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1.
J Biol Chem ; 292(5): 1785-1797, 2017 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-27994058

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it exerts an immunosuppressive function as part of an acquired mechanism of immune escape. Recently, we demonstrated that IDO1 expression is significantly higher in all thyroid cancer histotypes compared with normal thyroid and that its expression levels correlate with T regulatory (Treg) lymphocyte densities in the tumor microenvironment. BRAFV600E- and RET/PTC3-expressing PcCL3 cells were used as cellular models for the evaluation of IDO1 expression in thyroid carcinoma cells and for the study of involved signal transduction pathways. BRAFV600E-expressing PcCL3 cells did not show IDO1 expression. Conversely, RET/PTC3-expressing cells were characterized by a high IDO1 expression. Moreover, we found that, the STAT1-IRF1 pathway was instrumental for IDO1 expression in RET/PTC3 expressing cells. In detail, RET/PTC3 induced STAT1 overexpression and phosphorylation at Ser-727 and Tyr-701. STAT1 transcriptional regulation appeared to require activation of the canonical NF-κB pathway. Conversely, activation of the MAPK and PI3K-AKT pathways primarily regulated Ser-727 phosphorylation, whereas a physical interaction between RET/PTC3 and STAT1, followed by a direct tyrosine phosphorylation event, was necessary for STAT1 Tyr-701 phosphorylation. These data provide the first evidence of a direct link between IDO1 expression and the oncogenic activation of RET in thyroid carcinoma and describe the involved signal transduction pathways. Moreover, they suggest possible novel molecular targets for the abrogation of tumor microenvironment immunosuppression. The detection of those targets is becoming increasingly important to yield the full function of novel immune checkpoint inhibitors.


Assuntos
Regulação Enzimológica da Expressão Gênica , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas c-ret/metabolismo , Fator de Transcrição STAT1/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Substituição de Aminoácidos , Animais , Linhagem Celular , Linhagem Celular Tumoral , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Mutação de Sentido Incorreto , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-ret/genética , Ratos , Fator de Transcrição STAT1/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Microambiente Tumoral/genética
2.
Biomaterials ; 35(25): 7101-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24836306

RESUMO

Various tissue-specific antibodies have been attached to nanoparticles to obtain targeted delivery. In particular, nanodelivery systems with selectivity for breast, prostate and cancer tissue have been developed. Here, we have developed a nanodelivery system that targets the thyroid gland. Nanoliposomes have been conjugated to the thyroid-stimulating hormone (TSH), which binds to the TSH receptor (TSHr) on the surface of thyrocytes. The results indicate that the intracellular uptake of TSH-nanoliposomes is increased in cells expressing the TSHr. The accumulation of targeted nanoliposomes in the thyroid gland following intravenous injection was 3.5-fold higher in comparison to untargeted nanoliposomes. Furthermore, TSH-nanoliposomes encapsulated with gemcitabine showed improved anticancer efficacy in vitro and in a tumor model of follicular thyroid carcinoma. This drug delivery system could be used for the treatment of a broad spectrum of thyroid diseases to reduce side effects and improve therapeutic efficacy.


Assuntos
Nanoestruturas/química , Glândula Tireoide/efeitos dos fármacos , Tireotropina/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Células CHO , Fenômenos Químicos , Cromatografia Líquida , Cricetulus , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacologia , Feminino , Lipossomos/química , Microscopia Confocal , Ratos , Ratos Wistar , Receptores da Tireotropina/química , Espectrometria de Massas em Tandem , Glândula Tireoide/metabolismo , Tireotropina/química , Gencitabina
3.
J Clin Endocrinol Metab ; 99(5): E832-40, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24517146

RESUMO

CONTEXT: Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it appears to exert an immunosuppressive function as part of an acquired mechanism of immune escape mediated by the inhibition of lymphocyte proliferation and survival and by the induction of FoxP3+ T regulatory cells. OBJECTIVE: The objective of the study was to evaluate IDO1 expression in thyroid carcinoma and demonstrate its immunosuppressive function in the context of thyroid tumors. SETTING: IDO1 expression was evaluated by quantitative PCR in 105 papillary thyroid carcinomas (PTCs), 11 medullary thyroid carcinomas, six anaplastic thyroid carcinomas, and five thyroid carcinoma cell lines (TCCLs), by immunohistochemistry in 55 PTCs and by Western blotting in five TCCLs. FoxP3+ Treg lymphocyte density was evaluated by immunohistochemistry in 29 PTCs. IDO1 inhibitory effect on lymphocyte proliferation was tested in coculture experiments of TCCLs and activated lymphocytes. RESULTS: IDO1 mRNA expression resulted significantly higher in all the analyzed thyroid carcinoma histotypes compared with normal thyroid. Interestingly, an increase of IDO1 mRNA expression magnitude could be observed with gain of aggressiveness (PTCs and medullary thyroid carcinomas ≪ anaplastic thyroid carcinomas). In PTCs, IDO1 mRNA expression magnitude correlated with IDO1 immunostaining intensity in cancer cells and with FoxP3+ Treg lymphocyte density in the tumor microenvironment. IDO1 was expressed in human thyroid cancer cell lines in vitro, and FTC-133 cells showed high kynurenine concentration in the conditioned medium and a strong suppressive action on the proliferation of activated lymphocytes in coculture experiments. CONCLUSIONS: For the first time, this study demonstrates a pivotal role of IDO1 in the suppression of lymphocyte function in thyroid carcinoma microenvironment.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Linfócitos T Reguladores/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Microambiente Tumoral/imunologia , Regulação para Cima/fisiologia , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/imunologia , Adenocarcinoma Folicular/metabolismo , Adenocarcinoma Folicular/patologia , Carcinoma Medular/genética , Carcinoma Medular/imunologia , Carcinoma Medular/metabolismo , Carcinoma Medular/patologia , Carcinoma Papilar/genética , Carcinoma Papilar/imunologia , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patologia , Linhagem Celular Tumoral , Fatores de Transcrição Forkhead/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T Reguladores/imunologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/imunologia , Neoplasias da Glândula Tireoide/patologia
4.
Artigo em Inglês | MEDLINE | ID: mdl-22661970

RESUMO

RET gene rearrangements (RET/PTCs) represent together with BRAF point mutations the two major groups of mutations involved in papillary thyroid carcinoma (PTC) initiation and progression. In this review, we will examine the mechanisms involved in RET/PTC-induced thyroid cell transformation. In detail, we will summarize the data on the molecular mechanisms involved in RET/PTC formation and in its function as a dominant oncogene, on the activated signal transduction pathways and on the induced gene expression modifications. Moreover, we will report on the effects of RET/PTCs on the tumor microenvironment. Finally, a short review of the literature on RET/PTC prognostic significance will be presented.

5.
Thyroid ; 22(2): 138-44, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22191389

RESUMO

BACKGROUND: Novel molecularly targeted drugs are undergoing preclinical and clinical testing to assess their efficacy against refractory thyroid carcinomas. The multikinase inhibitor Sunitinib has been shown to inhibit the kinase activity of the RET oncogene and reduce proliferation in differentiated thyroid cancer cells harboring the RET/PTC rearrangement. In this study, we evaluated its effects in human cell lines derived from differentiated (TPC-1) and anaplastic (8505C, CAL-62, and C643) thyroid cancers. METHODS: The cells exposed to various concentrations of Sunitinib were examined for: (1) cell viability and presence of apoptosis, analyzed by cell counts, MTT assay, trypan blue exclusion assay, western blotting, and immunofluorescence; (2) expression of cyclin D1 and phosphorylated and nonphosphorylated extracellular signal-regulated kinase (ERK) and Akt proteins, analyzed by western blotting; and (3) transcription of genes encoding thyrocyte differentiation markers (thyroid-stimulating hormone receptor, sodium/iodide symporter, thyroglobulin, and thyroperoxidase) and proangiogenic factors (vascular endothelial growth factor A, platelet-derived growth factors A and B), measured by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: Exposure to nanomolar concentrations of Sunitinib significantly reduced cell viability in only TPC-1 cells, and this effect was paralleled by reduction of cyclin D1 levels. Western blotting revealed reduced phosphorylation of ERK and Akt after 3 and 6 hours of drug exposure. In contrast, the growth of 8505C, CAL-62, and C-643 cells was significantly reduced only by micromolar concentrations of Sunitinib, mainly due to induced necrotic rather than apoptotic death. In these cells, Sunitinib exerted a few significant effects on the transcription of angiogenic factors or thyrocyte differentiation markers. CONCLUSIONS: Sunitinib has little or no effect on the growth or differentiation of anaplastic thyroid cancer cells, thus suggesting that it is unlikely to be effective in the treatment of anaplastic thyroid cancer.


Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Indóis/farmacologia , Pirróis/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Indutores da Angiogênese/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclina D1/análise , Humanos , Iodeto Peroxidase/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Oncogênica v-akt/metabolismo , Fosforilação , Receptores da Tireotropina/metabolismo , Sunitinibe , Simportadores/metabolismo , Tireoglobulina/metabolismo
6.
Oncol Rep ; 26(5): 1075-80, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21850379

RESUMO

Sunitinib is a multikinase inhibitor approved for use in some human solid malignancies, including renal clear cell and gastrointestinal stromal cancer, and under investigation for many other neoplasias. In many preclinical cancer models sunitinib has shown anti-angiogenic and antitumor effects, acting mainly by inhibiting the activity of pro-angiogenic growth factor receptors. However, a percentage of tumors develop resistance to this treatment. The aim of this study was to identify novel potential molecular targets for the non- responsive tumors. The effects of sunitinib were investigated in xenograft tumors obtained by injecting HEK293 cells into NOD-SCID mice, focusing on the activity of growth-regulating pathways involved in tumorigenesis. During 11 days of oral administration of sunitinib (40 mg/kg/day), the growth of tumors was monitored by measuring the mass volume by a caliper. At the end of the treatment, tumor specimens were histologically examined for microvessel density (MVD) and presence of necrosis, and the phosphorylation of ERK and Akt was analyzed in protein extracts by Western blotting. Moreover, the mRNA levels of VEGF and its receptor genes were measured by quantitative RT-PCR. Treatment with sunitinib elicited a clear reduction of the tumor growth, associated with a reduction of MVD, correlated with an increased number of necrotic cells. In contrast, the levels of phosphorylated Akt and ERK proteins were similar in treated and non-treated animals. The VEGF and VEGFR-1 and 2 transcripts were not affected by sunitinib treatment. In conclusion, these findings confirm the anti-angiogenic action as the major effect of sunitinib against tumor growth. In contrast, other important growth regulatory pathways involved in malignant trans-formation, such as the ERK-MAPK and Akt/mTOR pathways are not affected by such a treatment, suggesting the use of specific inhibitors of these pathways as valid candidates for combinatorial therapies in sunitinib-resistant malignancies.


Assuntos
Inibidores da Angiogênese/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Indóis/farmacologia , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis/farmacologia , Proteínas Angiogênicas/biossíntese , Animais , Processos de Crescimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Microvasos/efeitos dos fármacos , Neoplasias Experimentais/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Distribuição Aleatória , Sunitinibe , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Arq. bras. endocrinol. metab ; 53(9): 1061-1073, dez. 2009. ilus, tab
Artigo em Inglês | LILACS | ID: lil-537057

RESUMO

Thyroid cancer incidence has significantly increased in the last three decades and many patients seek medical attention for its treatment every year. Among follicular cell-derived tumors, the majority are differentiated thyroid carcinomas (DTC), whose prognosis is very good with only 15 percent of the cases presenting disease persistence or recurrence after initial treatment. Medullary thyroid carcinoma has a worse prognosis, especially in patients with diffused cancers at the time of initial surgery. Traditional treatment options for persistent or recurrent disease include additional surgery, radioiodine treatment and TSH-suppression in DTC patients; external beam radiotherapy, and cytotoxic chemotherapy, often have low efficacy and many patients with advanced disease ultimately die. In the last two decades many of the molecular events involved in cancer formation have been uncovered. This knowledge has prompted the development of novel therapeutic strategies mainly based on the inhibition of key molecular mediators of the tumorigenic process. In particular the class of small-molecule tyrosine kinase inhibitors was enriched by many compounds that have reached clinical trials and in some cases have had approval for clinical use in specific cancers. Many of these compounds entered clinical trials also for locally advanced or metastatic thyroid carcinomas showing very promising results.


O câncer de tireoide tem aumentado significativamente nas últimas três décadas e muitos pacientes têm buscado cuidados médicos para o tratamento a cada ano. Entre os tumores derivados de células foliculares, a maioria é carcinoma diferenciado de tireoide (CDT), cujo prognóstico é muito bom, em que somente em 15 por cento dos casos a doença é persistente ou recorrente após o tratamento inicial. O carcinoma medular de tireoide tem um prognóstico pior, especialmente em pacientes com câncer difuso no momento da cirurgia inicial. As opções no tratamento tradicional para a doença persistente ou recorrente incluem cirurgia adicional, radioiodoterapia e supressão de TSH em pacientes CDT; a radioterapia externa e a quimioterapia citotóxica apresentam com frequência uma baixa eficácia e muitos pacientes com doença avançada não sobrevivem. Nas últimas duas décadas, muitos dos eventos envolvidos na formação do câncer tornaram-se conhecidos. Esse conhecimento possibilitou o desenvolvimento de novas estratégias terapêuticas, baseadas principalmente na inibição de mediador molecularchave no processo tumorigênico. Em particular, a classe das pequenas moléculas inibidoras de tirosina-quinase foi enriquecida por muitos compostos investigados em estudos clínicos e alguns casos foram aprovados para uso clínico em tipos específicos de câncer. Muitos desses compostos foram aplicados em estudos clínicos de câncer de tireoide com extensa invasão local ou metástase, mostrando resultados muito promissores.


Assuntos
Humanos , Antineoplásicos/uso terapêutico , Carcinoma Medular/tratamento farmacológico , Carcinoma Papilar/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Benzenossulfonatos/uso terapêutico , Carcinoma Medular/genética , Carcinoma Papilar/genética , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Indóis/uso terapêutico , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/classificação , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Quinazolinas/uso terapêutico , Neoplasias da Glândula Tireoide/genética
8.
Arq Bras Endocrinol Metabol ; 53(9): 1061-73, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20126863

RESUMO

Thyroid cancer incidence has significantly increased in the last three decades and many patients seek medical attention for its treatment every year. Among follicular cell-derived tumors, the majority are differentiated thyroid carcinomas (DTC), whose prognosis is very good with only 15% of the cases presenting disease persistence or recurrence after initial treatment. Medullary thyroid carcinoma has a worse prognosis, especially in patients with diffused cancers at the time of initial surgery. Traditional treatment options for persistent or recurrent disease include additional surgery, radioiodine treatment and TSH-suppression in DTC patients; external beam radiotherapy, and cytotoxic chemotherapy, often have low efficacy and many patients with advanced disease ultimately die. In the last two decades many of the molecular events involved in cancer formation have been uncovered. This knowledge has prompted the development of novel therapeutic strategies mainly based on the inhibition of key molecular mediators of the tumorigenic process. In particular the class of small-molecule tyrosine kinase inhibitors was enriched by many compounds that have reached clinical trials and in some cases have had approval for clinical use in specific cancers. Many of these compounds entered clinical trials also for locally advanced or metastatic thyroid carcinomas showing very promising results.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Medular/tratamento farmacológico , Carcinoma Papilar/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Axitinibe , Benzenossulfonatos/uso terapêutico , Carcinoma Medular/genética , Carcinoma Papilar/genética , Humanos , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Indóis/uso terapêutico , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Oligonucleotídeos , Compostos de Fenilureia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/classificação , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Quinazolinas/uso terapêutico , Sorafenibe , Sunitinibe , Neoplasias da Glândula Tireoide/genética
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