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1.
Cancer ; 130(13): 2351-2360, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38400828

RESUMO

BACKGROUND: The objective of this study was to investigate the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma (RMS) to develop a predictive model for event-free survival and provide a rationale for risk stratification in future trials. METHODS: The authors used data from patients enrolled in the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS 2005 study (EpSSG RMS 2005; EudraCT number 2005-000217-35). The following baseline variables were considered for the multivariable model: age at diagnosis, sex, histology, primary tumor site, Intergroup Rhabdomyosarcoma Studies group, tumor size, nodal status, and FOXO1 fusion status. Main effects and significant second-order interactions of candidate predictors were included in a multiple Cox proportional hazards regression model. A nomogram was generated for predicting 5-year event-free survival (EFS) probabilities. RESULTS: The EFS and overall survival rates at 5 years were 70.9% (95% confidence interval, 68.6%-73.1%) and 81.0% (95% confidence interval, 78.9%-82.8%), respectively. The multivariable model retained five prognostic factors, including age at diagnosis interacting with tumor size, tumor primary site, Intergroup Rhabdomyosarcoma Studies clinical group, and FOXO1 fusion status. Based on each patient's total score in the nomogram, patients were stratified into four groups. The 5-year EFS rates were 94.1%, 78.4%, 65.2%, and 52.1% in the low-risk, intermediate-risk, high-risk, and very-high-risk groups, respectively, and the corresponding 5-year overall survival rates were 97.2%, 91.5%, 74.3%, and 60.8%, respectively. CONCLUSIONS: The results presented here provide the rationale to modify the EpSSG stratification, with the most significant change represented by the replacement of histology with fusion status. This classification was adopted in the new international trial launched by the EpSSG.


Assuntos
Nomogramas , Rabdomiossarcoma , Humanos , Rabdomiossarcoma/mortalidade , Rabdomiossarcoma/patologia , Rabdomiossarcoma/terapia , Masculino , Feminino , Pré-Escolar , Criança , Prognóstico , Lactente , Medição de Risco , Adolescente , Europa (Continente)/epidemiologia , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Proteínas de Fusão Oncogênica/genética
2.
Br J Cancer ; 124(3): 539-551, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33106581

RESUMO

In tumours, hypoxia-a condition in which the demand for oxygen is higher than its availability-is well known to be associated with reduced sensitivity to radiotherapy and chemotherapy, and with immunosuppression. The consequences of hypoxia on tumour biology and patient outcomes have therefore led to the investigation of strategies that can alleviate hypoxia in cancer cells, with the aim of sensitising cells to treatments. An alternative therapeutic approach involves the design of prodrugs that are activated by hypoxic cells. Increasing evidence indicates that hypoxia is not just clinically significant in adult cancers but also in paediatric cancers. We evaluate relevant methods to assess the levels and extent of hypoxia in childhood cancers, including novel imaging strategies such as oxygen-enhanced magnetic resonance imaging (MRI). Preclinical and clinical evidence largely supports the use of hypoxia-targeting drugs in children, and we describe the critical need to identify robust predictive biomarkers for the use of such drugs in future paediatric clinical trials. Ultimately, a more personalised approach to treatment that includes targeting hypoxic tumour cells might improve outcomes in subgroups of paediatric cancer patients.


Assuntos
Antineoplásicos/metabolismo , Neoplasias/metabolismo , Consumo de Oxigênio , Pró-Fármacos/metabolismo , Hipóxia Tumoral/fisiologia , Antineoplásicos/uso terapêutico , Biomarcadores/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Hipóxia Celular/genética , Hipóxia Celular/fisiologia , Criança , Terapia Combinada/métodos , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imageamento por Ressonância Magnética/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Nitroimidazóis/metabolismo , Pró-Fármacos/uso terapêutico , Hipóxia Tumoral/genética , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
J Cell Sci ; 132(13)2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31138678

RESUMO

VGLL proteins are transcriptional co-factors that bind TEAD family transcription factors to regulate events ranging from wing development in fly, to muscle fibre composition and immune function in mice. Here, we characterise Vgll3 in skeletal muscle. We found that mouse Vgll3 was expressed at low levels in healthy muscle but that its levels increased during hypertrophy or regeneration; in humans, VGLL3 was highly expressed in tissues from patients with various muscle diseases, such as in dystrophic muscle and alveolar rhabdomyosarcoma. Interaction proteomics revealed that VGLL3 bound TEAD1, TEAD3 and TEAD4 in myoblasts and/or myotubes. However, there was no interaction with proteins from major regulatory systems such as the Hippo kinase cascade, unlike what is found for the TEAD co-factors YAP (encoded by YAP1) and TAZ (encoded by WWTR1). Vgll3 overexpression reduced the activity of the Hippo negative-feedback loop, affecting expression of muscle-regulating genes including Myf5, Pitx2 and Pitx3, and genes encoding certain Wnts and IGFBPs. VGLL3 mainly repressed gene expression, regulating similar genes to those regulated by YAP and TAZ. siRNA-mediated Vgll3 knockdown suppressed myoblast proliferation, whereas Vgll3 overexpression strongly promoted myogenic differentiation. However, skeletal muscle was overtly normal in Vgll3-null mice, presumably due to feedback signalling and/or redundancy. This work identifies VGLL3 as a transcriptional co-factor operating with the Hippo signal transduction network to control myogenesis.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Desenvolvimento Muscular , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Regulação da Expressão Gênica , Células HEK293 , Humanos , Camundongos Knockout , Desenvolvimento Muscular/genética , Fibras Musculares Esqueléticas/metabolismo , Mioblastos/metabolismo , Neoplasias/metabolismo , Ligação Proteica , Fatores de Transcrição de Domínio TEA , Transcriptoma/genética
4.
Pediatr Blood Cancer ; 68(3): e28798, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33306276

RESUMO

The diagnosis and classification of rhabdomyosarcoma (RMS) has undergone several shifts over the last 30 years. While the main diagnostic categories remained the same, changes in the histologic criteria necessary for diagnosis, as well as varied reliance on immunohistochemical and molecular data over time, have created confusion, particularly regarding how these shifts impacted risk stratification and enrollment onto clinical trials. The goal of this report is to review the evolution and current status of RMS diagnosis, focusing on diagnostic criteria in the Children's Oncology Group (COG), the European Paediatric Soft Tissue Sarcoma Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). In addition, we emphasize research tools used to classify RMS and address biological questions within current clinical trials run by each group. The INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT) initiative will maximize potential to optimize risk stratification by recognizing and accounting for differences in historical data and current practices.


Assuntos
Consenso , Rabdomiossarcoma/classificação , Rabdomiossarcoma/patologia , Criança , Humanos , Prognóstico , Sociedades Médicas
5.
Pediatr Blood Cancer ; 66(9): e27888, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31207107

RESUMO

BACKGROUND: Ewing sarcoma and desmoplastic small round cell tumors (DSRCT) are rare and clinically aggressive sarcomas usually characterized by oncogenic fusion proteins involving EWS. Emerging studies of Ewing sarcoma have demonstrated EWS-FLI1-driven chromatin remodeling as a key aspect of tumorigenicity. In particular, the lysine-specific demethylase KDM1A/LSD1 is linked to transcriptional regulation of target genes orchestrated by the EWS portion of the fusion protein interacting with repressive chromatin-remodeling complexes. Consistent with this model, depletion of KDM1A supports it is a molecular therapeutic target in Ewing sarcoma cells, but effective drugs need to be identified. PROCEDURE: A comprehensive phenotypic analysis of the effects of catalytic KDM1A inhibitors ORY-1001 and GSK2879552, including clinically relevant doses, was carried out in 2D and 3D spheroid models of Ewing sarcoma and DSRCT. RESULTS: Catalytic inhibition of KDM1A did not affect cell viability in 2D and 3D assays and had no impact on invasion in a 3D assay. CONCLUSIONS: Overall, evidence presented here does not support inhibition of KDM1A catalytic demethylase activity as an effective therapeutic strategy for Ewing sarcoma or DSRCT. However, roles of KDM1A beyond its demethylase activity should be considered for these sarcomas.


Assuntos
Antineoplásicos , Neoplasias Ósseas , Inibidores Enzimáticos , Histona Desmetilases/antagonistas & inibidores , Sarcoma de Ewing , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/enzimologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/metabolismo , Humanos , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/enzimologia
6.
Pediatr Blood Cancer ; 66(10): e27869, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31222885

RESUMO

Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Rabdomiossarcoma , Criança , Humanos , Projetos de Pesquisa
7.
J Pathol ; 244(2): 242-253, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29160922

RESUMO

Testicular germ cell tumours (TGCTs) are the most frequent malignancy and cause of death from solid tumours in the 20- to 40-year age group. Although most cases show sensitivity to cis-platinum-based chemotherapy, this is associated with long-term toxicities and chemo-resistance. Roles for receptor tyrosine kinases other than KIT are largely unknown in TGCT. We therefore conducted a phosphoproteomic screen and identified the insulin growth factor receptor-1 (IGF1R) as both highly expressed and activated in TGCT cell lines representing the nonseminomatous subtype. IGF1R was also frequently expressed in tumour samples from patients with nonseminomas. Functional analysis of cell line models showed that long-term shRNA-mediated IGF1R silencing leads to apoptosis and complete ablation of nonseminoma cells with active IGF1R signalling. Cell lines with high levels of IGF1R activity also showed reduced AKT signalling in response to decreased IGF1R expression as well as sensitivity to the small-molecule IGF1R inhibitor NVP-AEW541. These results were in contrast to those in the seminoma cell line TCAM2 that lacked IGF1R signalling via AKT and was one of the two cell lines least sensitive to the IGF1R inhibitor. The dependence on IGF1R activity in the majority of nonseminomas parallels the known role of IGF signalling in the proliferation, migration, and survival of primordial germ cells, the putative cell of origin for TGCT. Upregulation of IGF1R expression and signalling was also found to contribute to acquired cisplatin resistance in an in vitro nonseminoma model, providing a rationale for targeting IGF1R in cisplatin-resistant disease. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Receptores de Somatomedina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Testiculares/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1 , Receptores de Somatomedina/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia
8.
Cancer ; 124(15): 3201-3209, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29797665

RESUMO

BACKGROUND: Alveolar rhabdomyosarcoma (aRMS) with lymph node involvement (N1 classification) accounts for up to 10% of all cases of RMS. The prognosis is poor, and is comparable to that of distant metastatic disease. In the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS2005 protocol, patients with a histologic diagnosis of aRMS/N1 received intensified chemotherapy with systematic locoregional treatment. METHODS: Patients with aRMS/N1 were enrolled prospectively after primary surgery/biopsy and fusion status was assessed in tumor samples. All patients received 9 cycles of induction chemotherapy and 6 months of maintenance therapy. Local treatment included radiotherapy to the primary site and lymph nodes with or without secondary surgical resection. RESULTS: A total of 103 patients were enrolled. The clinical characteristics of the patients were predominantly unfavorable: 90% had macroscopic residual disease after initial surgery/biopsy, 63% had locally invasive tumors, 77% had a tumor measuring >5 cm, and 81% had disease at unfavorable sites. Fusion genes involving forkhead box protein O1 (FOXO1) were detected in 56 of 84 patients. Events occurred in 52 patients: 43 developed disease recurrence, 7 had disease that was refractory to treatment, and 2 patients developed second neoplasms. On univariate analysis, unfavorable disease site, tumor invasiveness, Intergroup Rhabdomyosarcoma Study group III, and fusion-positive status correlated with worse prognosis. The 5-year event-free survival rate of patients with fusion-positive tumors was 43% compared with 74% in patients with fusion-negative tumors (P = .01). On multivariate analysis, fusion positivity and tumor invasiveness proved to be unfavorable prognostic markers. CONCLUSIONS: Fusion status and tumor invasiveness appear to have a strong impact on prognosis in patients with aRMS/N1. Fusion status will be used to stratify these patients in the next EpSSG RMS study, and treatment will be intensified in patients with fusion-positive tumors. Cancer 2018. © 2018 American Cancer Society.


Assuntos
Proteína Forkhead Box O1/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Rabdomiossarcoma Alveolar/tratamento farmacológico , Rabdomiossarcoma Alveolar/epidemiologia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Pediatria , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/patologia , Fatores de Risco , Adulto Jovem
9.
BMC Cancer ; 18(1): 217, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29466962

RESUMO

BACKGROUND: MYCN is amplified in small cell lung cancers and several pediatric tumors, including alveolar rhabdomyosarcomas and neuroblastomas. MYCN protein is known to play a key oncogenic role in both alveolar rhabdomyosarcomas and neuroblastomas. MYCN opposite strand (MYCNOS) is a gene located on the antisense strand to MYCN that encodes alternatively spliced transcripts, two of which (MYCNOS-01 and MYCNOS-02) are known to be expressed in neuroblastoma and small cell lung cancer with reciprocal regulation between MYCNOS-02 and MYCN reported for neuroblastomas. We sought to determine a functional role for MYCNOS-01 in alveolar rhabdomyosarcoma and neuroblastoma cells and identify any associated regulatory effects between MYCN and MYCNOS-01. METHODS: MYCNOS-01, MYCNOS-02 and MYCN expression levels were assessed in alveolar rhabdomyosarcoma and neuroblastoma cell lines and tumor samples from patients using Affymetrix microarray data and quantitative RT-PCR. Following MYCNOS-01 or MYCN siRNA knockdown and MYCNOS-01 overexpression, transcript levels were assayed by quantitative RT-PCR and MYCN protein expression assessed by Western blot and immunofluorescence. Additionally, effects on cell growth, apoptosis and cell cycle profiles were determined by a metabolic assay, caspase activity and flow cytometry, respectively. RESULTS: MYCNOS-01 transcript levels were generally higher in NB and RMS tumor samples and cell lines with MYCN genomic amplification. RNA interference of MYCNOS-01 expression did not alter MYCN transcript levels but decreased MYCN protein levels. Conversely, MYCN reduction increased MYCNOS-01 transcript levels, creating a negative feedback loop on MYCN protein levels. Reduction of MYCNOS-01 or MYCN expression decreased cell growth in MYCN-amplified alveolar rhabdomyosarcoma and neuroblastoma cell lines. This is consistent with MYCNOS-01-mediated regulation of MYCN contributing to the phenotype observed. CONCLUSIONS: An alternative transcript of MYCNOS, MYCNOS-01, post-transcriptionally regulates MYCN levels and affects growth in MYCN-amplified rhabdomyosarcoma and neuroblastoma cells.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/metabolismo , RNA Longo não Codificante/metabolismo , Rabdomiossarcoma Alveolar/metabolismo , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/genética , Neuroblastoma/fisiopatologia , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/fisiopatologia
10.
J Pathol ; 242(3): 263-266, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28378394

RESUMO

Fusion of genes in tumours can have oncogenic roles in reprogramming cells through overexpression of oncogenes or the production of novel fusion proteins. A fundamental question in cancer biology is what genetic events are critical for initiation and whether these are also required for cancer progression. In recent work published in The Journal of Pathology, dependency on a fusion protein was addressed using a model of alveolar rhabdomyosarcomas - a sarcoma subtype with frequent fusion of PAX3 and FOXO1 genes that is associated with poor outcome. PAX3-FOXO1 encodes a potent transcription factor that together with MYCN alters the transcriptional landscape of cells. Building on previous work, an inducible model in human myoblast cells was used to show that PAX3-FOXO1 and MYCN can initiate rhabdomyosarcoma development but, contrary to current thinking, tumour recurrences occasionally arose independent of the fusion protein. Further work needs to identify the molecular nature of this independence and assess any relevance in human tumours. Such functional approaches are required together with computational modeling of molecular data to unravel spatial and temporal dependencies on specific genetic events. This may support molecular prognostic markers and therapeutic targets. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Fusão Gênica , Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Animais , Modelos Animais de Doenças , Proteína Forkhead Box O1/genética , Humanos , Camundongos , Recidiva Local de Neoplasia/genética , Fator de Transcrição PAX3/genética
11.
Pediatr Blood Cancer ; 64(7)2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28035744

RESUMO

BACKGROUND: Long-term toxicities from current treatments are a major issue in paediatric cancer. Previous studies, including our own, have shown prognostic value for the presence of PAX3/7-FOXO1 fusion genes in rhabdomyosarcoma (RMS). It is proposed to introduce PAX3/7-FOXO1 positivity as a component of risk stratification, rather than alveolar histology, in future clinical trials. PROCEDURE: To assess the potential impact of this reclassification, we have determined the changes to risk category assignment of 210 histologically reviewed patients treated in the UK from previous malignant mesenchymal tumour clinical trials for non-metastatic RMS based on identification of PAX3/7-FOXO1 by fluorescence in situ hybridisation and/or reverse transcription PCR. RESULTS: Using fusion gene positivity in the current risk stratification would reassign 7% of patients to different European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) risk groups. The next European trial would have 80% power to detect differences in event-free survival of 15% over 10 years and 20% over 5 years in reassigned patients. This would decrease treatment for over a quarter of patients with alveolar histology tumours that lack PAX3/7-FOXO1. CONCLUSIONS: Fusion gene status used in stratification may result in significant numbers of patients benefitting from lower treatment-associated toxicity. Prospective testing to show this reassignment maintains current survival rates is now required and is shown to be feasible based on estimated recruitment to a future EpSSG trial. Together with developing novel therapeutic strategies for patients identified as higher risk, this may ultimately improve the outcome and quality of life for patients with RMS.


Assuntos
Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Rabdomiossarcoma/classificação , Neoplasias de Tecidos Moles/classificação , Biomarcadores Tumorais/análise , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Projetos de Pesquisa , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Fatores de Risco , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Análise Serial de Tecidos , Reino Unido
12.
J Pathol ; 240(1): 3-14, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27184927

RESUMO

The Hippo effector YAP has recently been identified as a potent driver of embryonal rhabdomyosarcoma (ERMS). Most reports suggest that the YAP paralogue TAZ (gene symbol WWTR1) functions as YAP but, in skeletal muscle, TAZ has been reported to promote myogenic differentiation, whereas YAP inhibits it. Here, we investigated whether TAZ is also a rhabdomyosarcoma oncogene or whether TAZ acts as a YAP antagonist. Immunostaining of rhabdomyosarcoma tissue microarrays revealed that TAZ is significantly associated with poor survival in ERMS. In 12% of fusion gene-negative rhabdomyosarcomas, the TAZ locus is gained, which is correlated with increased expression. Constitutively active TAZ S89A significantly increased proliferation of C2C12 myoblasts and, importantly, colony formation on soft agar, suggesting transformation. However, TAZ then switches to enhance myogenic differentiation in C2C12 myoblasts, unlike YAP. Conversely, lentiviral shRNA-mediated TAZ knockdown in human ERMS cells reduced proliferation and anchorage-independent growth. While TAZ S89A or YAP1 S127A similarly activated the 8XGTIIC-Luc Hippo reporter, only YAP1 S127A activated the Brachyury (T-box) reporter. Consistent with its oncogene function, TAZ S89A induced expression of the ERMS cancer stem cell gene Myf5 and the serine biosynthesis pathway (Phgdh, Psat1, Psph) in C2C12 myoblasts. Thus, TAZ is associated with poor survival in ERMS and could act as an oncogene in rhabdomyosarcoma. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Proliferação de Células/fisiologia , Transformação Celular Neoplásica/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mioblastos/metabolismo , Rabdomiossarcoma/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Mioblastos/patologia , Prognóstico , Rabdomiossarcoma/genética , Rabdomiossarcoma/mortalidade , Rabdomiossarcoma/patologia , Taxa de Sobrevida , Análise Serial de Tecidos , Transativadores , Fatores de Transcrição , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional
13.
Br J Cancer ; 115(4): 473-9, 2016 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-27434038

RESUMO

BACKGROUND: Soft tissue sarcomas are a group of neoplasms with differentiation towards mesenchymal tissue, many of which are aggressive and chemotherapy resistant. Histology and immunoprofiles often overlap with neoplasms of other lineages, and establishing an accurate histopathological diagnosis is crucial for correct management, and therapeutic stratification. The endosialin cell surface glycoprotein is predominantly expressed by stromal fibroblasts and pericytes in epithelial neoplasms; however, tumour cell expression has been reported in small series of sarcomas. METHODS: We assessed endosialin expression by immunohistochemistry in a large set of 514 human soft tissue sarcomas. RESULTS: Tumour cell endosialin expression was seen in 89% of undifferentiated pleomorphic sarcomas (104/117), 77% adult fibrosarcomas/spindle cell sarcomas (20/26), 62% synovial sarcomas (37/60), 51% leiomyosarcomas (94/185) and 31% rhabdomyosarcomas (39/126). CONCLUSIONS: Endosialin immunohistochemistry has potential to distinguish undifferentiated and poorly differentiated sarcomas from other poorly differentiated, non-mesenchymal neoplasms. A Phase II trial randomising patients with advanced sarcomas to receive chemotherapy with/without an endosialin therapeutic antibody has recently completed enrolment. Endosialin expression could be used to select patients for such clinical trials. Based on our results, patients with undifferentiated pleomorphic sarcoma may be particularly suitable for such a therapeutic approach.


Assuntos
Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Fibrossarcoma/metabolismo , Leiomiossarcoma/metabolismo , Rabdomiossarcoma/metabolismo , Sarcoma Sinovial/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibrossarcoma/patologia , Humanos , Imuno-Histoquímica , Leiomiossarcoma/patologia , Pericitos/metabolismo , Rabdomiossarcoma/patologia , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/metabolismo , Rabdomiossarcoma Embrionário/patologia , Sarcoma/metabolismo , Sarcoma/patologia , Sarcoma Sinovial/patologia
14.
Br J Cancer ; 113(10): 1512-8, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26461055

RESUMO

BACKGROUND: The increasing incidence of testicular germ cell tumour (TGCT) combined with its strong heritable basis suggests that stratified screening for the early detection of TGCT may be clinically useful. We modelled the efficiency of such a personalised screening approach, based on genetic risk profiling in combination with other diagnostic tools. METHODS: We compared the number of cases potentially detectable in the population under a number of screening models. The polygenic risk scoring (PRS) model was assumed to have a log-normal relative risk distribution across the 19 currently known TGCT susceptibility variants. The diagnostic performance of testicular biopsy and non-invasive semen analysis was also assessed, within a simulated combined screening programme. RESULTS: The area under the curve for the TGCT PRS model was 0.72 with individuals in the top 1% of the PRS having a nine-fold increased TGCT risk compared with the population median. Results from population-screening simulations only achieved a maximal positive predictive value (PPV) of 60%, highlighting broader clinical factors that challenge such strategies, not least the rare nature of TGCT. In terms of future improvements, heritability estimates suggest that a significant number of additional genetic risk factors for TGCT remain to be discovered, identification of which would potentially yield improvement of the PPV to 80-90%. CONCLUSIONS: While personalised screening models may offer enhanced TGCT risk discrimination, presently the case for population-level testing is not compelling. However, future advances, such as more routine generation of whole genome data is likely to alter the landscape. More targeted screening programs may plausibly then offer clinical benefit, particularly given the significant survivorship issues associated with the successful treatment of TGCT.


Assuntos
Detecção Precoce de Câncer/métodos , Herança Multifatorial , Neoplasias Embrionárias de Células Germinativas/genética , Medicina de Precisão/métodos , Neoplasias Testiculares/genética , Biópsia , Predisposição Genética para Doença , Humanos , Masculino , Modelos Genéticos , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Modelagem Computacional Específica para o Paciente , Valor Preditivo dos Testes , Análise do Sêmen/métodos , Neoplasias Testiculares/diagnóstico
15.
J Pathol ; 232(5): 566-77, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24407904

RESUMO

Genomic changes affecting tumour suppressor genes are fundamental to cancer. We applied SNP array analysis to a panel of testicular germ cell tumours to search for novel tumour suppressor genes and identified a frequent small deletion on 6q25.3 affecting just one gene, ZDHHC14. The expression of ZDHHC14, a putative protein palmitoyltransferase with unknown cellular function, was decreased at both RNA and protein levels in testicular germ cell tumours. ZDHHC14 expression was also significantly decreased in a panel of prostate cancer samples and cell lines. In addition to our findings of genetic and protein expression changes in clinical samples, inducible overexpression of ZDHHC14 led to reduced cell viability and increased apoptosis through the classic caspase-dependent apoptotic pathway and heterozygous knockout of ZDHHC14 increased [CORRECTED] cell colony formation ability. Finally, we confirmed our in vitro findings of the tumour suppressor role of ZDHHC14 in a mouse xenograft model, showing that overexpression of ZDHHC14 inhibits tumourigenesis. Thus, we have identified a novel tumour suppressor gene that is commonly down-regulated in testicular germ cell tumours and prostate cancer, as well as given insight into the cellular functional role of ZDHHC14, a potential protein palmitoyltransferase that may play a key protective role in cancer.


Assuntos
Aciltransferases/genética , Genes Supressores de Tumor , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias da Próstata/genética , Neoplasias Testiculares/genética , Aciltransferases/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Regulação para Baixo , Deleção de Genes , Perfilação da Expressão Gênica/métodos , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias Embrionárias de Células Germinativas/enzimologia , Neoplasias Embrionárias de Células Germinativas/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/prevenção & controle , Interferência de RNA , Neoplasias Testiculares/enzimologia , Neoplasias Testiculares/patologia , Fatores de Tempo , Transfecção , Carga Tumoral
16.
Genes Chromosomes Cancer ; 53(3): 215-27, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24311530

RESUMO

Germ cell tumors (GCTs) are rare but clinically and pathologically diverse tumors that occur in an extensive range of age groups, from children to older adults and which include both seminomatous and nonseminomatous tumors. Current clinical management for both male and female teenagers and young adults (TYAs) with GCTs remains inconsistent, alternating between pediatric and adult multidisciplinary oncology teams, based on locally defined age cutoffs. Therefore, we reviewed available literature to determine the biological similarities and differences between GCTs in young children (0-12 years), TYAs (13-24 years), and older adults (>24 years). GCTs arising in pediatric and adult populations in general showed marked molecular biological differences within identical histological subtypes, whereas there was a distinct paucity of available data for GCTs in the TYA population. These findings highlight that clinical management based simply on chronological age may be inappropriate for TYA and suggests that the optimal future management of GCTs should consider specific molecular biological factors in addition to clinical parameters in the context of patient-specific age group rather than medical specialty.


Assuntos
Neoplasias Embrionárias de Células Germinativas/metabolismo , Adolescente , Adulto , Fatores Etários , Criança , Aberrações Cromossômicas , Loci Gênicos , Predisposição Genética para Doença , Impressão Genômica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Invasividade Neoplásica , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Fases de Leitura Aberta , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto Jovem
17.
Exp Cell Res ; 319(1): 103-12, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22982728

RESUMO

HES6, a member of the hairy-enhancer-of-split family of transcription factors, plays multiple roles in myogenesis. It is a direct target of the myogenic transcription factor MyoD and has been shown to regulate the formation of the myotome in development, myoblast cell cycle exit and the organization of the actin cytoskeleton during terminal differentiation. Here we investigate the expression and function of HES6 in rhabdomyosarcoma, a soft tissue tumor which expresses myogenic genes but fails to differentiate into muscle. We show that HES6 is expressed at high levels in the subset of alveolar rhabdomyosarcomas expressing PAX/FOXO1 fusion genes (ARMSp). Knockdown of HES6 mRNA in the ARMSp cell line RH30 reduces proliferation and cell motility. This phenotype is rescued by expression of mouse Hes6 which is insensitive to HES6 siRNA. Furthermore, expression microarray analysis indicates that the HES6 knockdown is associated with a decrease in the levels of Transgelin, (TAGLN), a regulator of the actin cytoskeleton. Knockdown of TAGLN decreases cell motility, whilst TAGLN overexpression rescues the motility defect resulting from HES6 knockdown. These findings indicate HES6 contributes to the pathogenesis of ARMSp by enhancing both proliferation and cell motility.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Movimento Celular , Neoplasias Pulmonares/patologia , Alvéolos Pulmonares/patologia , Proteínas Repressoras/fisiologia , Rabdomiossarcoma/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/genética , Alvéolos Pulmonares/metabolismo , Proteínas Repressoras/genética , Rabdomiossarcoma/química , Rabdomiossarcoma/genética , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Regulação para Cima/genética
18.
Cancers (Basel) ; 16(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38473371

RESUMO

Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma (STS) that predominantly affects children and teenagers. It is the most common STS in children (40%) and accounts for 5-8% of total childhood malignancies. Apart from surgery and radiotherapy in eligible patients, standard chemotherapy is the only therapeutic option clinically available for RMS patients. While survival rates for this childhood cancer have considerably improved over the last few decades for low-risk and intermediate-risk cases, the mortality rate remains exceptionally high in high-risk RMS patients with recurrent and/or metastatic disease. The intensification of chemotherapeutic protocols in advanced-stage RMS has historically induced aggravated toxicity with only very modest therapeutic gain. In this review, we critically analyse what has been achieved so far in RMS therapy and provide insight into how a diverse group of drug-metabolising enzymes (DMEs) possess the capacity to modify the clinical efficacy of chemotherapy. We provide suggestions for new therapeutic strategies that exploit the presence of DMEs for prodrug activation, targeted chemotherapy that does not rely on DMEs, and RMS-molecular-subtype-targeted therapies that have the potential to enter clinical evaluation.

19.
Cancers (Basel) ; 16(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38473359

RESUMO

The Frontline and Relapsed Rhabdomyosarcoma (FaR-RMS) clinical trial is an overarching, multinational study for children and adults with rhabdomyosarcoma (RMS). The trial, developed by the European Soft Tissue Sarcoma Study Group (EpSSG), incorporates multiple different research questions within a multistage design with a focus on (i) novel regimens for poor prognostic subgroups, (ii) optimal duration of maintenance chemotherapy, and (iii) optimal use of radiotherapy for local control and widespread metastatic disease. Additional sub-studies focusing on biological risk stratification, use of imaging modalities, including [18F]FDG PET-CT and diffusion-weighted MRI imaging (DWI) as prognostic markers, and impact of therapy on quality of life are described. This paper forms part of a Special Issue on rhabdomyosarcoma and outlines the study background, rationale for randomisations and sub-studies, design, and plans for utilisation and dissemination of results.

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