger ribonucleic acid (mRNA) levels were increased significantly by retinoic acid in all except the WRO cell line. ICAM-1 hyperexpression by retinoic acid was time dependent, reversible, and dependent on mRNA and protein synthesis. Furthermore, cytokines, such as interferon-gamma and tumor necrosis factor-alpha, both individually and, to a greater extent, in combination with retinoic acid, increased ICAM-1 surface expression and its mRNA levels. In conclusion, retinoic acid is able to induce ICAM-1 up-regulation via mRNA accumulation in human thyroid carcinoma cell lines.

Topics: Blotting, Northern; Cell Adhesion Molecules; Cycloheximide; Cytokines; Dactinomycin; Histocompatibility Antigens Class I; HLA-DR Antigens; Humans; Intercellular Adhesion Molecule-1; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

The effect of 17 beta-estradiol on calcitonin (CT) and calcitonin-gene-related peptide (CGRP) secretions in the murine CA-77 C cell line was studied after 1, 3, 5 and 6 d of treatment. The release of both CT and CGRP significantly increased 1, 3, 5 and 6 d after addition of 0.1 mumol/l estradiol alone to the culture medium. The C cell content of both peptides also increased after d of treatment with the same dose of estrogen. The enhanced CT and CGRP secretions induced by 17 beta-estradiol were not inhibited by the simultaneous addition of 5 mumol/l of all-trans-retinoic acid. Dexamethasone alone increased the release of both peptides within 6 d. However, when cells were treated simultaneously with estradiol and 1 mumol/l dexamethasone, the addition of retinoic acid blunted both the CT and CGRP secretions induced by dexamethasone. These results showed that the positive effects of 17 beta-estradiol on both CT and CGRP secretions were modulated by dexamethasone and retinoic acid.

Topics: Animals; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Medullary; Dexamethasone; Estradiol; Mice; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

The expression of all-trans-retinoic acid receptor (RAR) RNA was investigated by Northern blot and Reverse Transcription-Polymerase Chain Reaction in tissues and primary cultures of human thyrocytes. In normal and adenomatous samples the RAR alpha RNA was expressed, whereas the expression of RAR beta and gamma was undetectable. In carcinoma samples RAR alpha RNA expression could decline, whereas the RAR beta RNA expression could become detectable. TSH and retinoic acid did not significantly modify RAR alpha mRNA levels, whereas RA caused a significant decrease in basal and TSH-induced thyroid peroxidase (TPO) mRNA levels, and a decrease in DNA synthesis. These results demonstrate that RAR alpha gene is predominantly expressed in human thyrocytes, and suggest a molecular link between this gene and the negative regulation by RA of proliferation and function of follicular cells.

Topics: Adenoma; Cell Division; Cells, Cultured; DNA Replication; Enzyme Induction; Gene Expression; Humans; Iodide Peroxidase; Polymerase Chain Reaction; Receptors, Retinoic Acid; Reference Values; RNA, Messenger; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Tretinoin

Northern hybridizations were used to evaluate the modulated action of retinoic acid (R.A.) in presence of dexamethasone (Dex) and/or calcitriol (1,25-(OH)2D3) on calcitonin (CT) and calcitonin gene-related peptide (CGRP) mRNA steady state levels in the murine CA-77 C cell line. Dex was found to increase both CT and CGRP mRNAs in a time-and-dose-dependent way without changing the alternative splicing. A slight but significant increase in the steady-state CT mRNA level was found 3 days after addition of 10(-10) M Dex; the same dose slightly decreased the CGRP mRNA level; concentrations of Dex > or = 10(-9) M elevated both mRNAs. Calcium from 1-4 mM in short-term (1 hr. and 4 hrs.) or long-term stimulations (1 day and 4 days), with or without Dex cotreatment was ineffective. Dex alone (10(-6) M) elicited a 2-fold increase in CGRP mRNA and a 9-fold increase in CT mRNA steady state levels after 6 days of treatment whereas addition of 5.10(-5) M R.A. alone for 6 days decreased both the CGRP and the CT mRNA steady state level (12- and 4-fold decreases, respectively). Our results showed that 5.10(-7) M R.A. blunted in part (-30%) the rise of CT and CGRP mRNA induced under Dex; whereas doses > or = 5.10(-6) M maximally decreased both CT and CGRP mRNA (2- and 9-fold decreases, respectively). The fall under R.A. alone was enhanced when CA-77 cells were cotreated during 6 days with 10(-7) M 1,25-(OH)2D3 (-68% versus -37%). Moreover, the fall in CGRP mRNA (18-fold) of CA-77 cells treated simultaneously with 10(-6) M Dex, 5.10(-6) M R.A. and 10(-7) M 1,25-(OH)2D3 was greater than the decrease (9-fold) observed when the same dose of R.A. blunted the Dex induction. The results obtained by RIA for the CT and CGRP C cell content and release in the culture medium strengthened those observed on both CT and CGRP mRNAs, since a good parallelism was observed between the peptide biosynthesis, secretion and the mRNA levels. Our data suggest that R.A. and 1,25-(OH)2D3 exert a stronger inhibition of the CT gene by a likely coupled action of the two compounds probably via the formation of an heterodimer receptor.

Topics: Alternative Splicing; Animals; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Medullary; Cell Line; Dexamethasone; Dose-Response Relationship, Drug; Glucocorticoids; Mice; RNA, Messenger; Thyroid Neoplasms; Tretinoin

Iodothyronine 5'-deiodinase isoenzymes generate the thyroid hormone 3,3',5-triiodothyronine from the prohormone L-T4. Basal and retinoic acid (RA)-induced type I 5'-deiodinase (5'DI) activities were studied in human thyroid carcinoma cell lines. In the follicular thyroid carcinoma line FTC-133, nanomolar concentrations of 9-cis, 13-cis-, and all-trans-RA induced 5'DI activity. Kinetics with all-trans-RA revealed 5'DI stimulation after 1 day and a maximal effect after 3 days. Increased abundance of the p27 5'DI subunit was demonstrated after RA treatment by N-bromoacetyl-[125I]T4 affinity labeling. Actinomycin-D and cycloheximide blocked RA-mediated induction. RA stimulated 5'DI activity to a lesser extent in FTC-238 cells, whereas neither basal 5'DI activity nor stimulation by RA was found in anaplastic thyroid carcinoma, human lung, or leukemia cell lines. Steady state messenger ribonucleic acid levels of RA receptor-alpha and -beta were increased after incubation of FTC-133 cells with all-trans-RA. The high 5'DI activity of differentiated rat thyroid FRTL-5 cells was not further induced by RA. Butyrate did not alter 5'DI, but increased the activity of the differentiation marker alkaline phosphatase in FTC-133 and FTC-238 cells. T4 and T3 had no effect on basal or RA-stimulated 5'DI activity. These data suggest that expression and retinoid induction of 5'DI may serve as a sensitive and functional differentiation parameter of follicular thyroid carcinoma cells.

Topics: Adenocarcinoma, Follicular; Affinity Labels; Butyrates; Butyric Acid; Cycloheximide; Dactinomycin; Humans; Iodide Peroxidase; Isoenzymes; Kinetics; Retinoids; Thyroid Neoplasms; Thyroxine; Tretinoin; Triiodothyronine; Tumor Cells, Cultured

In order to demonstrate that Androgen binding activity in thyroid is caused by the canonic Androgen Receptor (AR), member of steroid receptor family, we studied the presence of AR mRNA in human thyroid tissues and primary cultured cells. Here we report a polymerase chain reaction protocol (RT-PCR) that we have designated to investigate the presence of AR mRNA in human cells. AR cDNA was synthesized and amplified with primers specific for C-terminal sequence of the protein. We demonstrated that AR gene expression i) is present in thyroid samples studied and ii) in a primary culture of follicular adenoma where it seems to be modulated by steroid hormones.

Topics: Adenoma; DNA; Estradiol; Gene Expression Regulation, Neoplastic; Humans; Polymerase Chain Reaction; Receptors, Androgen; RNA, Messenger; RNA, Neoplasm; Thyroid Gland; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

In order to clarify the effect of retinoids on thyroid cell growth and function, the presence of retinoic acid receptors (RARs) and the action of retinoic acid (RA) on DNA synthesis and on thyroid peroxidase (TPO) and thyroglobulin (TGB) mRNA expression were investigated in primary cultures of human thyroid follicular cells. A time and dose-dependent reduction in 3H-thymidine (3H-thy) incorporation was found in cells exposed for 48 h to all-trans-RA up to 1 microM. A cytotoxic effect was found only with the higher dose of 50 microM. The RA-induced decrease of 3H-thy incorporation was reflected by parallel change in DNA content of cell monolayers. The inhibitory effect of 1 microM RA on 3H-thy incorporation ranged from 28.5 +/- 4.6% in normal cells to 42 +/- 3.2% in adenomatous cells. In addition, 1 microM RA significantly reduced basal and TSH-induced TPO mRNA levels in normal, goitrous and adenomatous cells, but did not alter TGB mRNA levels. Furthermore, in these cells the study of RAR alpha and beta mRNA showed the presence of two major RAR alpha mRNA transcripts of approximately 3.5 and 2.8 Kb in size, whereas RAR beta mRNA was undetectable. Overall, our data indicate that RAR alpha gene is expressed in human thyrocytes and that RA may be involved in the regulation of the human thyroid by reducing proliferation and function of follicular cells.

Topics: Adenoma; Carrier Proteins; Cells, Cultured; DNA; Gene Expression; Goiter; Humans; Iodide Peroxidase; Receptors, Retinoic Acid; RNA, Messenger; Thyroglobulin; Thyroid Gland; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured

Dedifferentiation of human thyroid tumors is frequently found in humans. The effect of retinoids (13 cis-RA) was studied on the proliferation and differentiation of a human follicular cell line in vitro (UCLA R0 82 W-1). A significant and dose-dependent reduction (P less than 0.001) in cell number and [3H] thymidine uptake was found in cells exposed to 13 cis-RA up to 10 microM. Higher concentrations of 13 cis-RA, however, led to a dose-dependent restoration of cell proliferation. Various parameters of differentiation increased under the influence of 13 cis-RA (10 microM) over nonexposed cells. The 125I uptake increased 4-fold over that in control nonexposed cells (P less than 0.05). [125I] Epidermal growth factor binding increased 5-fold, and [125I] human TSH binding increased significantly after exposure to 13 cis-RA (P less than 0.02). Deiodinase activity, however, was significantly lower in 13 cis-RA exposed cells than in control cells. The present study shows that 13 cis-RA (10 microM) drives the tumor cells toward a more normal state of proliferation and differentiation.

Topics: Adenocarcinoma; Binding Sites; Cell Cycle; Cell Differentiation; Cell Survival; Dose-Response Relationship, Drug; Epidermal Growth Factor; Humans; Iodide Peroxidase; Iodine; Thymidine; Thyroid Neoplasms; Thyrotropin; Tretinoin; Tumor Cells, Cultured

Medullary carcinoma of the thyroid (MCT), a tumor of calcitonin (CT)-secreting C cells, can display a variable malignant potential with poor prognosis linked to decreased cell differentiation. In vitro study of MCT has been hampered by the fact that few cell lines derived from this neoplasm have been available for study. Herein are reported the characteristics of two new lines derived from human MCT that are tumorigenic in athymic mice and do not secrete CT. After treatment with various concentrations of retinoic acid (a vitamin A derivative) and cyclic adenosine monophosphate, both lines exhibit the traits of more differentiated cells with a decrease in cellular proliferation and an increase in cytoplasmic CT content as shown by in situ immunoperoxidase staining. These cell lines should prove of great value in the study of the biology of MCT and the mechanisms underlying induced differentiation in this type of tumor.

Topics: Animals; Calcitonin; Carcinoma; Cell Line; Cyclic AMP; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Thyroid Neoplasms; Tretinoin

A 59-year-old woman with a history of papillary carcinoma of the thyroid gland developed three reddish nodules on the scalp. A skin biopsy showed a dermal tumor composed of sheets of clearly differentiated thyroid vesicles. Cutaneous metastases of thyroid carcinoma are very rare and this case is the first case confirmed by immunoperoxidase studies using monoclonal antithyroglobulin antibody. Positive reactions were obtained in colloid and at apices of thyrocytes. Monoclonal antibodies to human thyroglobulin may offer a unique opportunity to confirm the tissue origin of cutaneous metastasis.

Topics: Acitretin; Antibodies, Monoclonal; Carcinoma, Papillary; Female; Humans; Immunoenzyme Techniques; Immunohistochemistry; Middle Aged; Skin Neoplasms; Thyroglobulin; Thyroid Neoplasms; Tretinoin