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1.
Urology ; 137: 173-177, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31945380

RESUMO

Rhabdomyosarcoma is the most common sarcoma diagnosed in childhood and adolescence, arising from the bladder/prostate in only 5%-10% of cases. Treatment-induced cytodifferention of tumor cells into mature rhabdomyoblasts has been reported following chemoradiation and is thought to suggest a more favorable outcome. We report a case of embryonal rhabdomyosarcoma of the bladder/prostate that exhibited extensive cytodifferentiation with downregulation of myogenin and MyoD1 gene expression in rhabdomyoblasts following treatment with chemoradiation therapy. The downregulation of myogenin and MyoD1 expression in rhabdomyoblasts following chemoradiation treatment has not previously been described in the literature and its significant remains uncertain.


Assuntos
Diferenciação Celular , Quimiorradioterapia , Proteína MyoD/genética , Miogenina/genética , Neoplasias da Próstata , Rabdomiossarcoma Embrionário , Neoplasias da Bexiga Urinária , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia/métodos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos da radiação , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Diagnóstico Diferencial , Regulação para Baixo , Expressão Gênica , Humanos , Imuno-Histoquímica , Lactente , Masculino , Proteína MyoD/análise , Miogenina/análise , Seleção de Pacientes , Prognóstico , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Rabdomiossarcoma Embrionário/diagnóstico por imagem , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/patologia , Rabdomiossarcoma Embrionário/terapia , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia
2.
Urology ; 137: 168-172, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31794814

RESUMO

Neurofibromatosis-1 has a known increased risk of malignancy with rhabdomyosarcoma occurring in up to 6% of patients. Here we report on an 8-year-old male with a history of Neurofibromatosis-1 and previously treated stage 3, group III bladder/prostate embryonal rhabdomyosarcoma (diagnosed at 18 months old) who presented with penile swelling concerning for priapism. Imaging and subsequent biopsy confirmed embryonal rhabdomyosarcoma of the penile corporal bodies. Penile rhabdomyosarcoma is exceedingly rare, with less than 15 case reports in the literature. Our patient received chemoradiation per D9803 with organ preserving local control and is doing well 3 months after treatment.


Assuntos
Quimiorradioterapia/métodos , Recidiva Local de Neoplasia , Neurofibromatose 1 , Neoplasias Penianas , Priapismo/diagnóstico , Neoplasias da Próstata , Rabdomiossarcoma Embrionário , Neoplasias da Bexiga Urinária , Biópsia/métodos , Criança , Diagnóstico Diferencial , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neurofibromatose 1/patologia , Neurofibromatose 1/terapia , Neoplasias Penianas/diagnóstico , Neoplasias Penianas/tratamento farmacológico , Neoplasias Penianas/patologia , Neoplasias Penianas/radioterapia , Pênis/diagnóstico por imagem , Pênis/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Rabdomiossarcoma Embrionário/patologia , Rabdomiossarcoma Embrionário/terapia , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia
3.
Biosci Biotechnol Biochem ; 84(1): 63-75, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31462179

RESUMO

A natural isoquinoline alkaloid, berberine, has been known to exhibit anti-tumor activity in various cancer cells via inducing cell cycle arrest. However, it has not been investigated whether berberine and its analogs inhibit the growth of rhabdomyosarcoma (RMS), which is the most frequent soft tissue tumor in children. The present study examined the anti-tumor effects of berberine and palmatine on expansions of three human embryonal RMS cell lines; ERMS1, KYM1, and RD. Intracellular incorporation of berberine was relatively higher than that of palmatine in every RMS cell line. Berberine significantly inhibited the cell cycle of all RMS cells at G1 phase. On the other hand, palmatine only suppressed the growth of RD cells. Both of berberine and palmatine strongly inhibited the growth of tumorsphere of RD cells in three-dimensional culture. These results indicate that berberine derivatives have the potential of anti-tumor drugs for RMS therapy.Abbreviations: ARMS: alveolar rhabdomyosarcoma; ERMS: embryonal rhabdomyosarcoma; RMS: rhabdomyosarcoma.


Assuntos
Antineoplásicos/farmacologia , Alcaloides de Berberina/farmacologia , Berberina/farmacologia , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/patologia , Antineoplásicos/química , Berberina/análogos & derivados , Berberina/química , Alcaloides de Berberina/química , Linhagem Celular Tumoral , Ciclina D1/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Avaliação Pré-Clínica de Medicamentos/métodos , Medicamentos de Ervas Chinesas/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Antígeno Ki-67/genética , Conformação Molecular , Simulação de Acoplamento Molecular , Phellodendron/química , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Embrionário/metabolismo
4.
Chem Biol Interact ; 312: 108813, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494105

RESUMO

Rhabdomyosarcoma (RMS) is a pediatric tumor, which arises from muscle precursor cells. Recently, it has been demonstrated that Hippo Pathway (Hpo), a pathway that regulates several physiological and biological features, is involved in RMS tumorigenesis. For instance, an upregulation of the Hpo downstream effector Yes-Associated Protein 1 (YAP) leads to the development of embryonal rhabdomyosarcoma (eRMS) in murine activated muscle satellite cells. On the other hand, the YAP paralog transcriptional co-activator with PDZ-binding motif (TAZ) is overexpressed in alveolar rhabdomyosarcoma (aRMS) patients with poor survival. YAP and TAZ exhibit both cytoplasmic and nuclear functions. In the nucleus, YAP binds TEADs (TEA domain family members) factors and together they constitute a complex that is able either to activate the transcription of several genes such as MYC, Tbx5 and PAX8 or to maintain the stability of others like p73. Due to the key role of YAP and TAZ in cancer, the identification and/or development of new compounds able to block their activity might be an effective antineoplastic strategy. Verteporfin (VP) is a molecule able to stop the formation of YAP/TEAD complex in the nucleus. The aim of this study is to evaluate the action of VP on RMS cell lines. This work shows that VP has an anti-proliferative activity on all RMS cell lines analyzed. Depending on RMS cell lines, VP affects cell cycle differently. Moreover, VP is able to decrease YAP protein levels, and to induce the activation of apoptosis mechanism through the cleavage of PARP-1. In addition, Annexin V assay showed the activation of apoptosis and necrosis after VP treatment. In summary, the ability of VP to disrupt RMS cell proliferation could be a novel and valuable strategy to improve the therapeutic approaches in treating rhabdomyosarcoma.


Assuntos
Proliferação de Células/efeitos dos fármacos , Verteporfina/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/metabolismo , Rabdomiossarcoma Embrionário/patologia , Fatores de Transcrição/metabolismo
5.
Autops. Case Rep ; 9(3): e2019104, July-Sept. 2019. ilus
Artigo em Inglês | LILACS | ID: biblio-1017386

RESUMO

Rhabdomyosarcoma (RMS) is a rare solid tumor in childhood and adolescence. The higher incidence is predominant during the first two decades of life. According to the Intergroup RMS Study Group, the embryonal RMS (ERMS), botryoidal variant, constitutes a histological subtype characterized as a "grape-like" lesion of 2.0 cm to 9.5 cm. The treatment involves chemotherapy, surgery, and/or radiotherapy. We present the case of a 14-year-old female patient diagnosed with ERMS, botryoidal variant, which originated in the uterine cervix with vaginal externalization. The initial therapeutic approach comprised an initial prolapsed mass excision followed by Wertheim­Meigs surgery due to the tumor extension. No consensual protocol to ERMS treatment is found in the medical literature; however, a combined approach seems to offer a better result. The postoperative time period was uneventful and the patient followed an adjuvant therapy with vincristine, d-actinomycin, and cyclophosphamide. A comprehensive evaluation of the therapeutic options preserving the reproductive function­unfortunately not always possible­is part of a multi-disciplined care team concerning the pediatric patients.


Assuntos
Humanos , Feminino , Adolescente , Neoplasias do Colo do Útero/patologia , Rabdomiossarcoma Embrionário/patologia , Colo do Útero/anormalidades
6.
Pediatr Blood Cancer ; 66(11): e27952, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31397065

RESUMO

PURPOSE/OBJECTIVE(S): Bladder and prostate are unfavorable sites for rhabdomyosarcoma (B/P-RMS), and represent a challenging location for radiotherapy. MATERIALS/METHODS: Nineteen patients with B/P-RMS were enrolled on a prospective registry protocol (2008-2017) and treated with chemotherapy, proton beam therapy (PBT), and surgical resection (n = 8; 42%). Emphasis was given to treatment technique, disease-related outcomes, and toxicity associated with PBT. RESULTS: The majority of patients had bladder RMS (74%) of embryonal histology (95%), Group III (68%), and intermediate-risk disease by Children's Oncology Group (COG) risk stratification (89%). Seven patients (37%) had primary tumors >5 cm in size. All patients were treated according to COG protocols. With a median follow-up of 66.2 months, 5-year overall survival (OS) and progression-free survival (PFS) were 76%. Four patients (21%) experienced disease relapse, all presenting with local failure. The 5-year local control (LC) rate was 76%. Tumor size predicted LC, with 5-year LC for patients with >5 cm tumors being 43% versus 100% for those with ≤5 cm tumors (P = .006). Univariate analysis demonstrated an effect of tumor size on OS (tumor >5 cm, hazard ratio [HR] 17.7, P = .049) and PFS (HR 17.7, P = .049). Acute grade 2 toxicity was observed in two patients (11%, transient proctitis). Late grade 2+ toxicity was observed in three patients (16%; n = 1 grade 2 skeletal deformity; n = 3 transient grade 2 urinary incontinence; one patient experienced both). CONCLUSIONS: PBT for B/P-RMS affords promising disease-related outcomes with an acceptable toxicity profile. Higher local failure rates were observed for larger tumors, supporting dose-escalation components of ongoing RMS clinical trials.


Assuntos
Neoplasias da Próstata/radioterapia , Terapia com Prótons , Rabdomiossarcoma Embrionário/radioterapia , Neoplasias da Bexiga Urinária/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pré-Escolar , Terapia Combinada , Cistectomia , Feminino , Seguimentos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Estadiamento de Neoplasias , Proctite/etiologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Prospectivos , Prostatectomia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Terapia com Prótons/efeitos adversos , Terapia com Prótons/métodos , Lesões por Radiação/etiologia , Sistema de Registros , Rabdomiossarcoma Alveolar/tratamento farmacológico , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Alveolar/radioterapia , Rabdomiossarcoma Alveolar/cirurgia , Rabdomiossarcoma Embrionário/tratamento farmacológico , Rabdomiossarcoma Embrionário/patologia , Rabdomiossarcoma Embrionário/cirurgia , Risco , Carga Tumoral , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Incontinência Urinária/etiologia
7.
Pathol Int ; 69(8): 488-495, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31328317

RESUMO

We herein report the case of a 2-year-old girl with neurofibromatosis type 1 (NF1), who presented with a 12-cm mass in the right retroperitoneum and underwent tumor resection. Histologically, the tumor was composed of two distinct components: one was teratoma, showing mature morphology; and the other was embryonal rhabdomyosarcoma. An interphase fluorescence in situ hybridization (FISH) analysis of the rhabdomyosarcoma component revealed the absence of isochromosome 12p. Although it is well known that rhabdomyosarcoma occurs in infantile NF1, and that rhabdomyosarcoma can arise from teratoma as a somatic-type malignancy, to the best of our knowledge, this is the first case of an infantile NF1 patient, who developed rhabdomyosarcoma within a retroperitoneal teratoma. The absence of chromosome 12p alteration suggests a possibility that the rhabdomyosarcoma occurred due to the NF1 background, not as a somatic-type malignancy of germ cell tumor.


Assuntos
Neoplasias Primárias Múltiplas/patologia , Neurofibromatose 1/patologia , Neoplasias Retroperitoneais/patologia , Rabdomiossarcoma Embrionário/patologia , Teratoma/patologia , Pré-Escolar , Feminino , Humanos , Neoplasias Primárias Múltiplas/diagnóstico , Neurofibromatose 1/diagnóstico , Neoplasias Retroperitoneais/diagnóstico , Rabdomiossarcoma Embrionário/diagnóstico , Teratoma/diagnóstico
8.
Rev. esp. patol ; 52(2): 87-91, abr.-jun. 2019. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-182694

RESUMO

We present a case of a nasal rhabdomyosarcoma (RMS) in a 27-year-old male with epistaxis and nasal obstruction due to a mass, which was subjected to prophylactic tumor embolization. However, histopathological study on the nasal biopsy was impossible due to necrotic changes. As blast cells were present in peripheral blood samples, a bone marrow biopsy was recommended in order to reach a definitive diagnosis. The possibility of an RMS in cases of bone marrow infiltration by a diffuse tumor constituted by small, round, blast-like cells mimicking acute leukemia should be assessed. Immunohistochemical staining in bone marrow biopsy and flow cytometry in aspirate samples may help to establish the diagnosis (CD45 negativity and CD56 positivity) and cytogenetic studies can be useful in identifying a RMS subtype. When clinically possible, it is desirable to await the results of the tumor immunophenotype and those of the primary mass or bone marrow biopsy to avoid possible errors of diagnosis and treatment


Se presenta el caso de un rabdomiosarcoma (RMS) en un varón de 27 años de edad con cuadro de epistaxis y obstrucción por masa nasal, que fue sometido a embolización tumoral profiláctica. El estudio en sangre periférica, fundamentalmente por la detección de células de apariencia blástica, recomendó biopsia de médula ósea que fue determinante para el diagnóstico, debido a que la embolización tumoral en la biopsia nasal, invalidó por cambios necróticos su estudio histopatológico. Se debe evaluar la posibilidad diagnóstica de un RMS, en casos de infiltración de médula ósea por un tumor difuso constituido por células pequeñas, redondas y similares a blastos que imitan una leucemia aguda. La tinción inmunohistoquímica en la biopsia de médula ósea y la citometría de flujo en muestras de aspirado, pueden ayudar a establecer el diagnóstico (negatividad CD45 y positividad CD56) y los estudios citogenéticos pueden ayudar a diferenciar el subtipo de RMS. Cuando sea clínicamente posible, se debe esperar a los resultados del inmunofenotipo celular del tumor y los de la masa primaria o la biopsia de la médula ósea, para así evitar posibles errores de diagnóstico y tratamiento


Assuntos
Humanos , Masculino , Adulto , Rabdomiossarcoma Embrionário/patologia , Neoplasias da Medula Óssea/patologia , Neoplasias da Medula Óssea/secundário , Metástase Neoplásica/patologia , Leucemia Mieloide Aguda/patologia , Diagnóstico Diferencial
9.
Skelet Muscle ; 9(1): 12, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113472

RESUMO

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). METHODS: We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. RESULTS: ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. CONCLUSION: Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.


Assuntos
Benzamidas/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Piridinas/uso terapêutico , Rabdomiossarcoma Embrionário/tratamento farmacológico , Adolescente , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Sistemas CRISPR-Cas , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/genética , Criança , Pré-Escolar , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/genética , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Piridinas/administração & dosagem , RNA-Seq , Rabdomiossarcoma Alveolar/tratamento farmacológico , Rabdomiossarcoma Alveolar/enzimologia , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/enzimologia , Rabdomiossarcoma Embrionário/patologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Vincristina/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
10.
PLoS One ; 14(4): e0214758, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30973903

RESUMO

Myo/Nog cells are identified by their expression of the skeletal muscle specific transcription factor MyoD and the bone morphogenetic protein inhibitor noggin, and binding of the G8 monoclonal antibody. Their release of noggin is critical for morphogenesis and skeletal myogenesis. In the adult, Myo/Nog cells are present in normal tissues, wounds and skin tumors. Myo/Nog cells in the lens give rise to myofibroblasts that synthesize skeletal muscle proteins. The purpose of this study was to screen human lens tissue, rhabdomyosarcoma cell lines, and tissue sections from rhabdomyosarcoma, Wilms and tumors lacking features of skeletal muscle for co-localization of antibodies to Myo/Nog cell markers and the lens beaded filament proteins filensin and CP49. Immunofluorescence localization experiments revealed that Myo/Nog cells of the lens bind antibodies to beaded filament proteins. Co-localization of antibodies to G8, noggin, filensin and CP49 was observed in most RC13 and a subpopulation of RD human rhabdomyosarcoma cell lines. Western blotting with beaded filament antibodies revealed bands of similar molecular weights in RC13 and murine lens cells. Human alveolar, embryonal, pleomorphic and spindle cell rhabdomyosarcomas and Wilms tumors contained a subpopulation of cells immunoreactive for G8, noggin, MyoD and beaded filaments. G8 was also co-localized with filensin mRNA. Staining for beaded filament proteins was not detected in G8 positive cells in leiomyosarcomas, squamous and basal cell carcinomas, syringocarciomas and malignant melanomas. Lens beaded filament proteins were thought to be present only in the lens. Myo/Nog-like cells immunoreactive for beaded filaments may be diagnostic of tumors related to the skeletal muscle lineage.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas do Olho/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Proteína MyoD/metabolismo , Rabdomiossarcoma/patologia , Tumor de Wilms/patologia , Animais , Anticorpos Monoclonais/imunologia , Proteínas de Transporte/imunologia , Linhagem Celular , Proteínas do Olho/genética , Proteínas do Olho/imunologia , Humanos , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/imunologia , Cristalino/citologia , Cristalino/metabolismo , Camundongos , Microscopia de Fluorescência , Proteína MyoD/imunologia , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma Embrionário/metabolismo , Rabdomiossarcoma Embrionário/patologia , Tumor de Wilms/metabolismo
11.
J Cancer Res Clin Oncol ; 145(6): 1461-1469, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31006845

RESUMO

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children. Pathogenesis of RMS is associated with aggressive growth pattern and increased risk of morbidity and mortality. There are two main subtypes or RMS: embryonal and alveolar. The embryonal type is characterized by distinct molecular aberrations, including alterations in the activity of certain protein kinases. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a vital role in focal adhesion (FA) assembly to promote cytoskeleton dynamics and regulation of cell motility. It is regulated by multiple phosphorylation sites: tyrosine 397, Tyr 576/577, and Tyr 925. Tyrosine 397 is the autophosphorylation site that regulates FAK localization at the cell periphery to facilitate the assembly and formation of the FA complex. The kinase activity of FAK is mediated by the phosphorylation of Tyr 576/577 within the kinase domain activation loop. Aberrations of FAK phosphorylation have been linked to the pathogenesis of different types of cancers. In this regard, pY397 upregulation is linked to increase ERMS cell motility, invasion, and tumorigenesis. METHODS: In this study, we have used an established human embryonal muscle rhabdomyosarcoma cell line RD as a model to examine FAK phosphorylation profiles to characterize its role in the pathogenies of RMS. RESULTS: Our findings revealed a significant increase of FAK phosphorylation at pY397 in RD cells compared to control cells (hTERT). On the other hand, Tyr 576/577 phosphorylation levels in RD cells displayed a pronounced reduction. Our data showed that Y925 residue exhibited no detectable change. The in vitro analysis showed that the FAK inhibitor, PF-562271 led to G1 cell-cycle arrest induced cell death (IC50, ~ 12 µM) compared to controls. Importantly, immunostaining analyses displayed a noticeable reduction of Y397 phosphorylation following PF-562271 treatment. Our data also showed that PF-562271 suppressed RD cell migration in a dose-dependent manner associated with a reduction in Y397 phosphorylation. CONCLUSIONS: The data presented herein indicate that targeting FAK phosphorylation at distinct sites is a promising strategy in future treatment approaches for defined subgroups of rhabdomyosarcoma.


Assuntos
Quinase 1 de Adesão Focal/metabolismo , Rabdomiossarcoma Embrionário/enzimologia , Rabdomiossarcoma Embrionário/patologia , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Criança , Inibidores Enzimáticos/farmacologia , Feminino , Quinase 1 de Adesão Focal/antagonistas & inibidores , Humanos , Imuno-Histoquímica , Indóis/farmacologia , Fosforilação , Rabdomiossarcoma Embrionário/tratamento farmacológico , Sulfonamidas/farmacologia
12.
Rev Esp Patol ; 52(2): 87-91, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30902383

RESUMO

We present a case of a nasal rhabdomyosarcoma (RMS) in a 27-year-old male with epistaxis and nasal obstruction due to a mass, which was subjected to prophylactic tumor embolization. However, histopathological study on the nasal biopsy was impossible due to necrotic changes. As blast cells were present in peripheral blood samples, a bone marrow biopsy was recommended in order to reach a definitive diagnosis. The possibility of an RMS in cases of bone marrow infiltration by a diffuse tumor constituted by small, round, blast-like cells mimicking acute leukemia should be assessed. Immunohistochemical staining in bone marrow biopsy and flow cytometry in aspirate samples may help to establish the diagnosis (CD45 negativity and CD56 positivity) and cytogenetic studies can be useful in identifying a RMS subtype. When clinically possible, it is desirable to await the results of the tumor immunophenotype and those of the primary mass or bone marrow biopsy to avoid possible errors of diagnosis and treatment.


Assuntos
Neoplasias da Medula Óssea/patologia , Neoplasias da Medula Óssea/secundário , Neoplasias Nasais/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Rabdomiossarcoma Embrionário/patologia , Rabdomiossarcoma Embrionário/secundário , Adulto , Diagnóstico Diferencial , Humanos , Masculino
13.
Cancer Lett ; 449: 135-144, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30771426

RESUMO

Rhabdomyosarcoma (RMS) is a pediatric soft tissue tumor classified in two major subtypes namely embryonal and alveolar, which have distinctive histopathological and genetic signatures and worse outcomes in the presence of metastases. Here, in order to evaluate the role of Caveolin-1 (Cav-1) in embryonal RMS dissemination, we employed an experimental in vivo metastasis assay using immunodeficient NOD/SCID mice. We found that the intravenous injection of human RD cells engineered for Cav-1 overexpression promoted the formation of lung metastases compared to parental cells. The arisen metastases were isolated and cultured in vitro to establish two derivative lines that showed greater metastatic capacity, as detected by performing in vivo metastasis and tumor spheroid invasion assays. Compared to parental cells, all metastatic lines were characterized by an increase in cell proliferation, migration and invasiveness that were downregulated by synthetic inhibition of Erk pathway. The metastatic cells showed a marked cell apoptosis induced by nutrient deprivation and consistent loss of differentiation characterized by depletion of MyoD and Myogenin factors. Furthermore, they showed marked changes in cell size, a re-organization of the three-dimensional cytoskeleton characterized by an increased actin stress fiber content, and increased adhesion and angiogenic properties. Collectively, these data provide new insights into Cav-1-driven metastatic process of embryonal RMS through cooperation of the Erk signaling pathway. Furthermore, our derivative metastatic lines represent useful tools for identifying genes or molecular pathways that regulate the metastatic progression of embryonal RMS.


Assuntos
Caveolina 1/genética , Caveolina 1/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Rabdomiossarcoma Embrionário/patologia , Animais , Movimento Celular , Proliferação de Células , Tamanho Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Transplante de Neoplasias , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/metabolismo
14.
Cancer Genet ; 231-232: 62-66, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30803559

RESUMO

Germline pathogenic variants in CBL are associated with an autosomal dominant RASopathy and an increased risk for malignancies, particularly juvenile myelomonocytic leukemia. Herein, we describe a patient with clinical features of a Noonan-spectrum disorder who developed embryonal rhabdomyosarcoma of the bladder at age two years. Tumor analysis using the OncoKids® cancer panel revealed a CBL pathogenic variant: NM_005188.3:c.1100A>C (p.Gln367Pro). Sanger sequencing of peripheral blood DNA confirmed a de novo heterozygous germline variant. This is the first report of embryonal rhabdomyosarcoma in association with a germline CBL pathogenic variant, further broadening the CBL cancer predisposition spectrum.


Assuntos
Mutação em Linhagem Germinativa/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Rabdomiossarcoma Embrionário/genética , Pré-Escolar , Humanos , Masculino , Rabdomiossarcoma Embrionário/patologia
17.
Oncogene ; 38(20): 3843-3854, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30670781

RESUMO

Circular RNAs (circRNAs) represent a class of covalently closed RNAs, derived from non-canonical splicing events, which are expressed in all eukaryotes and often conserved among different species. We previously showed that the circRNA originating from the ZNF609 locus (circ-ZNF609) acts as a crucial regulator of human primary myoblast growth: indeed, the downregulation of the circRNA, and not of its linear counterpart, strongly reduced the proliferation rate of in vitro cultured myoblasts. To deepen our knowledge about circ-ZNF609 role in cell cycle regulation, we studied its expression and function in rhabdomyosarcoma (RMS), a pediatric skeletal muscle malignancy. We found that circ-ZNF609 is upregulated in biopsies from the two major RMS subtypes, embryonal (ERMS) and alveolar (ARMS). Moreover, we discovered that in an ERMS-derived cell line circ-ZNF609 knock-down induced a specific block at the G1-S transition, a strong decrease of p-Akt protein level and an alteration of the pRb/Rb ratio. Regarding p-Akt, we were able to show that circ-ZNF609 acts by counteracting p-Akt proteasome-dependent degradation, thus working as a new regulator of cell proliferation-related pathways. As opposed to ERMS-derived cells, the circRNA depletion had no cell cycle effects in ARMS-derived cells. Since in these cells the p53 gene resulted downregulated, with a concomitant upregulation of its cell cycle-related target genes, we suggest that this could account for the lack of circ-ZNF609 effect in ARMS.


Assuntos
RNA/genética , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , RNA Circular , Rabdomiossarcoma/imunologia , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/imunologia , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/imunologia , Rabdomiossarcoma Embrionário/patologia , Regulação para Cima
18.
J Cancer Res Clin Oncol ; 145(1): 137-152, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30357520

RESUMO

PURPOSE: PARP inhibitors (PARPi) are used in a wide range of human solid tumours but a limited evidence is reported in rhabdomyosarcoma (RMS), the most frequent childhood soft-tissue sarcoma. The cellular and molecular effects of Olaparib, a specific PARP1/2 inhibitor, and AZD2461, a newly synthesized PARP1/2/3 inhibitor, were assessed in alveolar and embryonal RMS cells both as single-agent and in combination with ionizing radiation (IR). METHODS: Cell viability was monitored by trypan blue exclusion dye assays. Cell cycle progression and apoptosis were measured by flow cytometry, and alterations of specific molecular markers were investigated by, Real Time PCR, Western blotting and immunofluorescence experiments. Irradiations were carried out at a dose rate of 2 Gy (190 UM/min) or 4 Gy (380 UM/min). Radiosensitivity was assessed by using clonogenic assays. RESULTS: Olaparib and AZD2461 dose-dependently reduced growth of both RH30 and RD cells by arresting growth at G2/M phase and by modulating the expression, activation and subcellular localization of specific cell cycle regulators. Downregulation of phospho-AKT levels and accumulation of γH2AX, a specific marker of DNA damage, were significantly and persistently induced by Olaparib and AZD2461 exposure, this leading to apoptosis-related cell death. Both PARPi significantly enhanced the effects of IR by accumulating DNA damage, increasing G2 arrest and drastically reducing the clonogenic capacity of RMS-cotreated cells. CONCLUSIONS: This study suggests that the combined exposure to PARPi and IR might display a role in the treatment of RMS tumours compared with single-agent exposure, since stronger cytotoxic effects are induced, and compensatory survival mechanisms are prevented.


Assuntos
Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ftalazinas/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/genética , Tolerância a Radiação/efeitos dos fármacos , Radiação Ionizante , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/patologia , Apoptose/efeitos dos fármacos , Western Blotting , Divisão Celular/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Criança , Dano ao DNA , Relação Dose-Resposta a Droga , Citometria de Fluxo , Imunofluorescência , Histonas/metabolismo , Humanos , Isoenzimas/genética , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Piperidinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Reação em Cadeia da Polimerase em Tempo Real
19.
Pathol Oncol Res ; 25(1): 217-224, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29081033

RESUMO

Soft tissue sarcomas (STS) and neuroblastomas (NBL), are childhood malignancies still associated with poor prognoses despite the overall improvement in childhood tumor survival of the past decades. Anaplastic lymphoma kinase (ALK) inhibition is promising new strategy to improve the outcome of these pediatric tumors. Eighteen histologic samples of pediatric STS and 19 NBL patients were analyzed for ALK abnormalities using fluorescent in situ hybridization (FISH) with break-apart probes and immunohistochemistry (IHC). ALK alterations were presented in 20 of the 37 sections. The presence of ALK alteration in NBL samples were detected using IHC in 84,2% of all cases compared to 21,1% FISH positivity. In STS cases the results were less different (IHC 16,7% vs FISH 22,2%). The difference can be explained by the different type of molecular alterations. FISH method detected translocation and amplification, but not the point mutation of ALK gene. IHC confirmed the diagnosis by detecting the expression of ALK protein.After ALK positivity was proven, the effectiveness and safety of the crizotinib therapy was examined in 4 patients (1 alveolar rhabdomyosarcoma (RMA), 1 embryonal rhabdomyosarcoma (RME), 1 inflammatory myofibroblastic tumor (IMT), 1 NBL). We observed continuous remission of the IMT patient, all other cases the inhibitor treatment was not curative.Our findings underline the importance of screening the ALK status parallel with both IHC and FISH. Crizotinib treatment had a long-term effect in ALK positive IMT patients, however itwas only temporary efficient in relapsed, progressive STS and NBL.


Assuntos
Quinase do Linfoma Anaplásico/genética , Crizotinibe/uso terapêutico , Inflamação/genética , Neoplasias de Tecido Muscular/genética , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Embrionário/genética , Adolescente , Quinase do Linfoma Anaplásico/metabolismo , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Amplificação de Genes , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Neoplasias de Tecido Muscular/tratamento farmacológico , Neoplasias de Tecido Muscular/patologia , Mutação Puntual , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Rabdomiossarcoma Alveolar/tratamento farmacológico , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/tratamento farmacológico , Rabdomiossarcoma Embrionário/patologia , Translocação Genética
20.
Head Neck Pathol ; 13(2): 182-187, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29761260

RESUMO

Rhabdomyoma is a rare benign tumor with skeletal muscle differentiation. Rhabdomyoma is further classified into cardiac, adult, fetal, and genital subtypes. Out of these, fetal type rhabdomyoma (FTR) is the rarest. Only a small number of cases have been recorded in the literature. FTR typically affects male infants and young children and occurs predominantly in the head and neck region. FTR is exceedingly rare in the adult, with less than 30 cases reported. The classic FTR is composed of primitive undifferentiated spindle cells with scant eosinophilic cytoplasm embedded in a myxoid stroma. Immunohistochemically, the tumor cells are positive for desmin, muscle specific actin, and myogenin. Awareness and proper recognition of this rare entity is of considerable importance to avoid misdiagnosis of embryonal rhabdomyosarcoma. In this study, we report one case of FTR in an adult patient and reviewed the literature about the clinical and pathologic presentation of FTR in the adult.


Assuntos
Neoplasias Bucais/patologia , Palato Mole/patologia , Rabdomiossarcoma Embrionário/patologia , Adulto , Feminino , Humanos
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