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1.
Hum Pathol ; 112: 1-8, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33741347

RESUMO

Loss of SMARCB1 protein expression has recently been identified in a variety of tumor types such as poorly differentiated chordoma (PCh) and malignant rhabdoid tumor (MRT) including atypical teratoid/rhabdoid tumor (AT/RT). PCh is characterized by poorly differentiated epithelioid tumor cells, sheet arrangement, and coexpression of nonepithelial and epithelial markers. Rhabdoid cells are sometimes present. Therefore, the differentiation of these tumors is often difficult. Brachyury is a transcription factor within the T-box family typically expressed in notochord tissue and chordomas. Some studies have reported high specificity and sensitivity of brachyury expression in chordomas. In the present study, we analyzed immunohistochemical brachyury expression in SMARCB1-deficient tumors and discuss important clinicopathological and diagnostic points, especially in cases of intracranial SMARCB1-deficient tumors with brachyury expression. Brachyury and cytokeratin immunoexpression status was examined in 42 formalin-fixed paraffin-embedded SMARCB1-deficient tumor specimens (PCh, 6 cases; extra-central nervous system [CNS] MRT, 26 cases; AT/RT, 10 cases) and 25 cases of conventional chordoma (CCh). All cases of PCh and CCh showed diffuse immunopositivities for cytokeratin 8, pan-cytokeratin, and brachyury. Brachyury immunoexpression was present in 2 extra-CNS MRT (8%) and 5 AT/RT (50%) cases, but immunopositivity was focal not diffuse. Indeed, in almost all cases of AT/RT (cytokeratin 8, 7/10 cases; pan-cytokeratin, 7/10 cases) and extra-CNS MRT (cytokeratin 8, 23/26 cases; pan-cytokeratin, 25/26 cases), fewer than 50% of cells showed immunoreactivity. Although the histological and clinical features of PCh resemble those of AT/RT, semiquantitative evaluations of the degree of brachyury and cytokeratin immunoexpressivity may help to distinguish PCh from AT/RT.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/diagnóstico , Cordoma/diagnóstico , Proteínas Fetais/biossíntese , Tumor Rabdoide/diagnóstico , Proteínas com Domínio T/biossíntese , Teratoma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Cordoma/metabolismo , Cordoma/patologia , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1/deficiência , Teratoma/metabolismo , Teratoma/patologia
2.
Indian J Cancer ; 57(4): 473-477, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33078756

RESUMO

A 64-year-old man presented with multiple, bilateral pulmonary nodules, considered clinically to be intrapulmonary metastasis from lung carcinoma. On histopathologic examination, a tumor with a solid growth pattern and rhabdoid neoplastic morphology was seen. Initially, a diagnosis of nonsmall cell carcinoma of lung was considered but the immunophenotype was not supportive. Further, extensive immunohistochemistry revealed SOX10, Melan-A, and HMB45 expression in the absence of S-100. Strong globular cytoplasmic staining for vimentin, SMA, Desmin, and WT1 were observed. A final diagnosis of rhabdoid melanoma was made. The immunoprofile of our case was unique from previously described rhabdoid melanoma in English literature. The globular staining for intermediate filaments such as desmin and SMA is a novel finding. The strong WT1 intracytoplasmic staining reported previously was also observed in this case, with intense globular characteristics.


Assuntos
Biomarcadores Tumorais/metabolismo , Melanoma/diagnóstico , Tumor Rabdoide/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Melanoma/metabolismo , Pessoa de Meia-Idade , Prognóstico , Tumor Rabdoide/metabolismo
3.
Pathol Res Pract ; 216(10): 153151, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32853941

RESUMO

Mixed epithelial and stromal tumor (MEST) of the kidney is a rare biphasic tumor composed of both stromal and epithelial components, the latter showing a variable proportion of solid to cystic areas. These tumors show a marked female predominance, commonly occur in perimenopausal age groups, and often have an ovarian-type stroma with ER and PR positivity, suggesting steroids may play a role in pathogenesis. Although typically benign, rare cases showing malignant transformation have been reported. We present a case of a 42-year-old man with a 10 cm right kidney mass located in the renal pelvis. Histologically, the majority of the tumor was composed of a diffuse, sheet-like growth of malignant cells demonstrating a rhabdoid morphology with large nuclei, prominent nucleoli, and eosinophilic eccentric cytoplasm. Brisk mitotic activity and coagulative type necrosis was also noted. Intimately associated with this malignant rhabdoid component was a much smaller portion of tumor featuring variably sized bland epithelial tubules embedded within a stroma composed of bland spindle cells and areas of hyalinization, diagnostic of MEST. By immunohistochemistry, the malignant rhabdoid tumor portion of the neoplasm showed complete loss of nuclear INI-1, while the MEST component retained nuclear expression of this antigen. With these features taken together, our case represents a malignant rhabdoid tumor arising in a background of MEST. To our knowledge, this case represents the first case of a MEST showing malignant transformation in the form of malignant rhabdoid tumor in a male patient in the English language literature.


Assuntos
Neoplasias Complexas Mistas/patologia , Tumor Rabdoide/metabolismo , Neoplasias de Tecidos Moles/patologia , Células Estromais/patologia , Carcinoma/patologia , Humanos , Neoplasias Renais/patologia , Masculino
4.
J Pathol ; 252(1): 77-87, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32558936

RESUMO

Atypical teratoid rhabdoid tumor (ATRT) is a fatal pediatric malignancy of the central neural system lacking effective treatment options. It belongs to the rhabdoid tumor family and is usually caused by biallelic inactivation of SMARCB1, encoding a key subunit of SWI/SNF chromatin remodeling complexes. Previous studies proposed that SMARCB1 loss drives rhabdoid tumor by promoting cell cycle through activating transcription of cyclin D1 while suppressing p16. However, low cyclin D1 protein expression is observed in most ATRT patient tumors. The underlying mechanism and therapeutic implication of this molecular trait remain unknown. Here, we show that SMARCB1 loss in ATRT leads to the reduction of cyclin D1 expression by upregulating MIR17HG, a microRNA (miRNA) cluster known to generate multiple miRNAs targeting CCND1. Furthermore, we find that this cyclin D1 deficiency in ATRT results in marked in vitro and in vivo sensitivity to the CDK4/6 inhibitor palbociclib as a single agent. Our study identifies a novel genetic interaction between SMARCB1 and MIR17HG in regulating cyclin D1 in ATRT and suggests a rationale to treat ATRT patients with FDA-approved CDK4/6 inhibitors. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Ciclina D1/genética , Regulação Neoplásica da Expressão Gênica , Proteínas/genética , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Ciclina D1/metabolismo , Humanos , Proteínas/metabolismo , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1/metabolismo , Teratoma/metabolismo , Teratoma/patologia , Regulação para Cima
5.
Histopathology ; 77(2): 231-239, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32268438

RESUMO

AIMS: Anaplastic carcinoma arising in a mucinous tumour of the ovary and rarely in the retroperitoneum is an uncommon neoplasm with three morphological patterns; rhabdoid, sarcomatoid and pleomorphic. We investigated expression of switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex components and claudin-4 expression. METHODS AND RESULTS: Twenty-two ovarian and three retroperitoneal mucinous tumours were investigated using antibodies against SMARCB1, SMARCA4, SMARCA2, ARID1A and claudin-4. Loss of nuclear staining for any SWI/SNF protein was observed in the anaplastic component of nine of 25 (36%), with retained expression within the mucinous component of all tumours. Five (56%) showed loss of more than one protein, with dual loss of SMARCA4 and SMARCA2 in two, loss of SMARCA2 and ARID1A in two and loss of SMARCB1 and SMARCA2 in one. Retained expression of claudin-4 was seen in 39% of the anaplastic carcinomas and within the mucinous component of all tumours. Rhabdoid morphology was associated with poor prognosis [stages III or IV disease (six of six, 100% versus four of 14, 29%; P = 0.0108] and death from disease (three of four, 75% versus one of 13, 8%; P = 0.0223). Although loss of a SWI/SNF protein was not significantly associated with death from disease (three of five, 60% versus one of 12, 8%; P = 0.0525), it showed a trend in correlation with poor prognosis and was often noted in tumours with rhabdoid morphology within this small cohort. CONCLUSIONS: Our report adds to the growing list of female genital tract malignancies with loss of SWI/SNF proteins, underlining their broad differential diagnosis and the importance of careful, context-dependent interpretation of SWI/SNF protein loss.


Assuntos
Adenocarcinoma Mucinoso , Carcinoma , Claudina-4/metabolismo , Neoplasias Ovarianas/diagnóstico , Fatores de Transcrição/metabolismo , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma/metabolismo , Carcinoma/patologia , Claudina-4/administração & dosagem , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ovário/metabolismo , Ovário/patologia , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1
6.
Int J Mol Sci ; 21(7)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32244797

RESUMO

Human SNF5 and BAF155 constitute the core subunit of multi-protein SWI/SNF chromatin-remodeling complexes that are required for ATP-dependent nucleosome mobility and transcriptional control. Human SNF5 (hSNF5) utilizes its repeat 1 (RPT1) domain to associate with the SWIRM domain of BAF155. Here, we employed X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and various biophysical methods in order to investigate the detailed binding mechanism between hSNF5 and BAF155. Multi-angle light scattering data clearly indicate that hSNF5171-258 and BAF155SWIRM are both monomeric in solution and they form a heterodimer. NMR data and crystal structure of the hSNF5171-258/BAF155SWIRM complex further reveal a unique binding interface, which involves a coil-to-helix transition upon protein binding. The newly formed αN helix of hSNF5171-258 interacts with the ß2-α1 loop of hSNF5 via hydrogen bonds and it also displays a hydrophobic interaction with BAF155SWIRM. Therefore, the N-terminal region of hSNF5171-258 plays an important role in tumorigenesis and our data will provide a structural clue for the pathogenesis of Rhabdoid tumors and malignant melanomas that originate from mutations in the N-terminal loop region of hSNF5.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Mutação , Nucleossomos/genética , Proteína SMARCB1/genética , Fatores de Transcrição/genética , Sítios de Ligação/genética , Dicroísmo Circular , Cristalografia por Raios X , Regulação da Expressão Gênica , Humanos , Espectroscopia de Ressonância Magnética , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Nucleossomos/metabolismo , Ligação Proteica , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1/química , Proteína SMARCB1/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
7.
Turk Patoloji Derg ; 1(1): 261-267, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149361

RESUMO

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) / malignant rhabdoid tumor of the ovary (MRTO) is a rare tumor affecting young women. It is frequently misdiagnosed due to overlapping morphological and immunohistochemical features with many other ovarian tumors. The prognosis of the tumors is very poor; hence an accurate diagnosis is of utmost importance. Recently, the loss of BRG1 protein by immunohistochemistry has been shown to be a useful diagnostic marker. We present here two cases of SSCOHT/MRTO, in young women 22 and 32 years of age, where several differential diagnoses were considered on morphology and immunohistochemistry but were confirmed as SCCOHT/MRTO by the demonstration of loss of BRG1. As the prognosis of SCCOHT is very dismal, and accurate diagnosis is of necessity, we recommend the inclusion of BRG1 immunohistochemistry in the diagnostic armamentarium of poorly differentiated ovarian tumors, particularly in young adults.


Assuntos
Carcinoma de Células Pequenas/patologia , DNA Helicases/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/patologia , Tumor Rabdoide/patologia , Fatores de Transcrição/metabolismo , Adulto , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Pequenas/metabolismo , Feminino , Humanos , Hipercalcemia/etiologia , Hipercalcemia/patologia , Neoplasias Ovarianas/metabolismo , Síndromes Paraneoplásicas/etiologia , Síndromes Paraneoplásicas/patologia , Tumor Rabdoide/metabolismo , Adulto Jovem
8.
Semin Cancer Biol ; 61: 30-41, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31923457

RESUMO

Malignant Rhabdoid Tumours (MRT) are the quintessential example of an epigenetic cancer. Mutation of a single gene, SMARCB1 or more rarely SMARCA4, is capable of causing one of the most aggressive and lethal cancers of early childhood and infancy. SMARCB1 encodes a core subunit of the SWI/SNF complex and its mutation evokes genome-wide downstream effects which may be counteracted therapeutically. Here we review and discuss the use of translational genomics in the study of MRT biology and the ways in which this has impacted clinical practice or may do so in the future. First, the diagnosis and definition of MRT and the transition from a histopathological to a molecular definition. Second, epigenetic and transcriptomic subgroups within MRT, their defining features and potential prognostic or therapeutic significance. Third, functional genomic studies of MRT by mouse modelling and forced re-expression of SMARCB1 in MRT cells. Fourth, studies of underlying epigenetic mechanisms (e.g. EZH2, HDACs) or deregulated kinases (e.g. PDGFR, FGFR1) and the potential therapeutic opportunities these provide. Finally, we discuss likely future directions and proffer opinion on how future translational genomics should be integrated into future biological/clinical studies to select and evaluate the best anti-MRT therapeutic agents.


Assuntos
Transformação Celular Neoplásica/genética , Predisposição Genética para Doença , Genômica , Tumor Rabdoide/genética , Pesquisa Médica Translacional , Animais , Transformação Celular Neoplásica/metabolismo , DNA Helicases/genética , Epigênese Genética , Perfilação da Expressão Gênica , Estudos de Associação Genética , Heterogeneidade Genética , Genômica/métodos , Genótipo , Humanos , Camundongos , Mutação , Proteínas Nucleares/genética , Fenótipo , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/metabolismo , Fatores de Transcrição/genética
9.
Curr Cancer Drug Targets ; 20(4): 295-305, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31713485

RESUMO

BACKGROUND: Atypical teratoid rhabdoid tumor of the central nervous system (CNS ATRT) is a malignancy that commonly affects young children. The biological mechanisms contributing to tumor aggressiveness and resistance to conventional therapies in ATRT are unknown. Previous studies have shown the activity of insulin like growth factor-I receptor (IGF-1R) in ATRT tumor specimens and cell lines. IGF-1R has been shown to cross-talk with other receptor tyrosine kinases (RTKs) in a number of cancer types, leading to enhanced cell proliferation. OBJECTIVE: This study aims to evaluate the role of IGF-1 receptor cross-talk in ATRT biology and the potential for therapeutic targeting. METHODS: Cell lines derived from CNS ATRT specimens were analyzed for IGF-1 mediated cell proliferation. A comprehensive receptor tyrosine kinase (RTK) screen was conducted following IGF-1 stimulation. Bioinformatic analysis of publicly available cancer growth inhibition data to identify correlation between IC50 of a VEGFR inhibitor and IGF-1R expression. RESULTS: Comprehensive RTK screen identified VEGFR-2 cross-activation following IGF-1 stimulation. Bioinformatics analysis demonstrated a positive correlation between IC50 values of VEGFR inhibitor Axitinib and IGF-1R expression, supporting the critical influence of IGF-1R in modulating response to anti-angiogenic therapies. CONCLUSION: Overall, our data present a novel experimental framework to evaluate and utilize receptor cross-talk mechanisms to select effective drugs and combinations for future therapeutic trials in ATRT.


Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor Cross-Talk/efeitos dos fármacos , Receptor IGF Tipo 1/antagonistas & inibidores , Tumor Rabdoide/tratamento farmacológico , Teratoma/tratamento farmacológico , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Axitinibe/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Técnicas In Vitro , Fator de Crescimento Insulin-Like I/farmacologia , Terapia de Alvo Molecular/métodos , Receptor IGF Tipo 1/metabolismo , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Transdução de Sinais/efeitos dos fármacos , Teratoma/metabolismo , Teratoma/patologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
12.
Pediatr Dev Pathol ; 23(2): 132-138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31403913

RESUMO

Malignant rhabdoid tumors and atypical teratoid/rhabdoid tumors of the central nervous system are primitive malignancies associated with a poor prognosis. These tumors have previously been characterized by inactivation of the switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex protein integrase interactor 1 (INI1), encoded by the SMARCB1 gene. In the last decade, sporadic publications have shown that a different SWI/SNF protein, brahma-related gene 1 (BRG1), encoded by the SMARCA4 gene, is associated with a similar rhabdoid phenotype and possible germline mutation termed rhabdoid tumor predisposition syndrome type 2. We sought to determine the presence of BRG1 expression in pediatric embryonal tumors. Using a local tissue microarray consisting of 28 tumors diagnosed as having an undifferentiated, polyphenotypic, or rhabdoid morphology, expression of BRG1 by immunohistochemistry was performed. Four cases showed loss of INI1, while 3 of the remaining 24 cases demonstrated loss of BRG1. Two cases were diagnosed as soft tissue sarcomas, and 1 case was diagnosed as a small cell carcinoma of the ovary, hypercalcemic type. Survival ranged from less than 6 months after diagnosis to more than 5 years at the time of last follow-up. In conclusion, we demonstrate that BRG1 immunohistochemistry is a useful second-line immunostain for the workup of undifferentiated, polyphenotypic or rhabdoid pediatric tumors that demonstrate retained expression of INI1.


Assuntos
DNA Helicases/metabolismo , Proteínas Nucleares/metabolismo , Tumor Rabdoide/metabolismo , Proteína SMARCB1/metabolismo , Fatores de Transcrição/metabolismo , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , DNA Helicases/genética , Feminino , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Masculino , Proteínas Nucleares/genética , Pediatria , Fenótipo , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Fatores de Transcrição/genética
13.
Cell Rep ; 29(8): 2338-2354.e7, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31708418

RESUMO

Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOX genes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1 mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients.


Assuntos
Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/patologia , Criança , Metilação de DNA/genética , Metilação de DNA/fisiologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Mutação/genética , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Neoplasias da Base do Crânio/metabolismo , Neoplasias da Base do Crânio/patologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Teratoma/metabolismo , Teratoma/patologia
14.
Hum Pathol ; 93: 23-29, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31445842

RESUMO

Deciduoid mesothelioma is a rare variant of epithelioid mesothelioma. Malignant rhabdoid tumors, renal medullary carcinoma, and some synovial sarcomas show a loss of SMARCB1/INI1 protein, a member of the SWI/SNF chromatin-remodeling complex. All of those tumors are known to have rhabdoid cells. Some mesothelioma cases, such as those of the deciduoid type, have also been reported to possess such rhabdoid features. Since this topic has not been studied in malignant mesothelioma, we analyzed the immunohistochemical expression of SMARCB1/INI1 in malignant mesotheliomas [45 epithelioid type (including 9 deciduoid type), 12 biphasic type, and 17 sarcomatoid type]. We employed (a) SMARCB1/INI1 immunohistochemistry, using an antibody to the INI1 gene product and (b) Fisher exact test, logistic regression analysis, the Kaplan-Meier method, and the Wilcoxon test for survival analysis for prognostic factor evaluation (SAS 9.4; SAS Institute, Cary, NC). The results showed that 17 of 74 (23%) malignant mesothelioma cases (epithelioid: 24%; biphasic; 8%; sarcomatoid; 29%) had reduced SMARCB1/INI1 expression. Reduced SMARCB1/INI1 expression appeared to be more frequent in the deciduoid type (67%), of which there were admittedly only a few cases, than in either the epithelioid type (14%) or biphasic type (8%), whether or not rhabdoid cells were present, but not different between the deciduoid and sarcomatoid types. However, there was no statistically significant difference in prognosis between malignant mesotheliomas with reduced versus preserved SMARCB1/INI1 protein expression. The results suggest that in differential diagnosis, cases with reduced SMARCB1/INI1 protein expression should not be excluded from a diagnosis of malignant mesothelioma.


Assuntos
Mesotelioma/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1/metabolismo , Adulto , Biomarcadores Tumorais/análise , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica/métodos , Hibridização In Situ , Masculino , Mesotelioma/diagnóstico , Mesotelioma/patologia , Pessoa de Meia-Idade , Tumor Rabdoide/metabolismo , Sarcoma/metabolismo
15.
Clin Cancer Res ; 25(19): 5925-5936, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31300448

RESUMO

PURPOSE: Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive infantile brain tumors with poor survival. Recent advancements have highlighted significant molecular heterogeneity in AT/RT with an aggressive subgroup featuring overexpression of the MYC proto-oncogene. We perform the first comprehensive metabolic profiling of patient-derived AT/RT cell lines to identify therapeutic susceptibilities in high MYC-expressing AT/RT. EXPERIMENTAL DESIGN: Metabolites were extracted from AT/RT cell lines and separated in ultra-high performance liquid chromatography mass spectrometry. Glutamine metabolic inhibition with 6-diazo-5-oxo-L-norleucine (DON) was tested with growth and cell death assays and survival studies in orthotopic mouse models of AT/RT. Metabolic flux analysis was completed to identify combination therapies to act synergistically to improve survival in high MYC AT/RT. RESULTS: Unbiased metabolic profiling of AT/RT cell models identified a unique dependence of high MYC AT/RT on glutamine for survival. The glutamine analogue, DON, selectively targeted high MYC cell lines, slowing cell growth, inducing apoptosis, and extending survival in orthotopic mouse models of AT/RT. Metabolic flux experiments with isotopically labeled glutamine revealed DON inhibition of glutathione (GSH) synthesis. DON combined with carboplatin further slowed cell growth, induced apoptosis, and extended survival in orthotopic mouse models of high MYC AT/RT. CONCLUSIONS: Unbiased metabolic profiling of AT/RT identified susceptibility of high MYC AT/RT to glutamine metabolic inhibition with DON therapy. DON inhibited glutamine-dependent synthesis of GSH and synergized with carboplatin to extend survival in high MYC AT/RT. These findings can rapidly translate into new clinical trials to improve survival in high MYC AT/RT.


Assuntos
Diazo-Oxo-Norleucina/farmacologia , Glutamina/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Tumor Rabdoide/metabolismo , Teratoma/metabolismo , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Glutamina/metabolismo , Humanos , Metaboloma/efeitos dos fármacos , Camundongos , Camundongos Nus , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/patologia , Teratoma/tratamento farmacológico , Teratoma/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
World Neurosurg ; 128: 196-199, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082562

RESUMO

BACKGROUND: Atypical rhabdoid teratoid tumors are very rare embryonal tumors that typically affect children younger than 3 years old and are encountered intracranially. CASE DESCRIPTION: Here, we describe the case of a 19-year-old woman who presented with gait disturbances and coccydynia. Imaging revealed a cauda equina mass. The tumor was partially resected. Histology reported loss of SMARCB1/INI1 expression and therefore the diagnosis of atypical rhabdoid teratoid was established. The patient underwent radiation treatment, but within 3 months 2 relapses were manifested. CONCLUSIONS: Atypical rhabdoid teratoids are exceptionally rare in adults and are seldom found in spine; only 8 such cases have been reported in the medical literature. They are invariantly characterized by multiple relapses and dismal prognosis. The clinician must be attentive of leptomeningeal disseminations and 22q11 deletion-associated comorbidities.


Assuntos
Cauda Equina/diagnóstico por imagem , Neoplasias do Sistema Nervoso Periférico/diagnóstico por imagem , Tumor Rabdoide/diagnóstico por imagem , Teratoma/diagnóstico por imagem , Idade de Início , Cauda Equina/cirurgia , Feminino , Humanos , Laminectomia , Procedimentos Neurocirúrgicos , Neoplasias do Sistema Nervoso Periférico/metabolismo , Neoplasias do Sistema Nervoso Periférico/terapia , Radioterapia , Tumor Rabdoide/metabolismo , Tumor Rabdoide/terapia , Proteína SMARCB1/metabolismo , Teratoma/metabolismo , Teratoma/terapia , Adulto Jovem
17.
Int J Oncol ; 55(1): 191-202, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115498

RESUMO

Malignant rhabdoid tumour (MRT) is a rare, aggressive paediatric neoplasm, primarily diagnosed in those below the age of three. MRTs most commonly arise in the central nervous system and kidneys. A poor prognosis accompanies the MRT diagnosis, with a reported 2­year survival rate of 30%. Thus, there is an urgent need for the development of new therapies for this malignancy. Members of the inhibitor of apoptosis protein (IAP) family have previously been reported to be overexpressed in various cancers. As such, small molecule inhibitors of these family members have entered clinical trials. However, the role of IAPs in MRT has not been examined yet. The present study is the first report of the expression of a range of IAPs, including X­linked inhibitor of apoptosis (XIAP), cellular inhibitor of apoptosis protein 1 (cIAP1), cellular inhibitor of apoptosis protein 2 (cIAP2), livin and survivin in MRT cell lines. Furthermore, the results demonstrated the ability of the XIAP inhibitor, embelin, to sensitise MRT cell lines to TNF­related apoptosis­inducing ligand (TRAIL) treatment. The enhanced cell death detected upon cotreatment was dependent on caspase­8 and co­occurred with caspase­8 and caspase­3 cleavage, suggesting engagement of the extrinsic apoptotic pathway. Sensitisation to TRAIL was accompanied by livin cleavage, alongside downregulation of survivin and the caspase­8 inhibitor FLIPL. In addition, knockdown of XIAP using siRNA enhanced TRAIL­mediated cell death, suggesting that this process may in part mediate sensitisation. In conclusion, the present results suggested that IAP inhibition may present a novel avenue for the treatment of MRT.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Benzoquinonas/farmacologia , Tumor Rabdoide/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Tumor Rabdoide/tratamento farmacológico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores
18.
Oral Oncol ; 93: 116-119, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31053364

RESUMO

Myoepithelial carcinomas of the head and neck are often located in the major salivary glands, notably in the parotid glands, being less frequent in the minor salivary glands. Noteworthy, myoepithelial carcinoma in the maxillary sinus is extremely rare. In fact, only five cases have been previously published to date. Here, we present, for the first time, a detailed immunohistochemical and in situ hybridization analysis of a SMARCB1 (INI-1)-intact myoepithelial carcinoma with rhabdoid features, expanding the histopathological spectrum of high-grade sinonasal carcinomas.


Assuntos
Neoplasias do Seio Maxilar/metabolismo , Mioepitelioma/metabolismo , Tumor Rabdoide/metabolismo , Proteína SMARCB1/metabolismo , Adulto , Biomarcadores Tumorais/metabolismo , Humanos , Hibridização In Situ , Masculino
19.
AJNR Am J Neuroradiol ; 40(5): 872-877, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30948375

RESUMO

BACKGROUND AND PURPOSE: Atypical teratoid/rhabdoid tumors are rare, aggressive central nervous system tumors that are predominantly encountered in very young children. Our aim was to determine whether in vivo metabolic profiles correlate with molecular features of central nervous system pediatric atypical teratoid/rhabdoid tumors. MATERIALS AND METHODS: Twenty confirmed patients with atypical teratoid/rhabdoid tumors who underwent MR spectroscopy were included in this study. In vivo metabolite levels of atypical teratoid/rhabdoid tumors were compared with molecular subtypes assessed by achaete-scute homolog 1 expression. Additionally, brain-specific creatine kinase levels were determined in tissue samples. RESULTS: In vivo creatine concentrations were higher in tumors that demonstrated achaete-scute homolog 1 expression compared with those without achaete-scute homolog 1 expression (3.42 ± 1.1 versus 1.8 ± 0.8 IU, P < .01). Additionally, levels of myo-inositol (mI) (9.0 ± 1.5 versus 4.7 ± 3.6 IU, P < .05) were significantly different, whereas lipids approached significance (44 ± 20 versus 80 ± 30 IU, P = .07) in these 2 cohorts. Higher brain-specific creatine kinase levels were observed in the cohort with achaete-scute homolog 1 expression (P < .05). Pearson correlation analysis showed a significant positive correlation of brain-specific creatine kinase with absolute creatine (P < .05) and myo-inositol (P < .05) concentrations. CONCLUSIONS: In vivo MR spectroscopy may predict key molecular features of atypical teratoid/rhabdoid tumors at initial diagnosis, leading to timely patient risk stratification and accelerating the development of targeted therapies.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias Encefálicas/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Tumor Rabdoide/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Neuroimagem/métodos , Estudos Retrospectivos , Tumor Rabdoide/diagnóstico por imagem , Tumor Rabdoide/patologia , Teratoma/diagnóstico por imagem , Teratoma/metabolismo , Teratoma/patologia
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