Progress in Re-differentiating Therapy of Radioiodine-refractory Differentiated Thyroid Cancer / 肿瘤防治研究

The majority patients of differentiated thyroid carcinoma (DTC) with indolent progression have general good prognosis after standard primary treatments including surgery, thyroid stimulating hormone (TSH) suppression and radioactive iodine (RAI) therapy. However, there are still some patients suffered from recurrence or distant metastasis after initial treatment. They may lose the ability of uptaking iodine during their natural course of disease or treatment and could not benefit from subsequent RAI treatment, which will result in radioiodine-refractory differentiated thyroid cancer (RAIR-DTC). Options are very limited for RAIR-DTC patients, which is associated with a poor prognosis. Recently, with the research advances on the molecular mechanism of RAIR-DTC, redifferentiation combined with RAI therapy have been increasingly used to treat RAIR-DTC, and some outcomes are quite encouraging. This paper reviews the progress of signaling pathway inhibitors, histone deacetylase inhibitors, DNA methyltransferase inhibitors, retinoids and peroxisome proliferator-activated receptor agonists in redifferentiating therapy of RAIR-DTC.

Efficacy and safety of 13-cis retinoid acid and all trans retinoid acid in the redifferentiation therapy of poorly differentiated thyroid cancer / 中华内分泌代谢杂志

Objective To evaluate the efficacy and safety of 13-cis retinoid acid (13-CRA) and all trans retinoid acid (ATAR) redifferentiation therapy in patients with poorly differentiated thyroid cancer. Methods A single-center, randomized, double-blind, parallel controlled clinical trial was preformed. All patients were randomized into three groups. 78 cases were enrolled in each group. The patients were treated by 13-CRA in A group, by ATRA in B group, and by placebo in control group. The induced effects of retinoid acid (RA) and 131I treatment efficacies were defined as primary outcome of efficacy. Results After RA induction therapy, the effective rates in A, B, and control groups were 59.72%, 52.86% and 7.69%, respectively, with statistically significant difference among 3 groups (P<0.05). Compared with control group, A and B groups revealed significant induced efficacies (P<0.017), but there was no significant difference between A group and B group. After 131I treatment, the effective rates in A, B, and control group were 70.83%, 64.29%, and 28.21% respectively, with statistically significant difference (P<0.05). Compared with control group, the effective rates of 131I treatment in A and B groups were significantly raised (P<0.017), but there was no significant difference between A group and B group. The damage of skins and mucous membranes such as desquamation, dry skin, dry lips, dry eyes, etc occurred mostly in A group. The symptoms of nervous system such as headache, dizziness, etc occurred mostly in B group. Conclusions The induced differentiation of 13-CRA or ATRA is an effective method for the treatment of poorly differentiated thyroid carcinoma.

Research progress of redifferentiation of radioiodine-refractory differentiated thyroid carcinoma / 中华核医学与分子影像杂志

The effect of 131I therapy for primary and metastatic lesions of thyroid carcinoma depends on the ability of iodine uptake.The loss or down-regulation of iodine-metabolizing genes represents dedifferentiation of DTC,which results in the disability to take up and accumulate 131I and eventually leads to radioiodine-refractory DTC (RR-DTC).The management of RR-DTC is extremely difficult and the prognosis is poor.It is important for the treatment and prognosis of RR-DTC to investigate the mechanism of redifferentiation.The up-regulation of thyroid iodine-metabolizing genes expression,inhibition of the changes in epigenetic modifications and intervention of the abnormal activation of signaling pathways are reviewed in this article.

Cardiac Cells in Regenerative Processes in Patients with Heart Failure Due to Ischaemic Heart Disease.

Aims: This study aimed to find the cardiac cells which can participate in the processes of regeneration at patients with heart failure due to ischaemic heart disease. To investigate the participation of myosin activating protein kinases in sarcomerogenesis, because sarcomerogenesis is the crucial part of cardiomyocyte differentiation process. Study Design: Resident cardiomyocyte progenitors and dedifferentiated cardiomyocytes were found in left atrial appendages from patients with heart failure due to ischaemic heart disease. We used a cell model of fetal cardiomyocytes with the disassembly contractile apparatus to study the forming of new myofibrils (or sarcomerogenesis) regulated by myosin activating protein kinases. Place and Duration of Study: Cardiology Research and Production Center, Research Center for Obstetrics, Gynecology and Perinatology, Department of Fundamental and Applied Neurobiology of V. Serbsky Federal Medical Research Centre of Psychiatry and Narcology between June 2014 and October 2015. Methodology: We included 10 patients with heart failure due to ischaemic heart disease. Resident cardiomyocyte progenitors and dedifferentiated cardiomyocytes were found by the immunofluorescence approach and the electron microscopy. To determine the myosin activating protein kinases localization in human fetal cardiomyocytes at the 8-9 week heart gestation stage immunofluorescence approach was used. Results: We detected the cardiomyocyte progenitor cells which express c-Kit and Nkx-2.5, other cells express Mdr-1 and GATA-4. Dedifferentiated cardiomyocytes were found. It has been established that smooth muscle, nonmuscle and skeletal myosin light chain kinases are colocalized with nonmuscle myosin in premyofibrils in fetal human cardiomyocytes. Conclusion: We demonstrated that the heart of patients with heart failure due to ischaemic heart disease contains the progenitor resident cardiomyocytes and dedifferentiated cardiomyocytes. These cardiac cells possibly can proliferate and differentiate to mature cardiomyocytes and recover heart function and structure after injury. Myosin activating protein kinases may contribute in myofibril formation during the cardiomyocyte differentiation.

New Strategies for Combined Radioiodine Therapy in Refractory Thyroid Cancer / 대한갑상선학회지

The prognosis of differentiated thyroid cancer (DTC) is excellent, which is mainly due to the high therapeutic efficacy of radioactive iodine (RAI) therapy as well as indolent nature of thyroid cancer itself. Although most patients with DTC are well treated with RAI therapy, a certain number of patients have been suffered from refractoriness to RAI therapy. To overcome refractoriness, many alternative treatments have been investigated, and they could be classified based on the mechanisms of action; redifferentiation drug and molecular targeted drug. Not only redifferentiated drugs but also molecular targeted drugs could induce differentiation of thyroid cancer cells. Consequently, alternative treatments allowing tumor cells of RAI avidity followed by RAI therapy could utilize a synergistic effect of both therapies. Combined RAI therapy is expected to improve therapeutic effects and prognoses of RAI refractory thyroid cancers.

Expression of miR-9 in H/RS cells and its regulation on target PRDM1 / 白血病·淋巴瘤

Objective To explore the expression of miR-9 in H/RS cells and its regulation on target PRDM1.Methods miR-9 expression in normal CD19+ B-cell subsets and eight lymphoma cell lines was detected by fluorescence quantitative RT-PCR and in situ hybridization (ISH),for quantification and location,respectively.Chemically synthesizcd antisense oligonucleotide of miR-9 was transiently transfected into L428 for its silence,and the PRDM1 expression was tested.Results Fluorescence quantitative RT-PCR showed that the expression of miR-9 in L428 cells was marked higher than that of normal CD19+ B-cell subsets and other lymphoma cell lines (the expression of miR-9 in L428 cells was 47-fold of OCI-Ly1,50-fold of Raji cells,7-fold of EBV+ immortalized B cell line,and 6-fold of ALCL cell line).ISH indicated that miR-9 located in cytoplasm,it was a diffuse and strong positive in L428,scattered and weak in DLBCL and Burkitt' s lymphoma cell lines,while negative in KARPAS-299 or Jurkat cell lines.Transient down-regulation of miR-9 in L428 leded to the increase of PRDMI protein.Conclusion miR-9 plays the role of cancer gene in cHL,and may exert a potential function in regulating terminal B cell differentiation through a post transcription regulation of PRDM1 gene.

Research progress of retinoic acid in treatment of differentiated thyroid carcinoma / 肿瘤研究与临床

Differentiated thyroid carcinoma (DTC) cells can produce loss of differentiation in the progress of cancer development,especial of metastasis.The morphology and function of loss of differentiation DTC cell both generate degenerative changes,resulting in the reduction or loss of iodine uptake of the radioactive,which make radioactive iodine(131Ⅰ) treatment and thyroid hormone suppression therapy inefficient on treating DTC.Retinoic acid(RA) is a biologically active metabolite of vitamin A,which plays an important role in many cell morphology,degree of differentiation and proliferation process.Studies have shown that the application of RA can induce the loss differentiation of DTC redifferentiation,make its to reverse for functional thyroid organization.It’s important to produce the clinical significance,which can improve the cure rate and survival rate of the DTC patients.

Antiproliferation and Redifferentiation in Thyroid Cancer Cell Lines by Polyphenol Phytochemicals

Thyroid carcinogenesis is accompanied by loss of thyroid-specific functions and refractory to radioiodine and thyroid stimulating hormone (TSH) suppression therapy. Redifferentiating agents have been shown to inhibit tumor growth and improve the response to conventional therapy. Polyphenol phytochemicals (PPs) in fruits and vegetables have been reported to inhibit cancer initiation, promotion, progression and induce redifferentiation in selected types. In this study we examined PPs induce redifferentiation in thyroid cancer cell lines. We investigated the effects of genistein, resveratrol, quercetin, kaempferol, and resorcinol on the F9 embryonal carcinoma cell differentiation model. The thyroid cancer cell lines, TPC-1, FTC-133, NPA, FRO, and ARO, displayed growth inhibition in response to genistein, resveratrol, quercetin. We further demonstrated that genistein decreased the dedifferention marker CD97 in NPA cells and resveratrol decreased CD97 in FTC-133, NPA, FRO cells and quercetin decreased CD97 in all cell lines. We observed increased expression of differentiation marker NIS in FTC-133 cells in response to genistein, and resveratrol but no change in NPA, FRO, ARO cells. Quercetin increased or induced NIS in FTC-133, NPA, FRO cells. These findings suggest that PPs may provide a useful therapeutic intervention in thyroid cancer redifferentiation therapy.

Sonic Hedgehog Protein Expression in Various Thyroid Tissues and Its Clinical Implication / 대한내분비외과학회지

PURPOSE: The Hedgehog (Hh) signaling pathway is important in embryonic development including cell differentiation and proliferation. Recently, activation of this pathway has been implicated in several forms of solid cancers. We investigated sonic hedgehog (Shh) protein expression and its relation to differentiation and clinicopathologic characteristics in thyroid cancer cell lines and tissues. METHODS: FTC-236, FTC-238, and XTC-1. We made tissue microarray slides using 80 thyroid surgical specimen: 40 benign and 40 malignant lesions. Immunohistochemical staining was performed using anti-Shh antibody. mRNA expression of NIS, thyroglobulin, and CD97 were evaluated by RT-PCR. Cyclopamine was used as a Shh signal inhibitor. RESULTS: Shh expression was more prominent in TPC-1, FTC-133, and XTC-1 cell lines than the others. Cyclopamine downregulated CD97 and upregulated thyroglobulin mRNA expression, but did not induce mRNA expression of NIS. Thyroid tissues showed varied expression of Shh in both benign and malignant diseases. Shh expression was detected in 38 of 50 (76%) normal, in 18 of 25 (72%) non-neoplastic benign, in nine of 15 (60%) benign tumors, and in 31 of 40 (77%) malignant tumors. Shh over-expression was significantly less frequent in papillary thyroid carcinomas than in normal or benign thyroid tissues. In addition, Shh protein expression did not relate to clinicopathologic characteristics in papillary thyroid carcinomas. CONCLUSION: Thyroid tissues and cell lines vary in expression of Shh. Cyclopamine can induce redifferentiation in thyroid cancer cell lines. Shh protein expression, however, is unrelated to clinicopathologic characteristics in papillary thyroid carcinomas.

New Promising Therapeutic Modalities for Thyroid Cancers: Histone Deacetylase Inhibitor, PPAR-gamma Agonist, and Retinoic Acid / 대한내분비외과학회지

Most patients with thyroid cancer have well differentiated tumors that usually respond to conventional therapy including total or near total thyroidectomy, radioiodine ablation and TSH suppression. About 10% of patients, however, have aggressive cancers as a consequence of de-differentiation. During de-differentiation, thyroid cancers not only show more mitosis, fibrosis, and altered cell structure, they also lose thyroid-specific functions (iodine uptake, TSH receptor expression, and thyroglobulin production). These poorly differentiated or undifferentiated tumors mostly fail to take up radioiodine and are responsible for most deaths from thyroid cancer. New therapies need to be developed for patients with these types of tumors. Among the most promising antineoplastic therapies for these poorly differentiated and undifferentiated thyroid cancers are the histone deacetylase inhibitors, the PPAR-gamma agonist and retinoic acids. These drugs have therapeutic effects for thyroid cancers in inhibiting growth and inducing apoptosis and redifferentiation, in vivo and in vitro studies. And, clinical trials in patients with refractory thyroid cancers have been initiated. Further laboratory investigation of these drugs is necessary to understand molecular mechanisms and demonstrate therapeutic efficacy for thyroid cancers.

Redifferentiation Effects of Troglitazone in Human Thyroid Cancer Cell Lines

PURPOSE: Troglitazone is a potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARgamma), which is a ligand-activated transcription factor that regulates cell differentiation and growth. Antiproliferative effects of troglitazone have been reported in several human cancers including thyroid cancer. In the present study, we evaluated the redifferentiation effects of troglitazone in human cancers regarding the modulation of CD97 and sodium-iodide symporter (NIS) gene expression. METHODS: We used 3 human thyroid cancer cell lines: TPC-1 (papillary), FTC-133 (follicular), and XTC-1 (H rthle). Surface expression of CD97, a novel dedifferentiation marker, was measured by flow cytometry. mRNA expression of NIS gene was measured by real time quantitative PCR using TaqMan probe. RESULTS: Troglitazone down-regulated the surface expression of CD97 in FTC-133 cells and up-regulated (NIS) mRNA in TPC-1, FTC-133 and XTC-1 cells. CONCLUSION: Our investigations documented that troglitazone, a PPARgammaagonist, induced redifferentiation in thyroid cancer cell lines. In patients who have poorly differentiated thyroid cancer unresponsive to traditional treatments, PPARgammaagonists may therefore reintroduce the effectiveness of traditional treatments.

Dedifferentiation of Human Chondrocyte in Monolayer Culture and its Reversibility in Pellet Culture / 대한정형외과연구학회지

Articular cartilage is a unique tissue devoid of blood and nerve tissue and so its regeneration is very limited. Recently a clinical trial on transplantation using autologous chondrocyte with periosteal flap has drawn a great deal of attention. Chondrocytes cultured in a plastic flask in monolayer can rapidly dedifferentiate appearing fibroblastic, and exhibit a change in matrix gene expression characterized by a decrease in type II collagen synthesis. It is uncertain whether phenotypic change of dedifferentiated chondrocytes in vitro can be reversible to their original status alter long term culture. It is important to verify tile maintenance of the phenotype and determine the optimum period for culturing chondrocytes to be used in autologous chondrocyte transplantation. This study will be set up to confirm the reversibility of once-dedifferentiated chondrocytes with matrix-producing capability. The phenotype of cultured human chondrocyte is analysed by Northern blot and Western blot analysis for collagen type I and II. Chondrocytes appeared fibroblast right after adhering to the flask buttom at first week of culture. The proliferating rates of chondrocyte in a monolayer culture were maximum at 3rd and 4th week of culture. And thereafter, proliferation rate flowed down or stops as confluence rose. On Northern and Western blot analysis, collagen type II was well expressed by 3th to 4th week culture, thereafter progressively decreased its density with time. On the other hand, collagen type I m-RNA has not expressed until 3rd week of the culture, showing progressive increment of density thereafter. On Northern blot analysis in pellet culture, type II collagen m-RNA is apparantly reexpressed. This study indicates chat in the monolayor culture, the chondrocytic phenotype was lost with regards to morphology and mRNA expression and cartilage specific protein. However, these cells seemed to haute the potential to redifferentiate to well-differentiated chondrocytes in densely packed culture, such as pellet.