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Cell Proliferation Feb 2015Ewing's sarcoma (EWS) is the second most common primary bone cancer, and is a predominant childhood malignant disease. Due to limited understanding of its pathogenesis... (Review)
Review
Ewing's sarcoma (EWS) is the second most common primary bone cancer, and is a predominant childhood malignant disease. Due to limited understanding of its pathogenesis and frequent occurrence of resistance to conventional types of treatment, its management remains difficult, and mortality is frequent. Development of EWS is a multistep process involving genetic and epigenetic alterations of protein-coding proto-oncogenes and tumour-suppressor genes. MicroRNAs (miRNAs) have recently been discovered as a new category of non-protein coding; small RNA molecules that regulate gene expression at the post-transcriptional level. Substantial numbers of deregulated miRNAs have been documented in EWS and their biological significance has been confirmed in multiple functional experiments. Several studies have confirmed involvement of miRNAs in various steps of EWS pathogenesis, from occurrence to metastasis. Functionally, miRNA dysregulation may promote cell-cycle progression, confer resistance to apoptosis, and enhance invasiveness and metastasis. These miRNAs have opened a novel field in cancer research with potential clinical utilization for screening, diagnosis, prognostics and prediction of response to treatment. Elucidating biological aspects of miRNA dysregulation may help better understand pathogenesis of EWS and promote development of miRNA directed-therapeutics against it.
Topics: Animals; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Prognosis; Sarcoma, Ewing; Signal Transduction
PubMed: 25530497
DOI: 10.1111/cpr.12160 -
The Journal of International Medical... Aug 2022Ewing sarcoma (ES) is a highly aggressive bone and soft tissue tumor that occurs mainly in young children and adolescents and is associated with primary and metastatic... (Review)
Review
Ewing sarcoma (ES) is a highly aggressive bone and soft tissue tumor that occurs mainly in young children and adolescents and is associated with primary and metastatic disease. Intramedullary ES (either primary or secondary) is rare, and the ideal management remains inconclusive. We herein report intramedullary and extramedullary metastatic ES in a single patient. A 46-year-old woman was referred to our outpatient clinic from the oncology clinic with progressive paraparesis and paresthesia for 1 week prior to presentation. She had developed left clavicular ES 2 years earlier for which surgery and chemoradiotherapy had been performed. At the present evaluation, she was diagnosed with intramedullary thoracic and lumbar extradural masses. Thoracic surgery was performed, and a biopsy of the lesion was obtained. The diagnosis of ES was confirmed histopathologically, and she underwent adjuvant chemotherapy. Her neurological status did not improve after surgery, and she underwent rehabilitation and physical therapy. The lumbar lesion resolved with chemotherapy. Metastasis of ES to the spinal cord, especially intramedullary lesions, is extremely rare, and there is no standard management guideline. However, surgical decompression and adjuvant chemotherapy are the main treatments in these cases.
Topics: Adolescent; Chemotherapy, Adjuvant; Child; Child, Preschool; Female; Humans; Lumbosacral Region; Middle Aged; Sarcoma, Ewing
PubMed: 35938475
DOI: 10.1177/03000605221108095 -
Annals of Saudi Medicine 2011Ewing/PNET (peripheral neuroepithelioma) tumors are rare aggressive bone sarcomas occurring in young people. Rare-disease clinical trials can require global... (Review)
Review
Ewing/PNET (peripheral neuroepithelioma) tumors are rare aggressive bone sarcomas occurring in young people. Rare-disease clinical trials can require global collaborations and many years. In vivo models that as accurately as possible reflect the clinical disease are helpful in selecting therapeutics with the most promise of positive clinical impact. Human Ewing/PNET sarcoma cell lines developed over the past 45 years are described. Several of these have undergone genetic analysis and have been confirmed to be those of Ewing/PNET sarcoma. The A673 Ewing sarcoma line has proven to be particularly useful in understanding the biology of this disease in the mouse. The chromosomal translocation producing the EWS/FLI1 fusion transcript characterizes clinical Ewing sarcoma. Cell lines that express this genetic profile are confirmed to be those of Ewing sarcoma. The A673 Ewing sarcoma line grows in culture and as a xenograft in immunodeficient mice. The A673 model has been used to study Ewing sarcoma angiogenesis and response to antiangiogenic agents. Many Ewing sarcoma clinical specimens express the cell surface protein endosialin. Several Ewing sarcoma cell lines, including the A673 line, also express cell surface endosialin when grown as subcutaneous tumor nodules and as disseminated disease; thus the A673 is a useful model for the study of endosialin biology and endosialin-directed therapies. With the advent of tools that allow characterization of clinical disease to facilitate optimal treatment, it becomes imperative, especially for rare tumors, to develop preclinical models reflecting disease subsets. Ewing PNET sarcomas are a rare disease where models are available.
Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Disease Models, Animal; Humans; Mice; Neuroectodermal Tumors, Primitive; Sarcoma, Ewing
PubMed: 21422656
DOI: 10.4103/0256-4947.78206 -
In Vivo (Athens, Greece) 2021Ewing sarcomas most commonly arise in the bones, but can also manifest as extraskeletal tumours in soft tissues. Metastases from extraskeletal Ewing sarcomas occur in...
BACKGROUND/AIM
Ewing sarcomas most commonly arise in the bones, but can also manifest as extraskeletal tumours in soft tissues. Metastases from extraskeletal Ewing sarcomas occur in more diverse anatomical sites than skeletal tumours, and have poorer survival rates. Few animal models replicate the extraskeletal form of Ewing sarcoma, and those that have been developed do not reflect the widespread metastatic spread of these cancers.
MATERIALS AND METHODS
Luciferase-expressing Ewing sarcoma cells derived from a muscle tumour were intramuscularly or intravenously injected into nude mice.
RESULTS
Both models achieved metastatic spread to numerous sites including the lungs, liver, kidneys, and brain. We characterized the cellular composition of primary and metastatic tumours, observing a greater level of immune cell infiltration in metastases compared to primary intramuscular tumours.
CONCLUSION
These pre-clinical models will hopefully facilitate the evaluation of novel therapies and contribute to better understanding the disease progression of metastatic extraskeletal Ewing sarcoma.
Topics: Animals; Bone Neoplasms; Disease Models, Animal; Mice; Mice, Nude; Neoplasms, Second Primary; Sarcoma, Ewing
PubMed: 34697140
DOI: 10.21873/invivo.12604 -
International Journal of Molecular... Jul 2015Ewing sarcoma is an aggressive neoplasm occurring predominantly in adolescent Caucasians. At the genome level, a pathognomonic EWSR1-ETS translocation is present. The... (Review)
Review
Ewing sarcoma is an aggressive neoplasm occurring predominantly in adolescent Caucasians. At the genome level, a pathognomonic EWSR1-ETS translocation is present. The resulting fusion protein acts as a molecular driver in the tumor development and interferes, amongst others, with endogenous transcription and splicing. The Ewing sarcoma cell shows a poorly differentiated, stem-cell like phenotype. Consequently, the cellular origin of Ewing sarcoma is still a hot discussed topic. To further characterize Ewing sarcoma and to further elucidate the role of EWSR1-ETS fusion protein multiple genome, epigenome and transcriptome level studies were performed. In this review, the data from these studies were combined into a comprehensive overview. Presently, classical morphological predictive markers are used in the clinic and the therapy is dominantly based on systemic chemotherapy in combination with surgical interventions. Using sequencing, novel predictive markers and candidates for immuno- and targeted therapy were identified which were summarized in this review.
Topics: Epigenomics; Humans; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Sarcoma, Ewing; Sequence Analysis, DNA; Transcriptome
PubMed: 26193259
DOI: 10.3390/ijms160716176 -
Cancer Research Oct 2021Ewing sarcoma is characterized by pathognomonic translocations, most frequently fusing with . An estimated 30% of Ewing sarcoma tumors also display genetic alterations...
Ewing sarcoma is characterized by pathognomonic translocations, most frequently fusing with . An estimated 30% of Ewing sarcoma tumors also display genetic alterations in , , or (). Numerous attempts to develop relevant Ewing sarcoma models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic, and epigenetic features of Ewing sarcoma. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from a patient with Ewing sarcoma. Within this model, alterations strongly favored Ewing sarcoma oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed features of Ewing sarcoma. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in Ewing sarcoma and other cancers. Collectively, these results demonstrate that bone marrow-derived MSCs are a source of origin for Ewing sarcoma and also provide original experimental models to investigate Ewing sarcomagenesis. SIGNIFICANCE: These findings demonstrate that Ewing sarcoma can originate from human bone-marrow-derived mesenchymal stem cells and that recurrent mutations support EWSR1-FLI1 translocation-mediated transformation.
Topics: Animals; Biomarkers; CRISPR-Cas Systems; Cell Transformation, Neoplastic; Cells, Cultured; Computational Biology; Disease Models, Animal; Disease Susceptibility; Gene Editing; Gene Expression Profiling; Gene Rearrangement; Gene Targeting; Heterografts; Humans; Immunophenotyping; In Situ Hybridization, Fluorescence; Mesenchymal Stem Cells; Mice; Mutation; Sarcoma, Ewing; Translocation, Genetic
PubMed: 34341072
DOI: 10.1158/0008-5472.CAN-20-3837 -
Current Protocols Feb 2023Ewing Sarcoma (EwS) is the second most common malignant bone tumor in adolescents and young adults. The single-most powerful predictor of outcome in EwS is presence of...
Ewing Sarcoma (EwS) is the second most common malignant bone tumor in adolescents and young adults. The single-most powerful predictor of outcome in EwS is presence of metastatic burden at the time of diagnosis. Patients with metastatic Ewing Sarcoma have an abysmal 5-year survival rate of 10%-25%, which has not changed over the past 30-40 years. Thus, unraveling underlying mechanisms of EwS metastasis are imperative for developing effective therapeutic measures. Investigations towards this goal are limited by the lack of reliable genetically engineered mouse models and specialized metastatic models. Using two established cell lines, A673 and TC71, we generated lung specific metastatic cell lines by serial orthotopic intra-tibial injection followed by isolation of cells from lung metastases. The lung metastatic lines generated exhibit distinct differential molecular signatures from the parental cells when analyzed using a multi-omics approach. These signatures overlapped with EwS patient primary bone and metastatic lung specimens supporting the clinical relevance of these preclinical models of EwS. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Intra-Tibial injection in NSG mice Basic Protocol 2: Development and characterization of lung metastatic cell line.
Topics: Animals; Mice; Sarcoma, Ewing; RNA-Binding Protein EWS; Bone Neoplasms; Neuroectodermal Tumors, Primitive, Peripheral; Lung Neoplasms
PubMed: 36799651
DOI: 10.1002/cpz1.670 -
Pediatric Radiology May 2023Sarcopenia is an indicator of negative outcomes in many diseases in adults. Reports indicate this might also be true in children.
BACKGROUND
Sarcopenia is an indicator of negative outcomes in many diseases in adults. Reports indicate this might also be true in children.
OBJECTIVE
To evaluate the effect of sarcopenia and sarcopenic obesity on event-free survival (EFS) and overall survival (OS) in children with Ewing sarcoma and osteosarcoma.
MATERIALS AND METHODS
We retrospectively measured total muscle areas of the pectoralis, paraspinal (T12 level) and psoas (L4 level) muscles and total abdominal muscle area (L3 level) on computed tomography images in 60 children diagnosed with either Ewing sarcoma (n = 34) or osteosarcoma (n = 26). Skeletal muscle indices (SMI) were calculated by normalizing muscle area to patient height. Vertebral morphologic parameters of T12 and L4 vertebrae were measured and correlated to patient height to use as a substitute in cases of missing height data (SMI and SMI). We calculated sarcopenic obesity index by dividing SMI by body mass index. We subdivided children into two groups according to the median value of each parameter and assessed the differences in survival between the groups.
RESULTS
No skeletal muscle index or sarcopenic obesity index parameter significantly affected event-free or overall survival in the total group analysis. In the non-metastatic group, higher values of SMI-paraspinal and SMI-psoas were correlated with longer event-free survival and no patient died in this group. Boys and children in the metastatic group with higher SMI-paraspinal values had significantly longer event-free survival and both event-free and overall survival, respectively.
CONCLUSION
Although some parameters were correlated with event-free and overall survival, neither sarcopenia nor sarcopenic obesity were reliably associated with survival in children with Ewing sarcoma or osteosarcoma.
Topics: Male; Adult; Humans; Child; Sarcopenia; Sarcoma, Ewing; Retrospective Studies; Muscle, Skeletal; Obesity; Osteosarcoma; Bone Neoplasms
PubMed: 36600101
DOI: 10.1007/s00247-022-05583-5 -
Cells Sep 2021The ATP-binding cassette (ABC) transporter superfamily consists of several proteins with a wide repertoire of functions. Under physiological conditions, ABC transporters... (Review)
Review
The ATP-binding cassette (ABC) transporter superfamily consists of several proteins with a wide repertoire of functions. Under physiological conditions, ABC transporters are involved in cellular trafficking of hormones, lipids, ions, xenobiotics, and several other molecules, including a broad spectrum of chemical substrates and chemotherapeutic drugs. In cancers, ABC transporters have been intensely studied over the past decades, mostly for their involvement in the multidrug resistance (MDR) phenotype. This review provides an overview of ABC transporters, both related and unrelated to MDR, which have been studied in osteosarcoma and Ewing's sarcoma. Since different backbone drugs used in first-line or rescue chemotherapy for these two rare bone sarcomas are substrates of ABC transporters, this review particularly focused on studies that have provided findings that have been either translated to clinical practice or have indicated new candidate therapeutic targets; however, findings obtained from ABC transporters that were not directly involved in drug resistance were also discussed, in order to provide a more complete overview of the biological impacts of these molecules in osteosarcoma and Ewing's sarcoma. Finally, therapeutic strategies and agents aimed to circumvent ABC-mediated chemoresistance were discussed to provide future perspectives about possible treatment improvements of these neoplasms.
Topics: ATP-Binding Cassette Transporters; Animals; Antineoplastic Agents; Bone Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Osteosarcoma; Sarcoma, Ewing
PubMed: 34572110
DOI: 10.3390/cells10092461 -
Translational Research : the Journal of... Nov 2018Ewing sarcoma was first described in 1921 in the Proceedings of the New York Pathological Society by an eminent American pathologist from Cornell named James R. Ewing as... (Review)
Review
Ewing sarcoma was first described in 1921 in the Proceedings of the New York Pathological Society by an eminent American pathologist from Cornell named James R. Ewing as a "diffuse endothelioma of bone." Since this initial description, more has been discovered regarding Ewing sarcoma and in the 1980's both Ewing sarcoma and peripheral primitive neuroectodermal tumors due to their similar features and shared identical genetic abnormality were grouped into a class of cancers entitled Ewing sarcoma family of tumors (ESFTs). Ewing sarcoma is the second most common pediatric osseous malignancy followed by osteosarcoma, with highest incidence among 10-20 years old. Ewing sarcoma is consistently associated with chromosomal translocation and functional fusion of the EWSR1 gene to any of several structurally related transcription factor genes of the E26 transformation-specific family. These tumor-specific molecular rearrangements are useful for primary diagnosis, may provide prognostic information, and present potential therapeutic targets. Therefore, ways to rapidly and efficiently detect these defining genomic alterations are of clinical relevance. Within the past decade, liquid biopsies including extracellular vesicles (EVs), have emerged as a promising alternative and/or complimentary approach to standard tumor biopsies. It was recently reported that fusion mRNAs from tumor-specific chromosome translocations can be detected in Ewing sarcoma cell-derived exosomes. Within this review, we overview the current advances in Ewing sarcoma and the opportunities and challenges in exploiting circulating exosomes, primarily small bioactive EVs (30-180 nm), as developing sources of biomarkers for diagnosis and therapeutic response monitoring in children and young adult patients with ESFT.
Topics: Bone Neoplasms; Exosomes; Extracellular Vesicles; Humans; Liquid Biopsy; Microfluidic Analytical Techniques; Oncogene Proteins, Fusion; Proto-Oncogene Protein c-fli-1; RNA-Binding Protein EWS; Sarcoma, Ewing; Translocation, Genetic
PubMed: 30031766
DOI: 10.1016/j.trsl.2018.05.007