tretinoin and Adenocarcinoma--Follicular

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

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 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

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

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

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

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