Materiały źródłowe

• #1 Ewing Sarcoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK559183/

  Ewing sarcoma family tumors are characterized by non-random chromosomal translocations producing fusion genes that encode aberrant transcription factors. The t(11;22)(q24;q12) translocation is associated with 85% of tumors and leads to EWS-FLI-1 formation, whereas t(21;12)(22;12) and other less common translocations induced EWS-ERG fusion comprises the remaining 10% to 15% of cases. […] The cell of origin for Ewing sarcoma is not fully understood. Nonrandom gene rearrangements involving the EWS and the ETS (E26 transformation-specific or E-twenty-six) gene family distinguish Ewing sarcoma. The most frequent gene rearrangement is t(11;22)(q24;q12). A hybrid gene EWSFLI1 generated by the fusion of the EWS gene on 22q12 with the FLI1 gene on 11q24 occurs in greater than 80% of reported cases. The resulting EWS-FLI1 fusion protein acts as an aberrant transcription factor, which may play a role in the pathogenesis of Ewing sarcoma.

• #2 Molecular Pathogenesis of Ewing Sarcoma: New Therapeutic and Transcriptional Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3555146/

  Ewing sarcoma is the prototypical member of this group of sarcomas; it was the first to be recognized pathologically as a singular entity and to have its signature translocation defined cytogenetically, which led to the identification of its key driver alteration, the EWS-FLI1 gene fusion that encodes this aberrant, chimeric transcription factor. […] EWS-ETS fusions, as the presumed initiating oncogenic event in Ewing sarcoma, are required for proliferation and tumorigenesis. […] The EWS amino-terminal domain provides a strong transactivation domain, and its promoter is ubiquitously activated, which leads to relatively unrestricted high-level expression of the resulting fusion genes, in contrast to the highly regulated and lineage-restricted expression of native FLI1. […] EWS-FLI1 functions primarily as a transcription factor to regulate gene expression.

• #3 The second European interdisciplinary Ewing sarcoma research summit – A joint effort to deconstructing the multiple layers of a complex disease | Oncotarget

  https://www.oncotarget.com/article/6937/text/

  Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. […] Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. […] Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. […] Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intra-tumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease.

• #4

  https://www.orthobullets.com/pathology/8047/ewings-sarcoma

  Ewing’s Sarcoma is a malignant, distinctive small round cell sarcoma associated with a t(11:22) translocation which most commonly occurs in the diaphysis of long bones in patients 25 with regional pain, swelling and fevers. […] cell of origin in Ewing’s Sarcoma unknown, however, thought to be of neuroectodermal origin. […] t(11:22) translocation found in 85-95% of cases leads to the formation of a fusion protein (EWS-FLI1) which can be identified with PCR/FISH and useful to differentiate Ewing sarcoma from other round cell lesions. […] less common translocations including t(21:22) with fusion protein EWS-ERG comprise remaining 10-15%. […] p53 mutation in addition to t(11:22) translocation. […] overexpression of cell proliferation antigen Ki-67. […] overexpression of HER-2/neu.

• #5 Ewing sarcoma – Wikipedia

  https://en.wikipedia.org/wiki/Ewing_sarcoma

  The cause of Ewing sarcoma is unknown, most cases appearing to occur randomly. […] Accumulating evidence suggests a strong inherited risk factor, identifying a genetic component having multiple chromosome loci associated with Ewing sarcoma susceptibility. […] Sometimes Ewing sarcoma is associated with a germline mutation. […] The underlying mechanism often involves a genetic change known as a reciprocal translocation. […] Most cases of Ewing sarcoma (about 85%) are the result of a defining genetic event; a reciprocal translocation between chromosomes 11 and 22, t(11,22), which fuses the Ewing Sarcoma Breakpoint Region 1 (EWSR1) gene of chromosome 22 (which encodes the EWS protein) to the Friend Leukemia Virus Integration 1 (FLI1) gene (which encodes Friend Leukemia Integration 1 transcription factor (FLI1), a member of the ETS transcription factor family) of chromosome 11.

• #6 Ewing Sarcoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK559183/

  The second most common EWSETS gene family rearrangement is t(21;22)(q22;q12) translocation, resulting in the fusion of EWS with the ERG gene on 21q22 (observed in about 15% of cases). In the literature, other detected gene rearrangements are t(7;22)(p22;q12), t(17;22)(q21;q12) and (t(2;22)(q33;q12) where EWS is fused with ETS gene family ETV1, E1AF and FEV, respectively. More chromosomal translocations and complex gene rearrangements have also been reported in the literature. However, whether they are associated with more aggressive tumor features is unclear.

• #7 Pathology Outlines – Ewing sarcoma

  https://www.pathologyoutlines.com/topic/boneewing.html

  Small round cell sarcoma showing gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the E26 transformation specific (ETS) family of transcription factors […] Primary mutation generates fusion gene between the FET and ETS families, altering gene expression and promoting tumorigenesis […] Chromosomal translocation commonly involving EWSR1 and ETS partner […] Most common translocation is t(11;22)(q24;q12), resulting in EWSR1-FLI1 fusion (~85 – 90%) […] Second most common is t(21;22)(q22;q12), resulting in EWSR1-ERG fusion (~5 – 10%).

• #8 Ewing Sarcoma – NHSJS

  https://nhsjs.com/2018/ewing-sarcoma/

  The combination of the EWS transcriptional activator and the FLI1 DNA-binding domain, causes them to act as aberrant transcription factors, potent repressors, or to alter RNA processing. […] Mechanically, the translocation joins the N-terminal activation region of the EWS locus to the C-terminal ETS binding domain of the FLI1 gene, ultimately replacing the original transcription activation domains of the FLI1 and EWS sequences. […] The EWS/FLI1 fusion joins the activating domain of EWS to the DNA binding domain of FLI1, making it a probable aberrant transcription factor. […] Through ectopic expression of EWS-FLI1 in heterologous cell types as well as small interfering RNA-mediated knockdown of the fusion in ES cell lines, studies were able to discover potential target genes for therapies.

• #9 The Controversial Role of Autophagy in Ewing Sarcoma Pathogenesis—Current Treatment Options

  https://www.mdpi.com/2218-273X/11/3/355

  The EWS–FLI1 protein increases the deregulation of protein expression by either transcriptionally inducing or repressing specific target genes, many of which are associated with a different oncogenic process, such as cell proliferation, transformation, or tumor growth. […] In this review, we will try to address autophagy as a key regulator mechanism in ES development and eventually we will suggest this mechanism as a putative chemotherapeutic target for ES. […] The controversial role of autophagy as a survival or pro-death mechanism is also identified in different cases of ES. […] Several studies in this field support the hypothesis of autophagy as a protective mechanism under different conditions in ES models. […] In another study, the chimerical protein EWS–FLI1 was shown to trigger autophagy in the NIH3T3 ES cell line.

• #10 EWS-FLI1 positively regulates autophagy by increasing ATG4B expression in Ewing sarcoma cells

  https://www.spandidos-publications.com/10.3892/ijmm.2017.3112

  Ewing sarcoma (ES) is characterized by chromosomal translocations fusing the EWS gene with an ETS oncogene, most frequently FLI1. […] In the present study, the authors aimed to investigate the function of EWS-FLI1 in autophagy in ES cells, and identified that EWS-FLI1 positively regulates autophagy in ES cells. […] EWS-FLI1 induces massive deregulation of protein expression by either transcriptionally inducing or repressing specific target genes, many of which are involved in the oncogenic process, including cell proliferation, transformation and in vivo tumor growth, but the function of EWS-FLI1 in autophagy still remains unknown. […] In the present study, the authors investigated the function of EWS-FLI1 in autophagy in ES cells. It was identified that autophagy was promoted by overexpressing EWS-FLI1 in ES cells, as evidenced by the decreases in the amount of p62 and increases in the amount of LC3B-II, two important markers of autophagy, as well as the increased LC3 puncta in cells.

• #11 Molecular Pathogenesis of Ewing Sarcoma: New Therapeutic and Transcriptional Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3555146/

  EWS-FLI1 directly binds and upregulates the GLI1 promoter while GLI1, in turn, upregulates NKX2.2. […] Another recently identified critical EWS-FLI1 target gene is NR0B1. […] The function of NR0B1 in Ewing sarcoma is not well understood, but current data suggest that it may be a coregulator of gene expression. […] The use of GGAA microsatellites as EWS-FLI1 response elements is not limited to the NR0B1 gene. […] EWS-FLI1 also binds to more conventional, nonrepetitive ETS motifs, and these sites are associated with either repression or activation of transcription. […] Identifying the direct target genes that are upregulated by EWS-FLI1 can inform focused RNAi-based screens to define the genes that are the most essential for the survival and proliferation of Ewing sarcoma cells. […] A still-promising approach to the discovery of therapeutic targets in Ewing sarcoma is the identification of EWS-FLI1 target genes within pathways that encode known drug targets.

• #12 Ewing sarcoma – Wikipedia

  https://en.wikipedia.org/wiki/Ewing_sarcoma

  The resultant chromosomal translocation causes the EWS trans-activation domain (which is usually silent in the wild type) to become very active, this leads to the translation of a new EWS-FLI1 fusion protein. […] The EWS-FLI1 fusion protein has phase transition properties allowing it to transition into a liquid-like phase, separated by compartments consisting of membrane-less organelles. […] This phase transition property allows the fusion protein to access and activate micro-satellite regions of the genome that would otherwise be inaccessible. […] This fusion protein can convert usually silent chromatin regions into fully active enhancers leading to oncogenesis of the cells. […] The EWS-FLI1 fusion protein also causes variable expression of the genome via epigenetic mechanisms. […] The fusion protein does this by recruiting enzymes that affect DNA methylation, histone acetylation and direct inhibition of non-coding microRNA.

• #13 Ewing sarcoma – Wikipedia

  https://en.wikipedia.org/wiki/Ewing_sarcoma

  EWS-FLI1 promotes histone acetylation, which leads to uncoiling of DNA (which is usually tightly wound around histones); this chromatin relaxation leads to the DNA being more accessible to transcription factors and thus enhancing the expression of the associated genes. […] EWS-FLI1 reduces DNA methylation (which occurs mostly in areas corresponding to transcription enhancers), leading to increased gene expression. […] EWS-FLI1 inhibition of the microRNA miRNA-145 leads to increased pluripotency, decreased differentiation of cells and increased oncogenesis.

• #14 The second European interdisciplinary Ewing sarcoma research summit – A joint effort to deconstructing the multiple layers of a complex disease | Oncotarget

  https://www.oncotarget.com/article/6937/text/

  Some of the mystery behind Ewing sarcoma pathogenesis and the inter-patient heterogeneity in its response to treatment may arise from non-genetic sources, such as the epigenome. […] In Ewing sarcoma, widespread epigenetic rewiring of gene regulatory regions was recently demonstrated to be induced by EWS-FLI11. […] Knowledge about the exact mechanisms of epigenetic dysregulation may provide novel therapeutic opportunities. […] The notion that certain embryonal mesenchymal and neuronal tissues tolerate EWS-ETS gene expression in animal models, at least at defined developmental stages, is consistent with the current view that Ewing sarcoma arises from some potentially neural crest-derived mesenchymal or neuronal progenitor cells. […] Dysregulation of transcriptional programs by EWS-ETS driven wide-spread enhancer reprograming and promoter deregulation is a major factor shaping the biological and clinical characteristics of this monstrous disease.

• #15 Potential approaches to the treatment of Ewing’s sarcoma | Oncotarget

  https://www.oncotarget.com/article/12566/text/

  Thus, EWS-FLI1 is a perfect target for treating ES. […] Targeting EWS-FLI1 can be achieved by decreasing EWS-FLI1 expression through transcription impairment, by decreasing EWS-FLI1 activity through targeting the transcriptional modulators to which EWS-FLI1 binds, or by targeting genes that are deregulated by EWS-FLI1 expression. […] The interaction of EWS-FLI1 with RHA affects pre-mRNA processing, resulting in splicing isoforms involved in oncogenesis. […] In ES, EWS-FLI1 expression induces the epigenetic alterations to reprogram cells into the malignancy through activating HDACs. […] EWS-FLI1 knockdown in ES led to widespread epigenetic changes in promoters, enhancers, and super-enhancers; histone H3K27 acetylation was the most affected mark. […] High LSD1 expression is observed in ES clinical samples, and mechanistic and preclinical studies suggest that LSD1 inhibition globally impairs the function of EWS-ETS proteins.

• #16 Ewing’s Sarcoma | Cancer Genetics Web

  https://www.cancer-genetics.org/X0202.htm

  Ewing sarcoma usually expresses the EWS/FLI fusion transcription factor oncoprotein. […] EWS/FLI regulates myriad genes required for Ewing sarcoma development. […] EWS/FLI binds GGAA-microsatellite sequences in vivo and in vitro. […] The EWS-FLI1 chimeric protein uniquely expressed in Ewing’s sarcoma has an obligate role in its aetiology. […] EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma. […] EWS-FLI1 positively regulates autophagy by increasing ATG4B expression in Ewing sarcoma cells. […] Ewing sarcoma is an aggressive paediatric cancer of the bone and soft tissue. […] The presence of these aberrations did not correlate with age and sex of the patients, with the location of the primary tumor or with the extent of disease at diagnosis. […] Ewing sarcoma involves fusions between EWSR1 and various ETS family genes, most commonly FLI1. […] EWS/FLI1 expression is associated with the activation of a transcriptional program that drives tumorigenesis in Ewing sarcoma.

• #17 Molecular Pathogenesis of Ewing Sarcoma: New Therapeutic and Transcriptional Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3555146/

  Studies using this approach have demonstrated that diminished EWS-FLI1 expression causes decreased cell survival, proliferation, and oncogenic transformation. […] The top-down approach has allowed for the identification of genes that are comprehensively regulated by EWS-FLI1. […] Although this pathway is often considered to be a parallel or complementary pathway to the EWS-FLI1 oncoprotein, EWS-FLI1 itself may regulate the activity of the pathway in Ewing sarcoma. […] NKX2.2 is a transcription factor that harbors a homeodomain-type DNA-binding domain, as well as transcriptional activation and transcriptional repression domains. […] An important consequence of the identification of NKX2.2 as a transcriptional repressor is that this function could be targeted as a therapeutic approach.

• #18

  https://link.springer.com/article/10.1007/s00432-023-05441-3

  Ewing sarcoma (ES) is the second most frequent bone sarcoma affecting children and adolescents. […] Both survival and tumorigenesis of the Ewing sarcoma family of tumors are keyed to the function of EWS-FLI1, and it was shown that Gli1 is a transcriptional target of EWS-FLI1. […] Data suggest that Gli1 upregulation by EWS-FLI1 is Smo-independent, which indicates an involvement of the non-canonical activation pathway. […] The efficacy of ATO, a direct Gli inhibitor, has been shown in both cell lines and xenograft models of the EWS-FLI1 Ewing sarcoma. […] In vitro studies experiments demonstrated that another Gli inhibitor, GANT61, reduces the growth of Ewing sarcoma cells, mainly by inducing caspase-3/7-dependent cell apoptosis.

• #19 Molecular Pathogenesis of Ewing Sarcoma: New Therapeutic and Transcriptional Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3555146/

  Because the cell of origin of Ewing sarcoma is unknown, many studies have relied on heterologous cell types to study the fusion protein. […] These studies suggested that Ewing sarcoma may arise from a pluripotent precursor cell and that the tumor phenotype may be induced by EWS-FLI1, whereas the normal differentiation pathways of that pluripotent cell may be inhibited by the fusion protein. […] Consistent with this hypothesis, inhibition of EWS-FLI1 expression in patient-derived Ewing sarcoma cell lines, through the use of RNA interference (RNAi), induces a gene-expression pattern that is similar to that observed in MSCs. […] EWS-FLI1 induces expression of the embryonic stem cell genes OCT4, SOX2, and NANOG and upregulates the polycomb repressor EZH2. […] The advent of RNAi technology has allowed for the development of a complementary top-down approach to studying the development of Ewing sarcoma.

• #20 EWS-FLI1 positively regulates autophagy by increasing ATG4B expression in Ewing sarcoma cells

  https://www.spandidos-publications.com/10.3892/ijmm.2017.3112

  ATG4B was significantly upregulated by EWS-FLI1 overexpression, and ATG4B gene may be a transcript target of EWS-FLI1. […] The authors found that EWS-FLI1 induced the expression of ATG4B and EWS-FLI1 was observed to interact with the ATG4B promoter, which suggested that ATG4B as a transcriptional target of EWS-FLI1. […] Overexpression of ATG4B significantly promoted the autophagy in ES cells, consistently, silencing of ATG4B markedly suppressed the progression of autophagy. […] These findings suggested that ATG4B-dependent autophagy plays great roles in regulating cell viability and cell apoptosis in ES cells. […] In conclusion, in the present study, the authors revealed the promoting effect of EWS-FLI1 and ATG4B on autophagy in ES cells, and these findings may provide new venues for anti-autophagy drugs and new targets for the treatment of ES.

• #21 Genetic alterations in Ewing’s sarcoma: What do we know so far? – Journal of Musculoskeletal Surgery and Research

  https://journalmsr.com/genetic-alterations-in-ewings-sarcoma-what-do-we-know-so-far/

  EWS-FLI1 tends to activate genes involved in cellular differentiation, proliferation, and survival, such as IGF1, NKX2, TOPK, SOX2, and EZH2. EWS-FLI1 also tends to deactivate genes involved in apoptosis and cell cycle, including the IGFBP3, CDKN1C, CDKN1A, and TGFB2. […] This information opens the door to targeted therapies, including blocking IGF signaling and, more recently, interfering with key EWSR1-FLI1 protein-protein interactions conserved pathways in cancer which is likely to suggest additional ways to attack EwS therapeutically.

• #22 Molecular Pathogenesis of Ewing Sarcoma: New Therapeutic and Transcriptional Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3555146/

  The role of the IGF1R pathway in tumorigenesis has been investigated for years and was initially of interest in Ewing sarcoma due to the overexpression of IGF-1 and IGF-1R in tumor cell lines. […] Recently, great progress has been made in our understanding of the molecular pathogenesis of Ewing sarcoma.

• #23 Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours | Clinical Sarcoma Research | Full Text

  https://clinicalsarcomaresearch.biomedcentral.com/articles/10.1186/2045-3329-2-6

  Histone deacetylase inhibitors can restore TGF- receptor II allowing TFF- signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. […] Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. […] Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET. […] Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. […] IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge. […] The future treatment of Ewing sarcoma/PNET is likely to be improved by these scientific advances.

• #24 The Function of Wnt/beta-catenin Signaling in Ewing Sarcoma and its Contribution to Pathogenesis

  https://deepblue.lib.umich.edu/handle/2027.42/144020

  Ewing sarcoma is an aggressive bone and soft tissue tumor with a high propensity for metastasis; however, the mechanisms that contribute to this process are poorly understood. The Wnt/beta-catenin signaling pathway is critical for oncogenesis in numerous cancers, and although previous studies implicate a role for this pathway in Ewing sarcoma, its specific function and contribution is unknown. […] Patients whose tumors have nuclear beta-catenin or high expression of the downstream Wnt/beta-catenin target LEF1, experienced worse clinical outcomes and overall survival. […] RNA-sequencing revealed that Wnt/beta-catenin paradoxically inhibits EWS-ETS transcriptional activity, resulting in a phenotypic change from a proliferative to a migratory and metastatic state in vitro and in vivo. […] In conclusion these findings implicate a critical role for Wnt/beta-catenin-signaling in mediating migration and metastasis. This occurs in part through antagonism of EWS/ETS fusion protein activity and by up-regulation of the metastasis-associated gene Tenascin C. In addition, tumor-microenvironment interactions modulated by Wnt/beta-catenin further contribute to pathogenesis.

• #25 Hypoxia and HIFs in Ewing sarcoma: new perspectives on a multi-facetted relationship | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01750-w

  Hypoxia develops during the growth of solid tumors and influences tumoral activity in multiple ways. Low oxygen tension is also present in the bone microenvironment where Ewing sarcoma (EwS) a highly aggressive pediatric cancer mainly arises. Hypoxia inducible factor 1 subunit alpha (HIF-1-a) is the principal molecular mediator of the hypoxic response in cancer whereas EWSR1::FLI1 constitutes the oncogenic driver of EwS. Interaction of the two proteins has been shown in EwS. Although a growing body of studies investigated hypoxia and HIFs in EwS, their precise role for EwS pathophysiology is not clarified to date. This review summarizes and structures recent findings demonstrating that hypoxia and HIFs play a role in EwS at multiple levels. We propose to view hypoxia and HIFs as independent protagonists in the story of EwS and give a perspective on their potential clinical relevance as prognostic markers and therapeutic targets in EwS treatment.

• #26 The Controversial Role of Autophagy in Ewing Sarcoma Pathogenesis—Current Treatment Options

  https://www.mdpi.com/2218-273X/11/3/355

  Furthermore, it has been shown that EWS–FLI1-dependent autophagy inhibited apoptotic cell death, which was confirmed through the reduction of PUMA and cytosolic cyto-chrome-c, two major pro-apoptotic regulators. […] The authors suggested that autophagy might be a resistance mechanism against anti-cancer therapy in ES. […] This study highlighted the complexity of autophagy in cancer, especially in ES. […] The primary role of autophagy has been identified as a highly conservative homeostatic degradation mechanism for dysfunctional cellular organelles and proteins. […] The dual role of autophagy is also identified in rare ES tumors. Several in vitro studies on ES linked autophagy with the development and progression of this type of sarcoma.

• #27 Discovered one of the mechanism that influences aggressiveness in Ewing’s Sarcoma – IDIBELL

  https://idibell.cat/en/2013/08/discovered-one-of-the-mechanism-that-influences-aggressiveness-in-ewings-sarcoma/

  Discovered one of the mechanism that influences aggressiveness in Ewings Sarcoma […] Caveolin-1 participates in the formation of new blood vessels around the tumor, facilitating growth and proliferation […] Researchers from the Bellvitge Biomedical Research Institute (IDIBELL) led by the head of the research group in sarcomas, Oscar Martinez-Tirado, have discovered one of the mechanisms that triggers angiogenesis (formation of new blood vessels) around tumor cells of Ewings sarcoma, a very aggressive childhood cancer. […] Angiogenesis is a key process in the growth, proliferation and migration of solid tumors. Tumor cells need new blood vessels that provide extra oxygen and nutrients they need to grow so quickly. […] The group of Oscar Martinez-Tirado has described in several studies the functions of caveolin-1 protein in Ewings sarcoma, We have seen that it plays a tumorogenic role in this type of tumor, which is involved in resistance to chemotherapy, which favors metastasis and in this paper we have shown it plays a critical role in the angiogenic process.

• #28 Discovered one of the mechanism that influences aggressiveness in Ewing’s Sarcoma – IDIBELL

  https://idibell.cat/en/2013/08/discovered-one-of-the-mechanism-that-influences-aggressiveness-in-ewings-sarcoma/

  Therefore, the lack of caveolin-1 inhibits angiogenesis said Martinez-Tirado. […] In this sense, the study describes how caveolin-1 interacts with another protein called EphA2 activating a signalling pathway that induces angiogenesis, more particularly the migration of cells that should form the vessels to the tumor. […] Our vision for the future is to use this protein as a vehicle to release toxic substances in tumor cells Oscar Martinez-Tirado said. […] EphA2-induced angiogenesis in Ewing sarcoma celles works through bGFG production and is dependent on caveolin-1.

• #29

  https://link.springer.com/article/10.1007/s00223-017-0372-2

  To date, its origin remains elusive with three potential hypotheses: neural crest stem cells, embryonic osteochondrogenic progenitor cells or MSCs. […] The role of osteoclasts in bone sarcoma development is still unclear and osteoclasts could act as a pro-tumoral factor in the early stage of the disease due to their pro-angiogenic activity and could exert the opposite role at a later stage of the disease. […] The bilateral dialogue established between cancer cells and their neighbours is a central aspect of bone sarcoma development. […] The diverse modes of communication include soluble factors (e.g. chemokines, cytokines), direct cell interactions and extracellular vesicles. […] Gap junctions are clearly involved in the tumour development and the loss of connexin43 expression in Ewing sarcoma cells favours the development of the primary tumour growth. […] Overall, these results demonstrate the key role of macrophages which regulate the development of bone sarcoma according to their number and M1/M2 phenotype.

• #30 Tracking Ewing Sarcoma Origin by Developmental and Trans-species Genomics | Alex’s Lemonade Stand Foundation for Childhood Cancer

  https://www.alexslemonade.org/project/tracking-ewing-sarcoma-origin-developmental-and-trans-species-genomics

  Malignant bone tumors, mainly Ewing sarcoma and osteosarcoma, comprise about 6% of all cancers in children and adolescents. […] The genetic cause of Ewing sarcoma is a mutation that results in the expression of an oncogenic fusion protein called EWS-FLI1, with disastrous effects on the enigmatic Ewing sarcoma progenitor cell. […] There is evidence that Ewing sarcoma develops from some kind of mesenchymal stem cells from the bone marrow or the neural crest (as transient structure arising during fetal development). […] We aim at elucidating bone sarcoma origin considering cell type and its developmental stage at the time of tumor initiation to better understand disease pathogenesis and to develop urgently needed disease models for pre-clinical drug testing. […] We focus on the disruptive effect of the EWS-FLI1 oncogene and link disrupted differentiation to Ewing sarcoma.

• #31

  https://link.springer.com/article/10.1007/s00223-017-0372-2

  Bone sarcoma genesis can be explained by a conjunction between a minimum of one oncogenic event and an adequate microenvironment leading to the emergence of cancer, followed by its growth and potential migration to distant organs. […] Indeed, Ewing sarcoma cells are characterised by the expression of a fusion protein resulting from a chromosomal translocation between the EWS gene on chromosome 2 and a gene of the ETS family and consequently have been initially associated with the primitive neuroectodermal family of tumours. […] However, the main frequent location of Ewing sarcoma in bone and the functional consequence of EWSFLi1 silencing in Ewing sarcoma cells fed the controversy and put a label of mesenchymal origin on Ewing sarcoma. […] Indeed, Tirode et al. showed that the EWSFLI1 silencing in different Ewing cell lines resulted in the differentiation of sarcoma cells into mesenchymal lineages and more particularly into adipogenic and osteogenic lineages.

• #32 Molecular Heterogeneity of Ewing Sarcoma as Detected by Ion Torrent Sequencing | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153546

  The EWS-FLI1 gene fusion is the most common gene combination found in ES, and its transcript is considered as an important pathogenic factor due to its dysregulation of numerous target genes. However, EWS-FLI1 fails to transform human cells in vitro, indicating that additional cooperating mutations or other factors may contribute to ES tumorigenesis. […] In the present study, 62 mutational hotspots in 26 genes across 20 ES samples were detected using IT-PGM. Variants of these hotspot genes consisted of missense and nonsense mutations, of which missense mutation occurred at higher frequencies (87.1%). […] The high-throughput IT-PGM sequencing provided us with important information about alterations in cancer-related genes that may be critical to the dynamics of ES oncogenesis.

• #33 Ewing’s Sarcoma | Cancer Genetics Web

  https://www.cancer-genetics.org/X0202.htm

  Over 90% of Ewing’s sarcomas contain a t(11;22)(q24;q12) translocation which fuses the EWS gene on chromosome 22 with the FLI1 gene on chromosome 11. […] In a minority of Ewing’s tumours the EWS gene has a different fusion partner including either the ERG, ETV1 and the EA1F and genes. […] Ewing sarcoma is initiated and exacerbated by a chimeric oncoprotein, most commonly, EWS-FLI1. […] Ewing sarcoma is characterized by chromosomal translocations fusing the EWS gene with an ETS oncogene, most frequently FLI1. […] Ewing sarcoma cells display alterations in regulation of damage-induced transcription, accumulation of R-loops and increased replication stress. […] Ewing sarcoma is a pediatric cancer driven by EWS-ETS transcription factor fusion oncoproteins in an otherwise stable genomic background.

• #34

  https://www.omim.org/entry/612219

  Gorthi et al. (2018) showed that Ewing sarcoma cells show alterations in regulation of damage-induced transcription, accumulation of R-loops, and increased replication stress. […] In addition, homologous recombination is impaired in Ewing sarcoma owing to an enriched interaction between BRCA1 (113705) and the elongating transcription machinery. […] Finally, Gorthi et al. (2018) uncovered a role for EWSR1 (133450) in the transcriptional response to damage, suppressing R-loops and promoting homologous recombination. […] Gorthi et al. (2018) concluded that their findings improved the understanding of EWSR1 function, elucidated the mechanistic basis of the sensitivity of Ewing sarcoma to chemotherapy (including PARP1 (173870) inhibitors), and highlighted a class of BRCA-deficient-like tumors.

• #35 Remodeling of the Tumor Microenvironment in Ewing Sarcoma – American Association for Cancer Research (AACR)

  https://www.aacr.org/professionals/research-funding/grantees/aacr-quadw-grantee-identifies-a-mechanism-by-which-ewing-sarcoma-cells-remodel-the-tumor-microenvironment/

  Here we find that Ewing sarcomas, which do not typically contain many CAFs, in fact generate subpopulations of tumor cells that themselves remodel the ECM in a CAF-like manner. This raises the possibility of therapeutically targeting these cells and their functions in tumor microenvironment remodeling.

• #36 Potential approaches to the treatment of Ewing’s sarcoma | Oncotarget

  https://www.oncotarget.com/article/12566/text/

  Ewings sarcoma (ES) is a highly aggressive and metastatic tumor in children and young adults caused by a chromosomal fusion between the Ewing sarcoma breakpoint region 1 (EWSR1) gene and the transcription factor FLI1 gene. […] The reciprocal chromosomal translocation t (11;22) (q24;q12) is found in 85% of these tumors, which leads to the fusion between the 5 segment of the Ewing sarcoma breakpoint region 1 gene (EWSR1) on the chromosome 22 and the 3 portion of Friend leukemia virus integration site 1 (FLI1) on the chromosome 11. […] These translocations produce the chimeric proteins EWS-ETSs, which function as aberrant transcription factors, accounting for the tumorigenic potential of ES. […] EWS-FLI1 induces expression of many factors that promote tumorigenesis, and ES cells die when losing EWS-FLI1.

• #37 Potential approaches to the treatment of Ewing’s sarcoma | Oncotarget

  https://www.oncotarget.com/article/12566/text/

  Thus, EWS-FLI1 is a perfect target for treating ES. […] Targeting EWS-FLI1 can be achieved by decreasing EWS-FLI1 expression through transcription impairment, by decreasing EWS-FLI1 activity through targeting the transcriptional modulators to which EWS-FLI1 binds, or by targeting genes that are deregulated by EWS-FLI1 expression. […] The interaction of EWS-FLI1 with RHA affects pre-mRNA processing, resulting in splicing isoforms involved in oncogenesis. […] In ES, EWS-FLI1 expression induces the epigenetic alterations to reprogram cells into the malignancy through activating HDACs. […] EWS-FLI1 knockdown in ES led to widespread epigenetic changes in promoters, enhancers, and super-enhancers; histone H3K27 acetylation was the most affected mark. […] High LSD1 expression is observed in ES clinical samples, and mechanistic and preclinical studies suggest that LSD1 inhibition globally impairs the function of EWS-ETS proteins.

• #38 Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours | Clinical Sarcoma Research | Full Text

  https://clinicalsarcomaresearch.biomedcentral.com/articles/10.1186/2045-3329-2-6

  Insulin-like growth factor-1 receptor (IGF-1R) antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. […] Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. […] However drug delivery and degradation problems may limit this therapeutic approach. […] Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. […] Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. […] Interferons may be incorporated into future chemotherapeutic treatment paradigms.

• #39 Potential approaches to the treatment of Ewing’s sarcoma | Oncotarget

  https://www.oncotarget.com/article/12566/text/

  EWS-FLI1 mediated transcriptional repression is facilitated through the direct binding of a NuRD-LSD1 complex. […] Treatment of ES cells with the LSD1 inhibitor HCI-2509, comprehensively reverses the transcriptional profiles driven by both EWS-FLI and EWS-ERG, and markedly delays tumorigenesis in vivo. […] EWS-FLI1 interacts with PARP1, driving PARP1 expression, which in turn promotes the transcriptional activation by EWS-FLI1. […] PARP inhibition in ES disrupts the interaction between EWS-FLI1 and PARP1, and impairs DNA repair. […] Mithramycin, which represses EWS-FLI1 activity resulting in a decreased expression of EWS-FLI1 downstream targets, has been used to treat ES patients from 1960s. […] However, the mithramycin toxicity limits its use in ES.

• #40 Epigenetic Mechanisms underlying Ewing Sarcoma Pathogenesis – SFA

  https://curesarcoma.org/funded-research/epigenetic-mechanisms-underlying-ewing-sarcoma-pathogenesis/

  Rationale: Ewing sarcoma, the second most common pediatric bone cancer, is a highly lethal malignancy. Despite multimodal therapy, recurrence and mortality remain high for metastatic cases. It has been proposed that its refractory nature arises in part from resistance of a cancer stem cell (CSC) subpopulation to chemotherapy. […] We have found that the epigenetic modifier drug, JQ1, is highly toxic to Ewing sarcoma cells in vitro, and is especially efficacious in targeting the CSC subpopulation. […] JQ1 functions by inhibiting BET proteins, factors that bind to acetylated histones. […] Microarray and additional analyses reveal that JQ1 rapidly reverses the EWS-FLI1-dependent gene expression, indicating that EWS-FLI1 requires BET proteins for function. […] We hypothesize that EWS-FLI1 requires BET proteins to induce target genes that control proliferation, survival, and “stemness”.

• #41

  https://www.orthobullets.com/evidence/20543858

  Tumor development is a complex process resulting from interplay between mutations in oncogenes and tumor suppressors, host susceptibility factors, and cellular context. Great advances have been made by studying rare tumors with unique clinical, genetic, or molecular features. Ewing’s sarcoma serves as an excellent paradigm for understanding tumorigenesis because it exhibits some very useful and important characteristics. For example, nearly all cases of Ewing’s sarcoma contain the (11;22)(q24;q12) chromosomal translocation that encodes the EWS/FLI oncoprotein. […] These two features suggest that EWS/FLI is the primary mutation that drives the development of this tumor. Finally, Ewing’s sarcoma is an aggressive tumor that requires aggressive treatment. Thus, improved understanding of the pathogenesis of this tumor will not only be of academic interest, but may also lead to new therapeutic approaches for individuals afflicted with this disease. The purpose of this review is to highlight recent advances in understanding the molecular pathogenesis of Ewing’s sarcoma, while considering the questions surrounding this disease that still remain and how this knowledge may be applied to developing new treatments for patients with this highly aggressive disease.

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