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1.
Anticancer Res ; 40(1): 121-132, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892560

RESUMO

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (pNETs) are rare pancreatic neoplasms, and therapeutic options for pNETs are limited. Metformin is an anti-hypoglycemic drug that appears to have anticancer effects. However, little is known about the effect of metformin on pNETs. In this study, we investigated the anti-proliferative effect of metformin on a human pNET cell line. MATERIALS AND METHODS: The anti-proliferative properties of metformin were evaluated in QGP-1 and NCI-H727 cells using a cell counting kit-8 assay. Xenograft mouse models were used to assess the tumor effect in vivo. RESULTS: Metformin inhibited the proliferation and anti-tumor growth of QGP-1 cells, accompanied by their arrest during the cell cycle at the G0/G1 phase. Immunohistochemical analysis of tumor tissues revealed down-regulation of cyclin D1 and proliferating cell nuclear antigen in the metformin-treated group. Additionally, metformin induced apoptosis, and the expression of survivin and claspin were decreased in metformin-treated QGP-1 cells according to the apoptosis array. Furthermore, the angiogenic related protein TIMP-1 was down-regulated, and its miRNA expression was altered by metformin in QGP-1 cells. CONCLUSION: Taken together, our study demonstrated the therapeutic potential of metformin and provides molecular mechanistic insights into its anti-tumoral effect on pNETs. This study is the first one describing anti-tumoral effects in pNETs.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Metformina/farmacologia , Biomarcadores , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , MicroRNAs/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cancer Sci ; 111(2): 610-620, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31845438

RESUMO

High-grade neuroendocrine lung cancer (HGNEC), which includes small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung is a rapidly proliferating, aggressive form of lung cancer. The initial standard chemotherapeutic regimens of platinum doublets are recommended for SCLC and have been frequently used for LCNEC. However, there are currently no molecularly targeted agents with proven clinical benefit for this disease. The deubiquitinating enzyme ubiquitin C-terminal hydrolase-L1 (UCHL1) is a neuroendocrine cell-specific product that is known as a potential oncogene in several types of cancer, but little is known about the biological function of UCHL1 and its therapeutic potential in HGNEC. In this study, we found that preclinical efficacy evoked by targeting UCHL1 was relevant to prognosis in HGNEC. UCHL1 was found to be expressed in HGNEC, particularly in cell lines and patient samples of SCLC, and the combined use of platinum doublets with selective UCHL1 inhibitors improved its therapeutic response in vitro. Immunohistochemical expression of UCHL1 was significantly associated with postoperative survival in patients with HGNEC and contributed towards distinguishing SCLC from LCNEC. Circulating extracellular vesicles (EV), including exosomes isolated from lung cancer cell lines and serum from early-stage HGNEC, were verified by electron microscopy and nanoparticle tracking analysis. Higher levels of UCHL1 mRNA in EV were found in the samples of patients with early-stage HGNEC than those with early-stage NSCLC and healthy donors' EV. Taken together, UCHL1 may be a potential prognostic marker and a promising druggable target for HGNEC.


Assuntos
Carcinoma Neuroendócrino/patologia , Vesículas Extracelulares/genética , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Células A549 , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Vesículas Extracelulares/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Platina/farmacologia , Platina/uso terapêutico , Prognóstico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Regulação para Cima
4.
Cancer Sci ; 110(10): 3122-3131, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31369178

RESUMO

Delta-like 3 (DLL3) is a member of the Delta/Serrate/Lag2 (DSL) group of Notch receptor ligands. Five DSL ligands are known in mammals, among which DLL3 has a unique structure. In the last few years, DLL3 has attracted attention as a novel molecular targeting gene in neuroendocrine carcinoma of the lung due to its high expression. However, the expression pattern and functions of DLL3 in the gastrointestinal tract and gastrointestinal neuroendocrine carcinoma remain unclear. In this study, we examined the expression and role of DLL3 in the gastrointestinal tract, as well as in gastrointestinal neuroendocrine carcinoma. Immunohistochemical staining of the human normal gastrointestinal tract revealed that DLL3 localized in neuroendocrine cells. DLL3 showed intense staining in chromogranin A-positive gastric cancer specimens. Real-time quantitative RT-PCR and western blotting analyses showed considerable upregulation of DLL3 in gastrointestinal neuroendocrine carcinoma cell lines. Immuno-electron microscopy demonstrated abundant expression of DLL3 in neurosecretory granules in these cells. Furthermore, gene silencing of DLL3 caused significant growth inhibition through the induction of intrinsic apoptosis. Our findings suggest that DLL3 is expressed in neuroendocrine cells of the gastrointestinal tract and that it has a pivotal role in gastrointestinal neuroendocrine carcinoma cells. Based on these findings, further investigations are required to achieve a breakthrough in developing therapeutic strategies for gastrointestinal neuroendocrine carcinoma.


Assuntos
Carcinoma Neuroendócrino/metabolismo , Neoplasias Gastrointestinais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Células Neuroendócrinas/metabolismo , Idoso , Apoptose , Carcinoma Neuroendócrino/genética , Linhagem Celular Tumoral , Neoplasias Gastrointestinais/genética , Trato Gastrointestinal/citologia , Trato Gastrointestinal/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Regulação para Cima
5.
Med Sci Monit ; 25: 5170-5180, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31298226

RESUMO

BACKGROUND Medullary thyroid carcinoma (MTC), a rare type of thyroid cancer, is a big challenge in clinical treatment. However, the pathogenesis of MTC remains poorly understand. MicroRNAs (miRNAs) were previously demonstrated to be involved in the pathogenesis of MTC, however, the roles of majority of miRNAs in MTC are still undetermined. MATERIAL AND METHODS Two GEO miRNA expression profiles (GSE40807, GSE97070) were downloaded, and the differentially expressed miRNAs (DEmiRNAs) of GSE40807 and GSE97070 were analyzed by bioinformatics methods. Expressions of miRNAs were detected by quantitative real-time polymerase chain reaction; cell proliferation was examined through Cell Counting Kit-8, colony formation and in vivo tumor growth assays; the interaction between miRNA and mRNA was verified by dual-luciferase reporter assay; functional analysis of target genes was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID, www.david.ncifcrf.gov) software. RESULTS Ten miRNAs were identified to be dysregulated in both GSE40807 and GSE97070 datasets, and miR-31-3p showed the highest change fold (Log fold change=-3.460625 in GSE40807 and Log fold change=-0.07084374 in GSE97070). MiR-31-3p expression was significantly downregulated in MTC, and low miR-31-3p expression showed a poor prognosis relative to high miR-31-3p expression (P<0.05). Functionally, miR-31-3p inhibited MTC cell proliferation in vitro and in vivo. Functional analysis also showed that the target genes of miR-31-3p were involved in numerous of biochemical processes and pathways, of which Ras signaling pathway was selected for further study. RASA2, overexpressed in MTC, were negatively regulated by miR-31-3p. In addition, we found that knockdown of RASA2 inhibited MTC cell proliferation. CONCLUSIONS Reduced expression level of miR-31-3p might play a key role in the tumorigenesis of MTC by targeting critical pathways, especially Ras signaling pathway.


Assuntos
Carcinoma Neuroendócrino/genética , MicroRNAs/genética , Neoplasias da Glândula Tireoide/genética , Proteínas Ativadoras de ras GTPase/genética , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , MicroRNAs/metabolismo , RNA Mensageiro/genética , Transdução de Sinais , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Transcriptoma , Proteínas Ativadoras de ras GTPase/metabolismo
6.
Clin Nucl Med ; 44(9): e546-e547, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31283604

RESUMO

Neuroendocrine tumors (NETs) of the thyroid gland are generally considered to be derived from parafollicular endocrine or C cells and are known as medullary thyroid carcinomas. Non-calcitonin-producing NETs of the thyroid are extremely rare in occurrence and pose a significant diagnostic dilemma for the physician and pathologist. We describe a case of a 58-year-old woman who was diagnosed as having primary NET thyroid with normal calcitonin levels and Ga DOTANOC PET-CT scan findings which were done for initial extent evaluation of the disease.


Assuntos
Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/metabolismo , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/metabolismo , Calcitonina/metabolismo , Carcinoma Neuroendócrino/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Neoplasias da Glândula Tireoide/patologia
7.
PLoS One ; 14(6): e0217105, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166966

RESUMO

Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine lung carcinoma (LCNEC) are high-grade lung neuroendocrine tumors (NET). However, comparative protein expression within SCLC and LCNEC remains unclear. Here, protein expression profiles were obtained via mass spectrometry-based proteomic analysis. Weighted gene co-expression network analysis (WGCNA) identified co-expressed modules and hub genes. Of 34 identified modules, six were significant and selected for protein-protein interaction (PPI) network analysis and pathway enrichment. Within the six modules, the activation of cellular processes and complexes, such as alternative mRNA splicing, translation initiation, nucleosome remodeling and deacetylase (NuRD) complex, SWItch/Sucrose Non-Fermentable (SWI/SNF) superfamily-type complex, chromatin remodeling pathway, and mRNA metabolic processes, were significant to SCLC. Modules enriched in processes, including signal recognition particle (SRP)-dependent co-translational protein targeting to membrane, nuclear-transcribed mRNA catabolic process of nonsense-mediated decay (NMD), and cellular macromolecule catabolic process, were characteristically activated in LCNEC. Novel high-degree hub genes were identified for each module. Master and upstream regulators were predicted via causal network analysis. This study provides an understanding of the molecular differences in tumorigenesis and malignancy between SCLC and LCNEC and may help identify potential therapeutic targets.


Assuntos
Carcinoma de Células Grandes/genética , Carcinoma Neuroendócrino/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias Pulmonares/genética , Proteômica , Carcinoma de Pequenas Células do Pulmão/genética , Idoso , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mapeamento de Interação de Proteínas , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia
8.
Diagn Cytopathol ; 47(9): 943-947, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31190466

RESUMO

Medullary carcinoma of thyroid (MCT) is a neuroendocrine neoplasm derived from the parafollicular cells or C cells. It constitutes 5% of thyroid carcinomas. We present a case of 36-year-old female with a left lower lobe thyroid swelling since 8 to 9 years. Swelling was smooth, nontender, and moving with deglutition. Contrast-enhanced computed tomography (CECT) findings were suggestive of malignant thyroid nodule. Fine-needle aspiration cytology (FNAC) smears were highly cellular comprising predominantly Hurthle cells arranged in sheets, clusters, and follicles with few singly scattered cells. Background was hemorrhagic with scant colloids. An impression of follicular neoplasm or suspicious of follicular neoplasm was given with an additional note mentioning that the possibility of Hurthle cell neoplasm could not be excluded. Left hemithyroidectomy was done and sections showed a well-circumscribed tumor suggestive of MCT, which was confirmed based on immunohistochemistry for calcitonin and carcinoembryonic antigen. It is difficult to differentiate MCT from Hurthle cell neoplasm. There may be cellular pleomorphism within a single aspirate, but the presence of mixed cell population is a diagnostic pointer for MCT. In the presence of predominant Hurthle cell population, distinguishing these entities by cytomorphology alone is difficult. Hence, clinical findings and histopathology with immunohistochemistry are mandatory in such cases to reach to a correct diagnosis to ensure proper management.


Assuntos
Adenoma Oxífilo , Neoplasias da Glândula Tireoide , Tireoidectomia , Adenoma Oxífilo/diagnóstico , Adenoma Oxífilo/metabolismo , Adenoma Oxífilo/patologia , Adenoma Oxífilo/cirurgia , Adulto , Biópsia por Agulha Fina , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia
9.
Pathology ; 51(4): 369-374, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31040050

RESUMO

Neuroendocrine (NE) tumours are uncommon in the gynecological tract. In addition to their histological features, what defines NE carcinoma is the expression of markers such as chromogranin, synaptophysin and neural cell adhesion molecule (CD56) by immunohistochemistry (IHC). Although limited data have demonstrated that some high-grade uterine tumours may focally express these markers, the incidence of such labelling in endometrial carcinomas in general is not well known. The goal of this study was to characterise the expression of NE markers in a cohort of endometrial carcinomas. We searched our institutional surgical pathology database for hysterectomy specimens containing endometrial carcinomas. Cases demonstrating classic morphological features of NE carcinomas were excluded. IHC for synaptophysin, chromogranin and CD56 was performed in whole-tissue sections of formalin-fixed, paraffin-embedded (FFPE) tumours. Thyroid transcription factor 1 (TTF-1) was also included, given its positivity in a subset of small cell carcinomas. Marker expression was graded based on percentage of positive tumour cells (0, not detected; 1, 1-25%; 2, 25-50%; 3, >50%). Chi-square was used for statistical analysis and significance was set at p<0.05. In total, 71 carcinomas of endometrioid (EMCA; 26 cases), serous (20), clear cell (12), undifferentiated (2) and dedifferentiated (1) histologies were obtained, as well as 10 carcinosarcomas. The majority expressed one or more NE markers (47/71; 66%), with most positive cases showing focal (1+) staining of a single marker. Significantly more tumours stained positive for CD56 than synaptophysin (58% vs 7%, p<0.01). Clear cell carcinomas were the least likely to express any NE marker (4/12; 33%), whereas serous carcinomas (80%) and carcinosarcomas (100%) were the most likely. CD56 labelling was seen in 9/10 carcinosarcomas, in both epithelial (7/9) and mesenchymal (5/9) elements. A slightly greater proportion of non-endometrioid histological types stained positive for TTF-1 compared with endometrioid type (31% vs 12%, p=0.06). Immunohistochemical expression of NE markers is relatively common in endometrial carcinomas that lack classic NE histology. The most frequent pattern encountered in our study was focal (1-25%) labelling of a single marker. Synaptophysin appeared reliably negative, while CD56 was commonly present in non-NE histology. Clear cell carcinomas tend to be consistently negative, whereas carcinosarcomas and serous carcinomas frequently express at least one marker. Awareness of these data may help to avoid misdiagnosis of a neuroendocrine carcinoma in limited samples.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias Uterinas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno CD56/metabolismo , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Cromograninas/metabolismo , Estudos de Coortes , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Endométrio/metabolismo , Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Sinaptofisina/metabolismo , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologia
10.
Ann Diagn Pathol ; 40: 53-58, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31031215

RESUMO

Merkel cell carcinoma (MCC) is an uncommon primary neuroendocrine carcinoma of the skin. Nowadays, pathologists are required to perform immunohistochemistry to demonstrate neuroendocrine and epithelial differentiation for diagnosis of MCC. Insulinoma-associated protein 1 (INSM1) is a zinc-finger transcription factor expressed in tissues undergoing terminal neuroendocrine differentiation, and INSM1 immunohistochemistry is a well-validated nuclear marker of neuroendocrine differentiation. We evaluated 24 cases of MCC for the expression of INSM1 and compared it with frequently used neuroendocrine markers, Chromogranin A, Synaptophysin, and CD56. INSM1 was positive in all cases, and its expression was stronger, more extensive, clean and homogeneous compared to other markers. As a consequence, INSM1 can be used to serve as a solitary marker for neuroendocrine differentiation due to high sensitivity and specificity in MCC cases.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Célula de Merkel/metabolismo , Carcinoma Neuroendócrino/metabolismo , Insulinoma/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno CD56/metabolismo , Carcinoma de Célula de Merkel/patologia , Carcinoma Neuroendócrino/patologia , Cromogranina A/metabolismo , Feminino , Humanos , Insulinoma/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Proteínas Repressoras/metabolismo , Sensibilidade e Especificidade , Neoplasias Cutâneas/patologia , Sinaptofisina/metabolismo , Fatores de Transcrição/metabolismo
11.
PLoS Comput Biol ; 15(4): e1006878, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31026276

RESUMO

Drosophila provides an inexpensive and quantitative platform for measuring whole animal drug response. A complementary approach is virtual screening, where chemical libraries can be efficiently screened against protein target(s). Here, we present a unique discovery platform integrating structure-based modeling with Drosophila biology and organic synthesis. We demonstrate this platform by developing chemicals targeting a Drosophila model of Medullary Thyroid Cancer (MTC) characterized by a transformation network activated by oncogenic dRetM955T. Structural models for kinases relevant to MTC were generated for virtual screening to identify unique preliminary hits that suppressed dRetM955T-induced transformation. We then combined features from our hits with those of known inhibitors to create a 'hybrid' molecule with improved suppression of dRetM955T transformation. Our platform provides a framework to efficiently explore novel kinase inhibitors outside of explored inhibitor chemical space that are effective in inhibiting cancer networks while minimizing whole body toxicity.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Neuroendócrino , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases , Neoplasias da Glândula Tireoide , Animais , Carcinoma Neuroendócrino/enzimologia , Carcinoma Neuroendócrino/metabolismo , Biologia Computacional/métodos , Drosophila , Modelos Biológicos , Neoplasias Experimentais/enzimologia , Neoplasias Experimentais/metabolismo , Proteínas Quinases/efeitos dos fármacos , Proteínas Quinases/metabolismo , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/metabolismo
13.
Ann Surg Oncol ; 26(6): 1744-1750, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30924018

RESUMO

BACKGROUND: Lung combined neuroendocrine carcinomas (NECs) comprise NEC and non-NEC components, such as adenocarcinoma and squamous cell carcinoma. Mutation of epidermal growth factor receptor (EGFR) often is observed in non-NEC but is very rare in sporadic NEC, which almost always has p53 mutation. Therefore, we hypothesized the following research concept: mutation analysis of EGFR and p53 in each component of combined NEC tissues can provide important information on whether such components originate from the same tumor cells or incidentally arise as collision cancers. METHODS: We compared the mutations of EGFR and p53 in laser-microdissected NEC and non-NEC from lungs of eight cases affected by combined NEC. We examined the expression of EGFR and NEC markers in the combined NECs by immunohistochemistry. RESULTS: Five of eight cases of combined NEC had the same mutations of EGFR and/or p53 in both non-NEC and NEC. One case had EGFR mutation in only the non-NEC component, and two cases did not have these mutations. Replacement transformation was observed in borderline areas between non-NEC and NEC. The signal of activated EGFR in non-NEC with the same EGFR mutation was more intense than that in NEC components. CONCLUSIONS: Our study suggests the mechanism behind the carcinogenesis of lung combined NEC, which is partially caused by the transformation from epithelial carcinoma of non-NEC to NEC.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Mutação , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Idoso , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Análise Mutacional de DNA , Receptores ErbB/genética , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética
14.
Genesis ; 57(5): e23292, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30884088

RESUMO

Medullary thyroid carcinoma (MTC) develops from hyperplasia of thyroid C cells and represents one of the major causes of thyroid cancer mortality. Mutations in the cysteine-rich domain (CRD) of the RET gene are the most prevalent genetic cause of MTC. The current consensus holds that such cysteine mutations cause ligand-independent dimerization and constitutive activation of RET. However, given the number of the CRD mutations left uncharacterized, our understanding of the pathogenetic mechanisms by which CRD mutations lead to MTC remains incomplete. We report here that RET(C618F), a mutation identified in MTC patients, displays moderately high basal activity and requires the ligand for its full activation. To assess the biological significance of RET(C618F) in organogenesis, we generated a knock-in mouse line conditionally expressing RET(C618F) cDNA by the Ret promoter. The RET(C618F) allele can be made to be Ret-null and express mCherry by Cre-loxP recombination, which allows the assessment of the biological influence of RET(C618F) in vivo. Mice expressing RET(C618F) display mild C cell hyperplasia and increased numbers of enteric neurons, indicating that RET(C618F) confers gain-of-function phenotypes. This mouse line serves as a novel biological platform for investigating pathogenetic mechanisms involved in MTC and enteric hyperganglionosis.


Assuntos
Carcinoma Neuroendócrino/genética , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Animais , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Sistema Nervoso Entérico/metabolismo , Sistema Nervoso Entérico/patologia , Técnicas de Introdução de Genes/métodos , Mutação em Linhagem Germinativa , Humanos , Hiperplasia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Proteínas Proto-Oncogênicas c-ret/biossíntese , Proteínas Proto-Oncogênicas c-ret/metabolismo , Hiperplasia do Timo/genética , Hiperplasia do Timo/metabolismo , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo
16.
Cancer Cell ; 35(3): 385-400.e9, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30827887

RESUMO

Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.


Assuntos
Carcinoma Neuroendócrino/patologia , Regulação para Baixo , Isoenzimas/deficiência , Neoplasias da Próstata/patologia , Proteína Quinase C/deficiência , Serina/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Vias Biossintéticas , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , S-Adenosilmetionina/metabolismo
17.
Chin Med J (Engl) ; 132(5): 551-561, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30807354

RESUMO

BACKGROUND: Classification of the pulmonary neuroendocrine tumor (pNET) categories is a step-wise process identified by the presence of necrosis and number of mitoses per 2 mm. In neuroendocrine tumor pathology, Ki-67 was first described as a prognostic factor in the pancreas and incorporated into the grading system of digestive tract neuroendocrine neoplasms in the 2010 WHO classification. However, the significance of Ki-67 in pNETs was still a controversial issue. This study was to investigate the potentially diagnostic value of Ki-67 in pNETs. METHODS: We retrieved 159 surgical specimens of pNETs, including 35 typical carcinoids (TCs), 2 atypical carcinoid (ACs), 28 large-cell neuroendocrine carcinomas (LCNECs), 94 small-cell lung cancers (SCLCs). Manual conventional method (MCM) and computer-assisted image analysis method (CIAM) were used to calculate the Ki-67 proliferative index. In CIAM, 6 equivalent fields (500 × 500 µm) at 10× magnification were manually annotated for digital image analysis. RESULTS: The Ki-67 index among the 4 groups with ranges of 0.38% to 12.66% for TC, 4.34% to 29.48% for AC, 30.67% to 93.74% for LCNEC, and 40.71% to 96.87% for SCLC. The cutoff value of Ki-67 index to distinguish low grade with high grade was 30.07%. For the univariate survival analyses in pNETs, both the overall survival and progression-free survival correlated with Ki-67 index. In addition, the Ki-67 index performed by CIAM was proved to be of great positive correlation with MCM. CONCLUSIONS: Ki-67 index counted by CIAM is a reliable method and can be a useful adjunct to classify the low- and high-grade NETs.


Assuntos
Carcinoma Neuroendócrino/metabolismo , Antígeno Ki-67/metabolismo , Tumores Neuroendócrinos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Imuno-Histoquímica , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Prognóstico , Organização Mundial da Saúde
19.
Histopathology ; 74(7): 997-1004, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30667073

RESUMO

AIMS: Neuroendocrine carcinoma, small cell type, of the uterine cervix (SmCC-Cx) is a rare human papilloma virus (HPV) related tumour with limited therapeutic options. Merkel cell carcinoma, another virus-associated neuroendocrine malignancy, has significant programmed death ligand 1 (PD-L1) expression rates. PD-L1 expression has been reported in other malignancies of the cervix. We aimed to determine the prevalence of PD-L1 in the context of mismatch repair protein (MMR) and RB1 expression status in SmCC-Cx. METHODS AND RESULTS: Ten cases of SmCC-Cx were tested by immunohistochemistry for expression of PD-L1, MLH1, MSH2, MSH6, PMS2, RB1, CD3, CD20 and for HPV by in-situ hybridisation (ISH). PD-L1 expression was scored quantitatively (H-score) in tumour cells and lymphocytes (tumoral/peritumoral). PD-L1 positivity was seen in seven cases, focal in most (H-score range 3-140). Three of nine cases showed MMR deficiency. PD-L1 expression levels correlated with MMR expression status: all three MLH1/PMS2-deficient cases had a ≥5% PD-L1 staining and an H-score ≥10 (P = 0.01). RB1 was lost in four of nine cases, all PD-L1 positive, but this correlation was not statistically significant. Seven of nine tumours were positive for HPV-ISH; two of these had MLH1/PMS2 loss. Of the two HPV-ISH negative tumours, one had MLS1/PMS2 loss. CONCLUSIONS: PD-L1 expression, predominantly focal, is seen in 70% of SmCC-Cx, while loss of MMR expression is seen in 33% of SmCC-Cx in our cohort. PD-L1 expression in more than 10% of tumour cells is seen in a subset of tumours in association with loss of MMR expression. These patients may be amenable to immune checkpoint inhibitor therapy as a promising alternative for this aggressive disease.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/metabolismo , Proteínas de Ligação a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas , Carcinoma Neuroendócrino/patologia , Colo do Útero/metabolismo , Colo do Útero/patologia , Estudos de Coortes , Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA/genética , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias
20.
BMJ Case Rep ; 12(1)2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642849

RESUMO

We report a case of large cell neuroendocrine carcinoma of the uterine cervix. A 33-year-old woman presented with a 4-month history of irregular vaginal bleeding and suspicious cervix. Transvaginal ultrasound showed a 3×3.8 cm cervical mass with a marked increase in the blood flow. MRI pelvis showed an exophytic tumour with left external iliac lymph node metastasis. Immunohistochemistry of the tumour cells showed strong positivity for the neuroendocrine markers synaptophysin and a very high Ki67 proliferation index. A diagnosis of high-grade large cell neuroendocrine carcinoma of the uterine cervix was made with FIGO stage IIA2. She was treated with chemotherapy and palliative radiotherapy but died 21 months after presenting. Neuroendocrine tumour of the uterine cervix is an extremely aggressive cancer with the late presentation-the need for a more rigorous treatment protocol as well as potential screening methods could improve outcomes for these patients.


Assuntos
Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Colo do Útero/patologia , Neoplasias do Colo do Útero/patologia , Adulto , Carcinoma de Células Grandes/diagnóstico por imagem , Carcinoma de Células Grandes/metabolismo , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/radioterapia , Evolução Fatal , Feminino , Humanos , Linfonodos/patologia , Imagem por Ressonância Magnética/métodos , Metástase Neoplásica/patologia , Cuidados Paliativos , Sinaptofisina/metabolismo , Ultrassonografia/métodos , Neoplasias do Colo do Útero/metabolismo
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