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1.
Am J Pathol ; 182(5): 1494-500, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23485734

RESUMO

Spindle cell hemangioma (SCH) is a rare, benign vascular tumor of the dermis and subcutis. The lesions can be multifocal and are overrepresented in Maffucci syndrome, in which patients also have multiple enchondromas. Somatic mosaic R132C IDH1 hotspot mutations were recently identified in Maffucci syndrome. We evaluated the presence of mutations in solitary and multiple SCHs in patients without multiple enchondromas and tested a range of other vascular lesions that enter into the differential diagnosis. The R132C IDH1 mutation was identified by hydrolysis probes assay and confirmed by Sanger sequencing in 18 of 28 (64%) SCHs; of the 10 negative cases, 2 harbored a mutation in IDH2 (R172T and R172M) by Sanger sequencing. None of 154 other vascular malformations and tumors harbored an IDH1 R132C mutation, and R132H IDH1 mutations were absent in all 182 cases. All 16 SCHs examined by immunohistochemistry were negative for expression of HIF-1α. In conclusion, 20 of 28 (71%) SCHs harbored mutations in exon 4 of IDH1 or IDH2. Given that mutations were absent in 154 other vascular lesions, the mutation seems to be highly specific for SCH. The mutation does not induce expression of HIF-1α in SCH, and therefore the exact mechanism by which mutations in IDH1 or IDH2 lead to vascular tumorigenesis remains to be established.


Assuntos
Substituição de Aminoácidos/genética , Carcinoma/genética , Hemangioma/genética , Isocitrato Desidrogenase/genética , Mutação/genética , Malformações Vasculares/genética , Adolescente , Carcinoma/enzimologia , Carcinoma/patologia , Criança , Demografia , Feminino , Hemangioma/enzimologia , Hemangioma/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Malformações Vasculares/enzimologia , Malformações Vasculares/patologia , Adulto Jovem
2.
Am J Pathol ; 182(4): 1347-56, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23415961

RESUMO

The mesenchymal, clear cell, and dedifferentiated chondrosarcoma subtypes are extremely rare, together constituting 10% to 15% of all chondrosarcomas. Their poor prognosis and lack of efficacious treatment emphasizes the need to elucidate the pathways playing a pivotal role in these tumors. We constructed tissue microarrays containing 42 dedifferentiated, 23 clear cell, and 23 mesenchymal chondrosarcomas and performed immunohistochemistry to study the expression of growth plate-signaling molecules and molecules shown to be involved in conventional chondrosarcoma. We observed high expression of SOX-9 and FGFR-3, as well as aberrant cellular localization of heparan sulfate proteoglycans, in all subtypes. TGFß signaling through p-SMAD2 and PAI-1 was highly active in all chondrosarcoma subtypes, which suggests that TGFß inhibitors as a possible therapeutic strategy in rare chondrosarcoma subtypes. As in conventional chondrosarcoma, antiapoptotic proteins (Bcl-2, and/or Bcl-xl) were highly expressed in all subtypes. Inhibition with the BH-3 mimetic ABT-737 rendered dedifferentiated chondrosarcoma cell lines sensitive to doxorubicin or cisplatin. Our data indicate that antiapoptotic proteins may play an important role in chemoresistance, suggesting a promising role for targeting Bcl-2 family members in chondrosarcoma treatment, irrespective of the subtype.


Assuntos
Antineoplásicos/farmacologia , Desdiferenciação Celular/efeitos dos fármacos , Condrossarcoma Mesenquimal/patologia , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sarcoma de Células Claras/patologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Condrossarcoma Mesenquimal/classificação , Condrossarcoma Mesenquimal/tratamento farmacológico , Condrossarcoma Mesenquimal/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Inclusão em Parafina , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sarcoma de Células Claras/classificação , Sarcoma de Células Claras/tratamento farmacológico , Sarcoma de Células Claras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fixação de Tecidos , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
3.
BMC Cancer ; 12: 375, 2012 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-22928481

RESUMO

BACKGROUND: Chondrosarcoma is the second most common primary sarcoma of bone. High-grade conventional chondrosarcoma and dedifferentiated chondrosarcoma have a poor outcome. In pre-clinical research aiming at the identification of novel treatment targets, the need for representative cell lines and model systems is high, but availability is scarce. METHODS: We developed and characterized three cell lines, derived from conventional grade III chondrosarcoma (L835), and dedifferentiated chondrosarcoma (L2975 and L3252) of bone. Proliferation and migration were studied and we used COBRA-FISH and array-CGH for karyotyping and genotyping. Immunohistochemistry for p16 and p53 was performed as well as TP53 and IDH mutation analysis. Cells were injected into nude mice to establish their tumorigenic potential. RESULTS: We show that the three cell lines have distinct migrative properties, L2975 had the highest migration rate and showed tumorigenic potential in mice. All cell lines showed chromosomal rearrangements with complex karyotypes and genotypic aberrations were conserved throughout late passaging of the cell lines. All cell lines showed loss of CDKN2A, while TP53 was wild type for exons 5-8. L835 has an IDH1 R132C mutation, L2975 an IDH2 R172W mutation and L3252 is IDH wild type. CONCLUSIONS: Based on the stable culturing properties of these cell lines and their genotypic profile resembling the original tumors, these cell lines should provide useful functional models to further characterize chondrosarcoma and to evaluate new treatment strategies.


Assuntos
Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Condrossarcoma/patologia , Animais , Neoplasias Ósseas/genética , Movimento Celular , Condrossarcoma/genética , Hibridização Genômica Comparativa , Humanos , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Radiografia , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/patologia , Transplante Heterólogo
4.
Nat Genet ; 43(12): 1256-61, 2011 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-22057234

RESUMO

Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.


Assuntos
Encondromatose/genética , Isocitrato Desidrogenase/genética , Mutação de Sentido Incorreto , Adulto , Estudos de Casos e Controles , Linhagem Celular Tumoral , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Análise de Sequência de DNA , Transcrição Gênica , Adulto Jovem
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