RESUMEN
CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Lipoma/tratamiento farmacológico , Lipoma/enzimología , Terapia Molecular Dirigida , Anomalías Musculoesqueléticas/tratamiento farmacológico , Anomalías Musculoesqueléticas/enzimología , Nevo/tratamiento farmacológico , Nevo/enzimología , Tiazoles/uso terapéutico , Malformaciones Vasculares/tratamiento farmacológico , Malformaciones Vasculares/enzimología , Adulto , Animales , Niño , Modelos Animales de Enfermedad , Femenino , Células HeLa , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Ratones , Fenotipo , Escoliosis/complicaciones , Escoliosis/tratamiento farmacológico , Sirolimus/uso terapéutico , Síndrome , Neoplasias Vasculares/complicaciones , Neoplasias Vasculares/tratamiento farmacológicoRESUMEN
Myxoinflammatory fibroblastic sarcoma (MIFS) is a low grade soft tissue sarcoma with a predilection for acral sites, being associated with a high rate of local recurrence but very infrequent distant metastases. Although a t(1;10) translocation resulting in TGFBR3-MGEA5 fusion has been reported as a recurrent genetic event in MIFS, this abnormality is seen only in a subset of cases. As no studies to date have investigated the spectrum of alternative genetic alterations in TGFBR3-MGEA5 fusion negative MIFS, we undertook a genetic analysis of this particular cohort for further molecular classification. Triggered by an index case occurring in the finger of a 37-year-old female and harboring a novel TOM1L2-BRAF fusion by targeted RNA sequencing we investigated potential recurrent BRAF abnormalities by screening a large group of 19 TGFBR3-MGEA5 fusion negative MIFS by fluorescence in situ hybridization. There were 6 (32%) additional MIFS with BRAF genetic abnormalities, including 5 gene rearrangements and one showing BRAF amplification. Interestingly, VGLL3 amplification, a recurrent genetic abnormality coexisting with t(1;10) in some MIFS, was also detected by fluorescence in situ hybridization in 4/6 (67%) BRAF-rearranged MIFS, but not in the BRAF-amplified case. Up-regulated VGLL3 mRNA expression was also demonstrated in the index case by RNA sequencing. The 7 BRAF-rearranged/amplified MIFS arose in the fingers (n=3), and 1 each in wrist, forearm, foot, and knee, of adult patients (36 to 74 y; M:F=4:3). The histologic spectrum ranged from predominantly solid growth of plump histiocytoid to epithelioid tumor cells with focal myxoid change to a predominantly myxoid background with scattered tumor cells. Varying degree of inflammatory infiltrates and large tumor cells with virocyte-like macronucleoli were observed in most cases. Immunohistochemical stains of phosphorylated ERK, a downstream effector of BRAF activation, were positive in all 4 cases tested (2 diffuse strong, 2 focal strong). Unlike t(1;10), BRAF rearrangements were only found in MIFS but not in 6 hemosiderotic fibrolipomatous tumor (HFLT) lacking TGFBR3-MGEA5 fusions (including 2 pure HFLT, 2 hybrid HFLT-MIFS, and 2 associated with pleomorphic hyalinizing angiectatic tumors).
Asunto(s)
Biomarcadores de Tumor/genética , Fibrosarcoma/genética , Reordenamiento Génico , Hemosiderosis/genética , Lipoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de los Tejidos Blandos/genética , Adulto , Anciano , Antígenos de Neoplasias/genética , Biomarcadores de Tumor/análisis , Proteínas Portadoras/genética , Estudios de Casos y Controles , Quinasas MAP Reguladas por Señal Extracelular/análisis , Femenino , Fibrosarcoma/enzimología , Fibrosarcoma/patología , Amplificación de Genes , Fusión Génica , Predisposición Genética a la Enfermedad , Hemosiderosis/enzimología , Hemosiderosis/patología , Histona Acetiltransferasas/genética , Humanos , Hialuronoglucosaminidasa/genética , Inmunohistoquímica , Hibridación Fluorescente in Situ , Lipoma/enzimología , Lipoma/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Fenotipo , Fosforilación , Proteoglicanos/genética , ARN Mensajero/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ARN , Neoplasias de los Tejidos Blandos/enzimología , Neoplasias de los Tejidos Blandos/patología , Factores de Transcripción/genéticaRESUMEN
Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade sarcoma that most often involves the distal extremities of adults. Some MIFSs have been reported to show TGFBR3 and MGEA5 rearrangements. TGFBR3 and MGEA5 rearrangements have also been reported in hemosiderotic fibrolipomatous tumor (HFLT), in pleomorphic hyalinizing angiectatic tumor (PHAT), and in rare tumors allegedly showing features of both HFLT and MIFS (hybrid HFLT-MIFS). These findings have led to speculation that HFLT, MIFS, PHAT, and hybrid HFLT-MIFS are closely related; however, areas resembling HFLTs are only very rarely encountered in previous series of MIFSs. We studied classic examples of these tumors with the goal of clarifying the relationship between MIFS and HFLT-MIFS. Cases of MIFS (n=31), hybrid HFLT-MIFS (n=8), PHAT (n=2), HFLT (n=1), and undifferentiated pleomorphic sarcoma (n=4) were retrieved from our archives, and the diagnoses were verified by 5 soft tissue pathologists. Using previously validated break-apart fluorescence in situ hybridization probes, we analyzed for TGFBR3 and MGEA5 rearrangements. Only 2 of 31 MIFSs harbored MGEA5 rearrangements; all lacked TGFBR3 rearrangements. Six of 8 hybrid HFLT-MIFSs harbored rearrangements of TGFBR3 and/or MGEA5. Both PHATs were positive for rearrangements of TGFBR3 and/or MGEA5. The HFLT was positive for rearrangements of both TGFBR3 and MGEA5. All undifferentiated pleomorphic sarcomas with focal myxoid change were negative. We conclude that (1) TGFBR3 and/or MGEA5 rearrangements are much more common in hybrid HFLT-MIFSs than in classic MIFSs, (2) HFLTs and MIFSs may be unrelated lesions, and (3) hybrid HFLT-MIFSs most likely represent HFLTs with sarcomatous progression, rather than tumors strictly related to classic MIFSs.
Asunto(s)
Antígenos de Neoplasias/genética , Biomarcadores de Tumor/genética , Fibroblastos , Fibroma/genética , Reordenamiento Génico , Hemosiderosis/genética , Histona Acetiltransferasas/genética , Hialuronoglucosaminidasa/genética , Hibridación Fluorescente in Situ , Lipoma/genética , Proteoglicanos/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Diferenciación Celular , Progresión de la Enfermedad , Femenino , Fibroblastos/enzimología , Fibroblastos/patología , Fibroma/enzimología , Fibroma/patología , Predisposición Genética a la Enfermedad , Hemosiderosis/enzimología , Hemosiderosis/patología , Humanos , Lipoma/enzimología , Lipoma/patología , Masculino , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Sarcoma/enzimología , Sarcoma/patología , Neoplasias de los Tejidos Blandos/enzimología , Neoplasias de los Tejidos Blandos/patología , Adulto JovenRESUMEN
Liposarcoma is the second most common soft tissue sarcoma in adults, but treatment options have been quite limited thus far. In this study, we investigated the functional and therapeutic relevance of cyclin-dependent kinase 11 (CDK11) as a putative target in liposarcoma. CDK11 knockdown by synthetic siRNA or lentiviral shRNA decreased cell proliferation, and induced apoptosis in liposarcoma cells. Moreover, CDK11 knockdown enhances the cytotoxic effect of doxorubicin to inhibit cell growth in liposarcoma cells. These findings suggest that CDK11 is critical for the growth and proliferation of liposarcoma cells. CDK11 may be a promising therapeutic target for the treatment of liposarcoma patients.
Asunto(s)
Proliferación Celular , Quinasas Ciclina-Dependientes/metabolismo , Liposarcoma/enzimología , Antibióticos Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Supervivencia Celular , Quinasas Ciclina-Dependientes/genética , Doxorrubicina/farmacología , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Lipoma/enzimología , Liposarcoma/mortalidad , Liposarcoma/patología , Masculino , Persona de Mediana Edad , ARN Interferente Pequeño/genética , Análisis de Matrices TisularesRESUMEN
The discrimination between well-differentiated liposarcomas/atypical lipomatous tumors and lipomas can be diagnostically challenging at the histological level. However, cytogenetic identification of ring and giant rod chromosomes supports the diagnosis of well-differentiated liposarcoma/atypical lipomatous tumor. These abnormal chromosomes are mainly composed of amplified genomic sequences derived from chromosome 12q13-15, and contain several genes, including MDM2, CDK4 (SAS), TSPAN31, HMGA2, and others. MDM2 is consistently amplified in well-differentiated liposarcomas/atypical lipomatous tumors, and up to 25% in other sarcomas. As part of a large genomic study of lipomatous neoplasms, we initially found CPM to be consistently amplified in well-differentiated liposarcomas/atypical lipomatous tumors. To further explore this initial finding, we investigated the copy number status of MDM2 and CPM by fluorescent in situ hybridization (FISH) on a series of 138 tumors and 17 normal tissues, including 32 well-differentiated liposarcoma/atypical lipomatous tumors, 63 lipomas, 11 pleomorphic lipomas, 2 lipoblastomas, 30 other tumors and 17 normal fat samples. All 32 well-differentiated liposarcoma/atypical lipomatous tumors showed amplification of MDM2 and CPM, usually >20 copies per cell. The other tumors lacked MDM2 and/or CPM amplification. Chromogenic in situ hybridization confirmed the above results on a subset of these tumors (n=27). These findings suggest that identification of CPM amplification could be used as an alternative diagnostic tool for the diagnosis of well-differentiated liposarcoma/atypical lipomatous tumors.
Asunto(s)
Biomarcadores de Tumor/genética , Diferenciación Celular , Amplificación de Genes , Lipoma/diagnóstico , Liposarcoma/diagnóstico , Metaloendopeptidasas/genética , Hibridación Genómica Comparativa , Diagnóstico Diferencial , Proteínas Ligadas a GPI , Dosificación de Gen , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Pruebas Genéticas , Humanos , Hibridación Fluorescente in Situ , Lipoma/enzimología , Lipoma/genética , Lipoma/patología , Liposarcoma/enzimología , Liposarcoma/genética , Liposarcoma/patología , Valor Predictivo de las Pruebas , Proteínas Proto-Oncogénicas c-mdm2/genéticaRESUMEN
Glycosylation of lipoprotein lipase (LPL) was studied in human subcutaneous lipomas. Heparin-releasable LPL activities were higher in lipomas than those in adjacent normal adipose tissues, and showed good correlation with cellular LPL protein mass. Molecular weight of LPL subunit was 57 kDa in both tissues. After endoglycosidase H-digestion, two types of LPL subunits were found in normal adipose tissues; partially sensitive (55 kDa) and totally sensitive (52 kDa) form. In lipoma tissues, the fraction of partially sensitive form (55 kDa) was increased comparing with control adipose tissues. These results suggest that partially sensitive subunits constitute the major secretable form of LPL in human subcutaneous lipomas.
Asunto(s)
Lipoma/enzimología , Lipoproteína Lipasa/metabolismo , Neoplasias Cutáneas/enzimología , Tejido Adiposo/enzimología , Adulto , Fibrinolíticos/farmacología , Heparina/farmacología , Humanos , Immunoblotting , Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidasa/farmacología , Persona de Mediana EdadRESUMEN
The expression of the three catalytic subunits of protein phosphatase (PP) type 1 and 2A, PP1 alpha, PP1 gamma 1, and PP2AC, was examined in 8 cases of lipoma as a benign tumor and 4 cases of liposarcoma as a malignant tumor using immunohistochemical analysis. Both types of of tumor cells stained positively with antisera against PP1 catalytic subunit isoforms PP1 alpha and PP1 gamma 1 were significantly higher in liposarcoma than in lipoma. Furthermore, liposarcoma showed a markedly high S-phase fraction in the cell cycle of tumor cells, as compared with lipoma. These results suggest that PP1 is involved in the accelerated growth of malignant cells in liposarcoma.
Asunto(s)
Lipoma/enzimología , Liposarcoma/enzimología , Neoplasias/enzimología , Fosfoproteínas Fosfatasas/metabolismo , Adulto , Replicación del ADN , ADN de Neoplasias/metabolismo , Femenino , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Lipoma/patología , Liposarcoma/patología , Masculino , Persona de Mediana Edad , Neoplasias/patología , Fase SRESUMEN
Histiocytosis X, multicentric reticulohistiocytosis, juvenile xanthogranuloma, the "fibrous" type of dermatofibroma, dermatofibrosarcoma protuberans, and malignant fibrous histiocytoma are all characterized by dermal and/or subcutaneous infiltrates composed at least partially of cells having morphologic features suggestive of histiocytes. Paraffin-embedded tissues representing these conditions were stained for lysozyme (muramidase) with a peroxidase-antiperoxidase technic. The cells of juvenile xanthogranuloma were rich in lysozyme. Some of the cells of histiocytosis X showed a positive pattern, and the cells of the other three conditions were essentially negative. This study confirmed the histiocytic nature of juvenile xanthogranuloma and multicentric reticulohistiocytosis, supported the interpretation that there is a histiocytic component in the lesions of histiocytosis X, and cast some doubt on the alleged histiocytic nature of "fibrous" dermatofibroma, dermatofibrosarcoma protuberans, and malignant fibrous histiocytoma.
Asunto(s)
Histiocitos/enzimología , Muramidasa/análisis , Enfermedades de la Piel/enzimología , Fibroma/enzimología , Granuloma/enzimología , Histiocitoma Fibroso Benigno/enzimología , Histiocitosis de Células de Langerhans/enzimología , Humanos , Técnicas para Inmunoenzimas , Lipoma/enzimología , Enfermedades Linfáticas/enzimología , Neoplasias Cutáneas/enzimologíaRESUMEN
Some of the control elements required for the fine regulation of metabolic processes in the adipocyte are described. These include substrate carriers, hormone receptors, allosteric enzymes and template surfaces. A possible example of an acquired defect of a rate-determining enzyme of glycolysis in the lipoma adipocyte is described. This is manifest as an impaired sensitivity of phosphofructokinase to feedback inhibtion by citrate. The orgin and consequences of this lesion are discussed.
Asunto(s)
Tejido Adiposo/metabolismo , Lipoma/metabolismo , Adenilil Ciclasas/metabolismo , Tejido Adiposo/enzimología , Regulación Alostérica , Sitios de Unión , Transporte Biológico , Membrana Celular/metabolismo , Citratos/farmacología , Retroalimentación , Glucosa/metabolismo , Humanos , Metabolismo de los Lípidos , Lipoma/enzimología , Fosfofructoquinasa-1/antagonistas & inhibidores , Receptores de Superficie Celular , Moldes GenéticosAsunto(s)
Hemangioma , Lipoma , Adenosina Trifosfatasas/metabolismo , Adulto , Fosfatasa Alcalina/metabolismo , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/fisiopatología , Frío , Hemangioma/diagnóstico por imagen , Hemangioma/tratamiento farmacológico , Hemangioma/enzimología , Hemangioma/patología , Hemangioma/fisiopatología , Histamina/farmacología , Histocitoquímica , Calor , Humanos , Lipoma/diagnóstico por imagen , Lipoma/tratamiento farmacológico , Lipoma/enzimología , Lipoma/patología , Lipoma/fisiopatología , Masculino , Métodos , Persona de Mediana Edad , Dolor , Palpación , Radiografía , Vasoconstrictores/farmacología , Vasodilatadores/farmacologíaRESUMEN
A metabolic defect has been observed in extracts of lipomata in which citrate fails to inhibit the conversion of glucose-6-phosphate to glyceride-glycerol. Phospho-fructokinase extracted from lipomata was less sensitive to inhibition by citrate than the enzyme of normal adipose tissue. However, maximal rates of lipogenesis (from glucose or palmitate) and lipolysis (stimulated with isoprenaline) in lipomata were similar to those of normal adipose tissue. This work suggests that loss of negative feedback control of regulatory enzymes may be an early feature in the development of neoplasia.