Ewing's Sarcoma
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Ewing's sarcoma / Peripheral Primitive Neuroectodermal Tumours (PNET) of bone is a type of cancer usually found in children and young adults. The peak incidence is between ages 10 and 20, it is less common in children under 5 or in adults over 30. Ewing's s can occur in any bone in the body; the most common sites are the pelvis, thigh, lower leg, upper arm, and rib. The tumour is composed of small round blue cells. Ewing's sarcoma can also arise in soft tissue (extra-skeletal); see Soft Tissue Sarcoma in this guide.

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See also: Genetic features of Ewing's Sarcoma

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Choi EY, Gardner JM, Lucas DR, et al.
Ewing sarcoma.
Semin Diagn Pathol. 2014; 31(1):39-47 [PubMed] Related Publications
Classification of small round cell tumors of bone is often challenging due to overlapping clinicopathologic features. The purpose of this article is to review the clinical, radiological, histologic, and molecular features of Ewing sarcoma and to provide a discussion of the differential diagnosis of small round cell tumors of bone.

Related: Bone Cancers

Ulaner GA, Magnan H, Healey JH, et al.
Is methylene diphosphonate bone scan necessary for initial staging of Ewing sarcoma if 18F-FDG PET/CT is performed?
AJR Am J Roentgenol. 2014; 202(4):859-67 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to determine whether methylene diphosphonate (MDP) bone scans are necessary during initial staging in patients with Ewing sarcoma (ES) in whom (18)F-FDG PET/CT is performed.
MATERIALS AND METHODS: A retrospective review was performed of patients who underwent FDG PET/CT and MDP bone scan before treatment of newly diagnosed ES from January 2004 to November 2012. Studies were reviewed to document suspected primary and metastatic malignancy. Pathology and imaging follow-up were used to determine the presence or absence of disease at suspected sites.
RESULTS: Sixty patients were identified in whom FDG PET/CT and MDP bone scans were performed before treatment of newly diagnosed ES. Forty-four primary malignancies had a lytic CT appearance, three were sclerotic, and 13 involved only soft tissue. In 11 of 12 patients with osseous metastases, these were detected on PET/CT, with the one false-negative occurring in a sclerotic primary tumor; in nine of 12 patients with osseous metastases, these were detected on MDP bone scan, with the three false-negatives occurring in patients with lytic primary tumors. Only one of 13 patients with a soft-tissue primary malignancy had bone metastases on both bone scan and PET/CT. PET/CT also showed that eight patients had lung metastases and three patients had lymph node metastases, which were not evident on MDP bone scan.
CONCLUSION: When ES is lytic, MDP bone scan does not add to staging performed by FDG PET/CT; thus, MDP bone scanning may be omitted. However, when ES is sclerotic, MDP bone scan may detect osseous metastases not detected by FDG PET/CT.

Related: Bone Cancers Bisphosphonates

Sikri V, Sobti S
Askin tumour: a rare thoracopulmonary tumour in adults.
Indian J Chest Dis Allied Sci. 2013 Oct-Dec; 55(4):233-5 [PubMed] Related Publications
Askin tumour, a primitive neuroectodermal tumour of the thoracopulmonary region, is a rare tumour presenting in childhood. Its presentation in adults is rare. We report a case of an Askin tumour in an adult patient who presented to us with worsening breathlessness and vague chest pain. Investigations including immunohistochemistry confirmed the diagnosis of Askin tumour.

Related: Bone Cancers Lung Cancer

Fleuren ED, Versleijen-Jonkers YM, Boerman OC, van der Graaf WT
Targeting receptor tyrosine kinases in osteosarcoma and Ewing sarcoma: current hurdles and future perspectives.
Biochim Biophys Acta. 2014; 1845(2):266-76 [PubMed] Related Publications
Osteosarcoma (OS) and Ewing sarcoma (ES) are the two most common types of primary bone cancer, which mainly affect children and young adults. Despite intensive multi-modal treatment, the survival of both OS and ES has not improved much during the last decades and new therapeutic options are awaited. One promising approach is the specific targeting of transmembrane receptor tyrosine kinases (RTKs) implicated in these types of bone cancer. However, despite encouraging in vitro and in vivo results, apart from intriguing results of Insulin-like Growth Factor-1 Receptor (IGF-1R) antibodies in ES, clinical studies are limited or disappointing. Primary resistance to RTK inhibitors is frequently observed in OS and ES patients, and even patients that initially respond well eventually develop acquired resistance. There are, however, a few remarks to make concerning the current set-up of clinical trials and about strategies to improve RTK-based treatments in OS and ES. This review provides an overview concerning current RTK-mediated therapies in OS and ES and discusses the problems observed in the clinic. More importantly, we describe several strategies to overcome resistance to RTK inhibitors which may significantly improve outcome of OS and ES patients.

Related: Osteosarcoma IGF1R

Li J, You T, Jing J
MiR-125b inhibits cell biological progression of Ewing's sarcoma by suppressing the PI3K/Akt signalling pathway.
Cell Prolif. 2014; 47(2):152-60 [PubMed] Related Publications
OBJECTIVES: Increasing evidence has suggested the close relationship between microRNAs (miRNAs) dysregulation and the carcinogenesis of Ewing's sarcoma (ES), among of which miR-125b has been reported to be decreased in ES tissues recently. Strikingly, ectopic expression of miR-125b could suppress cell proliferation of ES cell line A673, suggesting the tumor suppressor role of miR-125b in ES. However, the other accurate mechanistic functions and relative molecule mechanisms are largely unknown.
MATERIALS AND METHODS: Herein, we completed a series of experiments to investigate the role of miR-125b in Ewing's sarcoma. We restored the expression of miR-125b in ES cell line A673 through transfection with miR-125b mimics. To further understand the role of miR-125b in ES, we detected the effects of miR-125b on the cell proliferation, migration and invasion, cell cycle as well as cell apoptosis.
RESULTS: We found that restored expression of miR-125b in ES cell line A673 inhibited cell proliferation, migration and invasion, arrested cell cycle progression, and induced cell apoptosis. Moreover, bioinformatic prediction suggested the oncogene, phosphoinositide-3-kinase catalytic subunit delta (PIK3CD), was a target gene of miR-125b in ES cells. Further quantitative RT-PCR and western blot assays identified over-expression of miR-125b suppressed the expression of PIK3CD mRNA and protein. PIK3CD participates in regulating the PI3K signaling pathway, which has been reported to play an important role in the development of ES. Suppression of PIK3CD down-regulated the expression of phospho-AKT and phospho-mTOR proteins and inhibited the biologic progression of A673 cells.
CONCLUSIONS: Collectively, these data suggest that miR-125b functions as a tumor suppressor by targeting the PI3K/Akt/mTOR signaling pathway, and may provide potential therapy strategy for ES patients by targeting miRNA expression.

Related: Bone Cancers AKT1 Signal Transduction

Na KY, Kim HS, Jung WW, et al.
CXCL16 and CXCR6 in Ewing sarcoma family tumor.
Hum Pathol. 2014; 45(4):753-60 [PubMed] Related Publications
Chemokines are a family of peptide mediators that play an essential role in cellular migration and intracellular communication in tumor cells as well as immune cells. We hypothesized that the CXCL16-CXCR6 ligand-receptor system plays an important role in Ewing sarcoma (ES) family tumor (ESFT) progression. Using real-time quantitative reverse transcription-polymerase chain reaction, we investigated the mRNA expression of CXCL16, CXCR6, and ADAM 10 in various cell lines. We also investigated the expression of CXCL16, CXCR6, ADAM 10, and ADAM 17 in tissue samples from 61 ESFT patients using immunohistochemistry. The mRNA expression levels of CXCL16 and CXCR6 in the ES cell line were higher than those in the other cell lines. Immunohistochemical staining revealed that CXCL16 and CXCR6 were highly expressed in tumor cells of ESFT and showed a positive correlation between them. The expression of CXCL16 and CXCR6 was associated with the occurrence of lung metastasis. Univariate analysis revealed that CXCL16 or CXCR6 expression was associated with worse prognosis of ESFT patients. In addition, CXCL16 and CXCR6 expression was associated with shorter overall survival irrespective of other prognostic factors. Our results suggest that the CXCL16/CXCR6 axis appears to be important in the progression of ESFT, resulting in more aggressive clinical behavior. Furthermore, there may be a decrease in the overall survival in ESFT patients who have tumors that stain strongly for CXCL16 and CXCR6.

Related: Bone Cancers

Jahangiri FR, Al Eissa S, Jahangiri AF, Al-Habib A
Intraoperative neurophysiological monitoring during sacrectomy procedures.
Neurodiagn J. 2013; 53(4):312-22 [PubMed] Related Publications
Previously intraoperative neurophysiological monitoring (IONM) has not been used along with a computer based navigation system for en bloc resection of a sacral Ewing sarcoma. In order to improve the post-operative neurological outcome of the patient we decided to include IONM in our procedure. A partial or complete resection of a sacral tumor may result in the loss of neurological functions due to close proximity of vascular, neural, and visceral structures. A prolonged two-stage surgical procedure may be a high risk procedure for position related brachial plexus injury. An 18-year-old male presented with left lower extremity weakness, which worsened with gait. His MRI was consistent with a sacral mass causing compression on the left S1 and S2 roots. A surgical resection was planned with anterior and posterior approaches. IONM helped guide the surgical team to prevent damaging the sacral roots on the normal side (right) and position related upper extremity brachial plexus injuries. Our technique involving IONM can be used safely for accurate en bloc removal of a sacral tumor with a safe margin while protecting the neural function and minimizing recurrence. This case report demonstrates that intraoperative neurophysiological monitoring was useful in identifying and reversing impending nerve injury during sacrectomy surgery. Significant changes were seen in ulnar and posterior tibial somatosensory evoked potentials (SSEPs). We recommend that IONM should be considered for safe margin en bloc sacral tumor resection and prevention of injury to the sacral root and brachial plexus.

Monson DK, Vojdani S, Dean TJ, Louis-Ugbo J
Lateral ankle stabilization after distal fibular resection using a novel approach: a surgical technique.
Clin Orthop Relat Res. 2014; 472(4):1262-70 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
BACKGROUND: After tumor resection involving the distal fibula, the method for recreating stability of the lateral ankle remains controversial. Many reconstructive options exist, including allograft reconstruction and arthrodesis; however, each of these approaches has significant potential disadvantages.
DESCRIPTION OF TECHNIQUE: The distal fibula is resected as necessary to obtain negative margins for local control of the neoplasm. Reconstruction of the lateral ankle ligamentous complex is performed using the peroneus brevis tendon to reestablish lateral and anterior stability of the tibiotalar joint. The peroneus brevis tendon is transected proximally at it myotendinous junction and then sutured to the calcaneofibular and anterior talofibular ligaments in sequence and then tenodesed to the lateral distal tibia with suture anchors and a staple.
METHODS: We present three patients who underwent distal fibulectomy for tumors originating in the distal fibula. All patients who have undergone the reconstruction being described are included within this cohort study. The patients were assessed clinically and radiographically at a range of 14 months to 9.5 years (average, 4.8 years) for functional recovery, return of range of motion, stability of the ankle, and imaging evidence of arthrosis and instability.
RESULTS: There were no episodes of instability or early progression to arthrosis. In addition, all patients obtained excellent ankle stability and range of motion on examination, but two had complications. One sustained a traumatic fracture to the base of the fifth metatarsal that healed with nonsurgical treatment and another who underwent further fibular shortening and bursectomy at the tip of the residual fibula with complete relief of his symptoms.
CONCLUSIONS: Reconstruction of the lateral ankle after distal fibular resection is possible using the peroneus brevis tenodesed to the distal tibia and sutured to the remnants of the calcaneofibular and anterior talofibular ligaments as described in this surgical technique. In this small group, we found that patients were able to return to normal daily activities without instability or progression to tibiotalar arthrosis at short term; however, longer followup and larger series of patients are called for to confirm these findings.

Related: Bone Cancers Chondrosarcoma

Zhou Z, Yu L, Kleinerman ES
EWS-FLI-1 regulates the neuronal repressor gene REST, which controls Ewing sarcoma growth and vascular morphology.
Cancer. 2014; 120(4):579-88 [PubMed] Article available free on PMC after 15/02/2015 Related Publications
BACKGROUND: RE1-silencing transcription factor (REST), a neuronal repressor gene, regulates neuronal stem cell differentiation. Ewing sarcoma may originate from neural crest cells. In the current study, the authors investigated whether REST plays a role in the growth of this tumor.
METHODS: REST expression was determined by Western blot analysis and reverse transcription-polymerase chain reaction in 3 human Ewing sarcoma cell lines and 7 patient tumor samples. The role of REST in tumor growth and tumor vascular morphology was determined using a Ewing sarcoma xenograft model. Immunofluorescence staining, Hypoxyprobe, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays were performed to investigate the impact of REST on pericyte marker expression, hypoxia, and apoptosis in vivo.
RESULTS: High levels of REST were expressed in all 3 human Ewing sarcoma cell lines and in 6 of the 7 patient tumor samples. Overexpression of EWS-FLI-1 in human mesenchymal stem cells and human neural progenitor cells was found to increase REST expression. Inhibition of EWS-FLI-1 using small interfering RNA decreased REST expression in human Ewing sarcoma cells. Inhibition of REST did not affect EWS-FLI-1, but significantly suppressed tumor growth in vivo, reduced the tumor vessel pericyte markers α- smooth muscle actin (SMA) and desmin, increased hypoxia and apoptosis in tumor tissues, and decreased the expression of delta-like ligand 4 (DLL4) and Hes1.
CONCLUSIONS: Inhibition of REST suppressed tumor growth, inhibited pericyte marker expression, and increased tumor hypoxia and apoptosis. Because tumor vessel function has been linked to tumor growth and metastases, REST may be a new therapeutic target in patients with Ewing sarcoma.

Related: Apoptosis FLI1 gene

Zhang Z, Huang L, Yu Z, et al.
Let-7a functions as a tumor suppressor in Ewing's sarcoma cell lines partly by targeting cyclin-dependent kinase 6.
DNA Cell Biol. 2014; 33(3):136-47 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
MicroRNAs play an important role in the development and progression of Ewing's sarcoma (ES). Especially, the expression of let-7a has been reported to be significantly downregulated in various cancers, and can affect the initiation and maintenance of tumor progression. However, the relative effects of let-7a on ES cells and relative mechanisms are largely unknown. In this study, we identified the underexpression of let-7a in human ES cells comparing with the human mesenchymal stem cells. Then, we sought to compensate for its loss through exogenous transfection with let-7a mimic into ES cell lines A673 and SK-ES-1. Restored let-7a expression inhibited cell proliferation, migration, as well as invasion; arrested cell cycle progression; and induced cell apoptosis of both cell lines. Moreover, bioinformatic prediction suggested that cyclin-dependent kinase 6 (CDK6), which is overexpressed and functions as an oncoprotein in ES cells, is a putative target gene of let-7a. Using mRNA and protein expression analysis and luciferase assays, we further identified the target role of CDK6. Finally, we found that restored CDK6 expression in ES cells that had been treated with let-7a mimic before could partly dampen let-7a-mediated tumor suppression. Taken together, our results showed that let-7a acted as a tumor suppressor in ES by targeting CDK6, and it may provide novel diagnostic and therapeutic options for human Ewing sarcoma clinical operation in future.

Elbashier SH, Nazarina AR, Looi LM
Cytokeratin immunoreactivity in Ewing sarcoma/ primitive neuroectodermal tumour.
Malays J Pathol. 2013; 35(2):139-45 [PubMed] Related Publications
Ewing sarcoma (ES)/ primitive neuroectodermal tumour (PNET) is an aggressive malignant neoplasm affecting mainly children and young adults. The tumour is included with other primitive neoplasms under the category of small round cell tumour. Cytokeratin expression in ES/PNET has been described in sporadic case reports as well as a few systemic series. We studied this feature in Malaysian patients diagnosed in University Malaya Medical Centre on the basis of typical morphology and immunohistochemical assays. Immunohistochemical staining for AE1/AE3 and MNF116 were performed in 43 cases. Cytokeratin was expressed in 17 cases (39.5%) in focal, intermediate or diffuse patterns. There was no significant association between cytokeratin immunoreactivity and the following parameters: patient age, sex, skeletal and extraskeletal primary location as well as primary, metastastic or recurrent tumours or chemotherapy treatment. A significant association between cytokeratin and neuron specific enolase (NSE) expression was demonstrated. Our study supports evidence of epithelial differentiation in ES/PNET and emphasizes that the expression of cytokeratin does not exclude ES/PNET in the differential diagnosis of small round cell tumours.

Dmitriev P, Kairov U, Robert T, et al.
Cancer-related genes in the transcription signature of facioscapulohumeral dystrophy myoblasts and myotubes.
J Cell Mol Med. 2014; 18(2):208-17 [PubMed] Related Publications
Muscular dystrophy is a condition potentially predisposing for cancer; however, currently, only Myotonic dystrophy patients are known to have a higher risk of cancer. Here, we have searched for a link between facioscapulohumeral dystrophy (FSHD) and cancer by comparing published transcriptome signatures of FSHD and various malignant tumours and have found a significant enrichment of cancer-related genes among the genes differentially expressed in FSHD. The analysis has shown that gene expression profiles of FSHD myoblasts and myotubes resemble that of Ewing's sarcoma more than that of other cancer types tested. This is the first study demonstrating a similarity between FSHD and cancer cell expression profiles, a finding that might indicate the existence of a common step in the pathogenesis of these two diseases.

Related: Chromosome 4

Aydin R, Bilgici MC, Dagcinar A
A very rare cause of neck pain: primary Ewing sarcoma of the axis.
Pediatr Emerg Care. 2013; 29(11):1197-200 [PubMed] Related Publications
We report the case of a 7-year-old boy who presented with a 1-month history of neck pain, left-sided torticollis, and no neurological deficit. Computed tomography and magnetic resonance imaging revealed an expansile lesion in the axis, with epidural and prevertebral soft tissue components. Histopathologic examination of the biopsy specimen revealed primary vertebral Ewing sarcoma. This is the first case of primary vertebral Ewing sarcoma that has presented with torticollis. It is essential for physicians to be familiar with this condition and the associated imaging findings because early diagnosis of such cases is the key to better prognosis.

Huang WY, Tan WL, Geng DY, et al.
Imaging findings of the spinal peripheral Ewing's sarcoma family of tumours.
Clin Radiol. 2014; 69(2):179-85 [PubMed] Related Publications
AIM: To present the neuroradiological and clinical characteristics of Ewing's sarcoma family of tumours (ESFTs) and to increase awareness of this neoplasm.
MATERIALS AND METHODS: The magnetic resonance imaging (MRI) features and clinical presentations of seven patients with pathologically documented ESFTs were retrospectively analysed. The tumour location, morphological features, signal intensity, contrast enhancement characteristics, involvement of the paraspinal soft tissues, and adjacent bony structures were assessed.
RESULTS: Most of the ESFTs in young adults were well-circumscribed. The present study demonstrated that ESFTs often have a hypo- or iso-intense signal on T1-weighted imaging and an iso-intense signal on T2-weighted imaging. Spinal ESFTs tended to present homogeneous signal intensity and diffuse enhancement. ESFTs are more likely to occur in the thoracic spine and later to infiltrate into the paraspinal area or vertebral bone. A broad dural attachment is another common feature in the cases presented here.
CONCLUSIONS: ESFT is a rare neoplasm that can have significant overlap in imaging appearance compared with other spinal neoplasms. A well-demarcated extradural mass invading the paraspinal soft or vertebral bones, with iso-intense on T2 weighted imaging and homogeneous enhancement could facilitate the diagnosis of spinal ESFT.

Kurmasheva RT, Reynolds CP, Kang MH, et al.
Initial testing (stage 1) of the topoisomerase II inhibitor pixantrone, by the pediatric preclinical testing program.
Pediatr Blood Cancer. 2014; 61(5):922-4 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Pixantrone, a novel aza-anthracenedione with cytotoxic activity, was tested against the PPTP in vitro panel (3.0 nM to 30.0 μM) and against a limited panel of PPTP Wilms tumors and sarcomas (7.5 mg/kg) administered intravenously using an every 4 day × 3 schedule. In vitro pixantrone showed a median relative IC50 value of 54 nM (range <3 nM to 1.03 μM). In vivo pixantrone induced significant differences in EFS distribution compared to controls in two of eight solid tumor xenografts at dose levels relevant to human drug exposure. A complete response was observed for one Wilms tumor xenograft.

Related: Bone Cancers Kidney Cancer Rhabdomyosarcoma Wilms' Tumour Wilms Tumour

Sasaki T, Onishi T, Yabana T, Hoshina A
Ewing's sarcoma/primitive neuroectodermal tumor arising from the adrenal gland: a case report and literature review.
Tumori. 2013 May-Jun; 99(3):e104-6 [PubMed] Related Publications
We report a rare case of Ewing's sarcoma (ES)/primitive neuroectodermal tumor (PNET) arising from the adrenal gland. A 17-year-old Japanese woman presented with left upper abdominal pain and high fever. Computed tomography and magnetic resonance imaging revealed a 15 × 10 cm tumor replacing the adrenal gland. Preoperative diagnosis was an adrenocortical carcinoma. Resection of the tumor was performed. We obtained the final diagnosis of ES/PNET by immunohistochemical molecular study with positive staining for the MIC2 gene product (CD99) and a Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangement. Local recurrence was observed one month after the surgery. The patient was then treated with systemic chemotherapy and localized radiotherapy.

Related: MIC2 Expression in Cancer EWSR1 gene

Aryee DN, Niedan S, Ban J, et al.
Variability in functional p53 reactivation by PRIMA-1(Met)/APR-246 in Ewing sarcoma.
Br J Cancer. 2013; 109(10):2696-704 [PubMed] Article available free on PMC after 12/11/2014 Related Publications
BACKGROUND: Though p53 mutations are rare in ES, there is a strong indication that p53 mutant tumours form a particularly bad prognostic group. As such, novel treatment strategies are warranted that would specifically target and eradicate tumour cells containing mutant p53 in this subset of ES patients.
METHODS: PRIMA-1(Met), also known as APR-246, is a small organic molecule that has been shown to restore tumour-suppressor function primarily to mutant p53 and also to induce cell death in various cancer types. In this study, we interrogated the ability of APR-246 to induce apoptosis and inhibit tumour growth in ES cells with different p53 mutations.
RESULTS: APR-246 variably induced apoptosis, associated with Noxa, Puma or p21(WAF1) upregulation, in both mutant and wild-type p53 harbouring cells. The apoptosis-inducing capability of APR-246 was markedly reduced in ES cell lines transfected with p53 siRNA. Three ES cell lines established from the same patient at different stages of the disease and two cell lines of different patients with identical p53 mutations all exhibited different sensitivities to APR-246, indicating cellular context dependency. Comparative transcriptome analysis on the three cell lines established from the same patient identified differential expression levels of several TP53 and apoptosis-associated genes such as APOL6, PENK, PCDH7 and MST4 in the APR-246-sensitive cell line relative to the less APR-246-sensitive cell lines.
CONCLUSION: This is the first study reporting the biological response of Ewing sarcoma cells to APR-246 exposure and shows gross variability in responses. Our study also proposes candidate genes whose expression might be associated with ES cells' sensitivity to APR-246. With APR-246 currently in early-phase clinical trials, our findings call for caution in considering it as a potential adjuvant to conventional ES-specific chemotherapeutics.

Related: Apoptosis Bone Cancers TP53

Tsugita M, Yamada N, Noguchi S, et al.
Ewing sarcoma cells secrete EWS/Fli-1 fusion mRNA via microvesicles.
PLoS One. 2013; 8(10):e77416 [PubMed] Article available free on PMC after 12/11/2014 Related Publications
Tumours defined as Ewing sarcoma (ES) constitute a group of highly malignant neoplasms that most often affect children and young adults in the first 2 decades of life. The EWS/Fli-1 fusion gene, a product of the translocation t(11;22) (q24; 12), is detected in 95% of ES patients. Recently, it was validated that cells emit a heterogeneous mixture of vesicular, organelle-like structures (microvesicles, MVs) into their surroundings including blood and body fluids, and that these MVs contain a selected set of tumor-related proteins and high levels of mRNAs and miRNAs. In this present study, we detected the Ewing sarcoma-specific EWS/Fli-1 mRNA in MVs from the culture medium of ES cell lines carrying t(11;22) (q24; 12). Also, we detected this fusion gene in approximately 40% of the blood samples from mice inoculated with xenografts of TC135 or A673 cells. These findings indicate the EWS/Fli-1 mRNA in MVs might be a new non-invasive diagnostic marker for specific cases of Ewing sarcoma.

Related: FLI1 gene

Silva DS, Raimann PE, Moro T, et al.
Neutrality of miniSTR D22S1045 marker by Ewing's sarcoma phenotype.
Leg Med (Tokyo). 2013; 15(6):335-7 [PubMed] Related Publications
Neutrality investigations of markers with forensic use are important to see if a phenotypic trait is being expressed in relation to the alleles of the marker. MiniSTR marker D22S1045 (locus 22q12.3) is localized near the breakpoint region of the EWS gene (22q12.2), which leads to the development of Ewing's Sarcoma. Analyzing allele frequencies and linkage disequilibrium in Ewing's sarcoma patients and non-affected populations, we found that the marker mD22S1045 was neutral when related to Ewing's Sarcoma.

Cote GM, Choy E
Update in treatment and targets in Ewing sarcoma.
Hematol Oncol Clin North Am. 2013; 27(5):1007-19 [PubMed] Related Publications
The improvement in outcome for patients with localized and metastatic Ewing sarcoma since the development of cytotoxic chemotherapy remains one of the most profound advances in oncology and one of the proudest achievements of sarcoma researchers. Identification of molecular targets for new treatments has become an intense area within Ewing sarcoma research. The development of improved preclinical Ewing sarcoma models and advanced molecular techniques will build on knowledge of EWS/FLI1 function, EWS/FLI1 transcription targets, and the other critical driver events in these tumors.

Related: Bone Cancers

Pérez-Muñoz I, Grimer RJ, Spooner D, et al.
Use of tissue expander in pelvic Ewing's sarcoma treated with radiotherapy.
Eur J Surg Oncol. 2014; 40(2):197-201 [PubMed] Related Publications
INTRODUCTION: The local treatment option for pelvic Ewing sarcoma (ES) remains uncertain and challenging as surgery is often disabling while radiotherapy alone has a higher risk of local recurrence but not necessarily a worse survival. The aim is to analyse the outcome of patients with pelvic ES after radiotherapy as the primary local treatment in combination with a temporary intrapelvic surgically placed tissue expander (TE) to reduce bowel complications.
MATERIALS AND METHODS: 20 patients were retrospectively analysed. All patients had neoadjuvant and adjuvant chemotherapy. We identified survival, time to develop local recurrence and metastasis, dose of radiotherapy administered, local complications related to the use of the tissue expander and bowel effects of radiotherapy.
RESULTS: The median follow-up was 41 months. 14 patients were stage IIb and six stage III. There were no problems after insertion of the TE and only one patient who developed mild diarrhoea. Local recurrence occurred in six patients. At the last follow-up 12 patients have died from sarcoma, five are disease free and three have had recurrent disease.
CONCLUSIONS: In this paper we reviewed pelvic Ewing sarcoma with all the special considerations that this entails. We think that tissue expander can be safely used when radiotherapy is chosen to treat pelvic ES. It does appear to prevent bowel problems and is a low morbidity procedure. New treatment approaches should be considered to give a chance of cure to those patients with "bad prognostic" pelvic ES.

Related: Bone Cancers

Yang Y, Zhen T, Zhang F, et al.
p53 and hepatoma-derived growth factor expression and their clinicopathological association with Ewing family tumour.
J Clin Pathol. 2014; 67(3):235-42 [PubMed] Related Publications
PURPOSE: To investigate p53 and hepatoma-derived growth factor (HDGF) expression and their association with clinicopathological features of Ewing family tumour (EFT).
EXPERIMENTAL DESIGN: A total of 108 cases of EFT were retrospectively analysed. p53 and HDGF expression were detected using immunohistochemistry, and the relationships between p53 expression and HDGF expression and clinicopathological features of EFT were analysed. Kaplan-Meier curves were applied to estimate overall survival, log-rank test was used to assess prognostic relevance of p53 expression with overall survival and Cox regression model was performed to evaluate HRs.
RESULTS: p53 expression and high HDGF expression was found in 17 (15.7%) and 55 (50.9%) patients, respectively. p53 expression was significantly associated with metastatic stage at initial diagnosis (p=0.007) and tumour venous/nerve invasion (p=0.023). A significant positive correlation was found between p53 expression and HDGF expression in EFT (p=0.022). p53 expression was an independent prognostic factor for overall survival of patients with EFT (p<0.001). Patients with p53-positive/high HDGF expression had a significantly shorter overall survival than those with p53-positive/low HDGF expression or p53-negative/high HDGF expression or p53-negative/low HDGF expression. We first constructed a novel molecular staging system by combining p53 expression and HDGF expression, which significantly improved prognostic stratification for patients with EFT.
CONCLUSIONS: p53 expression was an independent prognostic factor for patients with EFT. Combining p53 expression and HDGF expression significantly improved prognostic stratification for patients with EFT.

Related: Bone Cancers TP53

Jinkala SR, Basu D, Mathath D, et al.
A rare case of congenital Ewing sarcoma/PNET of the scapula.
J Pediatr Hematol Oncol. 2014; 36(2):e134-5 [PubMed] Related Publications
Ewing sarcoma (ES)/primitive neuroectodermal tumors (PNET) are known to occur at both central and peripheral locations, as well as at skeletal and extraskeletal sites. They most commonly occur in the first 2 decades of life. We report a rare case of congenital Ewing sarcoma/primitive neuroectodermal tumor arising from the scapula.

Related: Bone Cancers

Sankar S, Tanner JM, Bell R, et al.
A novel role for keratin 17 in coordinating oncogenic transformation and cellular adhesion in Ewing sarcoma.
Mol Cell Biol. 2013; 33(22):4448-60 [PubMed] Article available free on PMC after 12/11/2014 Related Publications
Oncogenic transformation in Ewing sarcoma is caused by EWS/FLI, an aberrant transcription factor fusion oncogene. Glioma-associated oncogene homolog 1 (GLI1) is a critical target gene activated by EWS/FLI, but the mechanism by which GLI1 contributes to the transformed phenotype of Ewing sarcoma was unknown. In this work, we identify keratin 17 (KRT17) as a direct downstream target gene upregulated by GLI1. We demonstrate that KRT17 regulates cellular adhesion by activating AKT/PKB (protein kinase B) signaling. In addition, KRT17 is necessary for oncogenic transformation in Ewing sarcoma and accounts for much of the GLI1-mediated transformation function but via a mechanism independent of AKT signaling. Taken together, our data reveal previously unknown molecular functions for a cytoplasmic intermediate filament protein, KRT17, in coordinating EWS/FLI- and GLI1-mediated oncogenic transformation and cellular adhesion in Ewing sarcoma.

Related: Bone Cancers FLI1 gene AKT1 Signal Transduction GLI

Morland B, Platt K, Whelan JS
A phase II window study of irinotecan (CPT-11) in high risk Ewing sarcoma: a Euro-E.W.I.N.G. study.
Pediatr Blood Cancer. 2014; 61(3):442-5 [PubMed] Related Publications
BACKGROUND: The prognosis for patients with nonpulmonary metastatic Ewing sarcoma remains poor with survival in the order of 15-20%. The need to introduce effective new agents into clinical practice is clear. Based on a preclinical rationale of responses in xenografts and backed by a phase I study in children, the Euro-E.W.I.N.G consortium planned a phase II window study of irinotecan in newly diagnosed high risk metastatic patients with Ewing sarcoma.
PROCEDURES: Patients were recruited between April 2004 and December 2007. Two courses of irinotecan were administered at a dose of 600 mg/m(2) as a 1 hour infusion at 21 day intervals. Response evaluation was determined after the second course of treatment by radiological assessment of primary and metastatic sites and, where appropriate bone marrow sampling.
RESULTS: Twenty-three patients were recruited. Two patients were deemed inevaluable for response. Five patients (24%) demonstrated a partial response. Grade 3 or 4 diarrhoea was seen in 4/43 course of treatment and was managed with loperamide.
CONCLUSIONS: This is the first report of single agent irinotecan activity in an untreated population of patients with Ewing sarcoma. In common with other paediatric tumours and other camptothecin analogues such as topotecan, single agent activity is only modest. The exact role for the use of irinotecan in patients with ES, dose schedule and combinations with other agents still requires further investigation.

Related: Bone Cancers Irinotecan

Bazzocchi A, Bacci A, Serchi E, et al.
Intradural extramedullary Ewing's sarcoma. Recurrence with acute clinical presentation and literature review.
Neuroradiol J. 2013; 26(4):476-81 [PubMed] Related Publications
The intradural extramedullary space is an extremely unusual site for the onset of Ewing's sarcoma. We describe a case of recurrence of intradural extramedullary Ewing's sarcoma and review the literature available on this topic.

Sharib J, Horvai A, Gray Hazard FK, et al.
Comparison of Latino and non-Latino patients with Ewing sarcoma.
Pediatr Blood Cancer. 2014; 61(2):233-7 [PubMed] Related Publications
BACKGROUND: Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES.
METHODS: Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing.
RESULTS: Latino patients were diagnosed at a younger age (P = 0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (P = 0.001), were less likely to have insurance (P = 0.001), and were more likely to present to the emergency room at onset of symptoms (P = 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% P = 0.37; OS: 77.6% vs. 68.6% P = 0.54).
CONCLUSION: Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients.

Related: Bone Cancers

Lee HJ, Yoon C, Schmidt B, et al.
Combining PARP-1 inhibition and radiation in Ewing sarcoma results in lethal DNA damage.
Mol Cancer Ther. 2013; 12(11):2591-600 [PubMed] Article available free on PMC after 01/11/2014 Related Publications
Ewing sarcomas (ES) harbor a chromosomal translocation that fuses the EWS gene to an ETS transcription factor, most commonly Friend leukemia integration 1 (FLI1). The EWS-FLI1 fusion protein acts in a positive feedback loop to maintain the expression of PARP-1, which is involved in repair of DNA damage. Here, we examine the effects of PARP-1 inhibition and radiation therapy on Ewing sarcomas. In proliferation assays, the Ewing sarcoma cell lines RD-ES and SK-N-MC were much more sensitive than non-Ewing sarcoma cell lines to the PARP-1 inhibitor olaparib (Ola; IC50 0.5-1 μmol/L vs. >5 μmol/L) and to radiation (IC50 2-4 Gy vs. >6 Gy). PARP-1 inhibition with short hairpin RNA (shRNA) or Ola sensitized Ewing sarcoma cells, but not non-Ewing sarcoma cells, to radiation therapy in both proliferation and colony formation assays. Using the Comet assay, radiation of Ewing sarcoma cells with Ola, compared to without Ola, resulted in more DNA damage at 1 hour (mean tail moment 36-54 vs. 26-28) and sustained DNA damage at 24 hours (24-29 vs. 6-8). This DNA damage led to a 2.9- to 4.0-fold increase in apoptosis and a 1.6- to 2.4-fold increase in cell death. The effect of PARP-1 inhibition and radiation therapy on Ewing sarcoma cells was lost when EWS-FLI1 was silenced by shRNA. A small dose of radiation therapy (4 Gy), when combined with PARP-1 inhibition, stopped the growth of SK-N-MC flank tumors xenografts. In conclusion, PARP-1 inhibition in Ewing sarcomas amplifies the level and duration of DNA damage caused by radiation therapy, leading to synergistic increases in apoptosis and cell death in a EWS-FLI1-dependent manner.

Related: FLI1 gene

Redini F, Odri GA, Picarda G, et al.
Drugs targeting the bone microenvironment: new therapeutic tools in Ewing's sarcoma?
Expert Opin Emerg Drugs. 2013; 18(3):339-52 [PubMed] Related Publications
INTRODUCTION: Ewing's sarcoma (ES) is the second most frequent malignant primary bone tumour in children, adolescents and young adults. The overall survival is 60 - 70% at 5 years but still very poor for patients with metastases, disease relapse or for those not responding to chemotherapy. For these high risk patients, new therapeutic approaches are needed beyond conventional therapies (chemotherapy, surgery and radiation) such as targeted therapies.
AREAS COVERED: Transcriptomic and genomic analyses in ES have revealed alterations in genes that control signalling pathways involved in many other cancer types. To set up more specific approaches, it is reasonable to think that the particular microenvironment of these bone tumours is essential for their initiation and progression, including in ES. To support this hypothesis, preclinical studies using drugs targeting bone cells (bisphosphonate zoledronate, anti-receptor activator of NF-κB ligand strategies) showed promising results in animal models. This review will discuss the new targeted therapeutic options in ES, focusing more particularly on the ones modulating the bone microenvironment.
EXPERT OPINION: Targeting the microenvironment represents a new option for patients with ES. The proof-of-concept has been demonstrated in preclinical studies using relevant animal models, especially for zoledronate, which induced a strong inhibition of tumour progression in an orthotopic bone model.

Related: Bone Cancers

Sáinz-Jaspeado M, Huertas-Martinez J, Lagares-Tena L, et al.
EphA2-induced angiogenesis in ewing sarcoma cells works through bFGF production and is dependent on caveolin-1.
PLoS One. 2013; 8(8):e71449 [PubMed] Article available free on PMC after 01/11/2014 Related Publications
Angiogenesis is the result of the combined activity of the tumor microenvironment and signaling molecules. The angiogenic switch is represented as an imbalance between pro- and anti-angiogenic factors and is a rate-limiting step in the development of tumors. Eph receptor tyrosine kinases and their membrane-anchored ligands, known as ephrins, constitute the largest receptor tyrosine kinase (RTK) subfamily and are considered a major family of pro-angiogenic RTKs. Ewing sarcoma (EWS) is a highly aggressive bone and soft tissue tumor affecting children and young adults. As other solid tumors, EWS are reliant on a functional vascular network for the delivery of nutrients and oxygen and for the removal of waste. Based on the biological roles of EphA2 in promoting angiogenesis, we explored the functional role of this receptor and its relationship with caveolin-1 (CAV1) in EWS angiogenesis. We demonstrated that lack of CAV1 results in a significant reduction in micro vascular density (MVD) on 3 different in vivo models. In vitro, this phenomenon correlated with inactivation of EphA2 receptor, lack of AKT response and downregulation of bFGF. We also demonstrated that secreted bFGF from EWS cells acted as chemoattractant for endothelial cells. Furthermore, interaction between EphA2 and CAV1 was necessary for the right localization and signaling of the receptor to produce bFGF through AKT and promote migration of endothelial cells. Finally, introduction of a dominant-negative form of EphA2 into EWS cells mostly reproduced the effects occurred by CAV1 silencing, strongly suggesting that the axis EphA2-CAV1 participates in the promotion of endothelial cell migration toward the tumors favoring EWS angiogenesis.

Related: Bone Cancers FGF2 Angiogenesis and Cancer AKT1 Signal Transduction

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