Ewing sarcoma from molecular biology to the clinic

Abstract

In Europe, with an incidence of 7.5 cases per million, Ewing sarcoma (ES) is the second most common primary malignant bone tumor in children, adolescents and young adults, after osteosarcoma. Since the 1980s, conventional treatment has been based on the use of neoadjuvant and adjuvant chemotherapeutic agents combined with surgical resection of the tumor when possible. These treatments have increased the patient survival rate to 70% for localized forms, which drops drastically to less than 30% when patients are resistant to chemotherapy or when pulmonary metastases are present at diagnosis. However, the lack of improvement in these survival rates over the last decades points to the urgent need for new therapies. Genetically, ES is characterized by a chromosomal translocation between a member of the FET family and a member of the ETS family. In 85% of cases, the chromosomal translocation found is (11; 22) (q24; q12), between the EWS RNA-binding protein and the FLI1 transcription factor, leading to the EWS-FLI1 fusion protein. This chimeric protein acts as an oncogenic factor playing a crucial role in the development of ES. This review provides a non-exhaustive overview of ES from a clinical and biological point of view, describing its main clinical, cellular and molecular aspects.

Keywords: EWS-FLI1; cellular biology; clinical; ewing sarcoma; molecular biology.

FIGURE 1

(A) Primary and metastatic sites of Ewing sarcoma. Ewing sarcoma mainly affects the humerus, ribs, pelvis and femur and metastasized to the lungs, bones and bone marrow (B) Schematic representation of the EWS-FLI1 fusion protein. The main chromosomal translocation in Ewing sarcoma occurs between EWS on the chromosome 22 and FLI1 on the chromosome 11. The resulting fusion protein displays the N-terminal domain of EWS and the C-terminal domain of FLI1.

FIGURE 2

(A) Metastatic development of Ewing sarcoma. Tumor cells invade the primary tumor site (Invasion), before passing through the bloodstream (Intravasation) to the metastatic site, where they exit the bloodstream (Extravasation) to form metastases (Colonization) (B) Mechanism of proliferation and dissemination of Ewing sarcoma according to EWS-FLI1 expression (based on Franzetti et al., 2017). Cells strongly expressing EWS-FLI1 are undifferentiated, more proliferative and display more cell-cell interactions. On the other hand, cells weakly expressing EWS-FLI1 are more mesenchymal, migrate more and display more cell-matric interactions.

FIGURE 3

(A) Detailed schematic representation of the EWS-FLI1 fusion protein. EWS has Serine—Tyrosine—Glycine—Glutamine rich domain (SYGQ), Arginine—Glycine—Glycine rich domain (RGG) and a RNA Recognition Motif (RRM). FLI1 has an E26 Transformation-Specific domain (ETS), a FLI1-Specific Region (FLS) and a Carboxy-terminal Transcriptional Activation domain (CTA). After the chromosomal translocation, the EWS-FLI1 fusion protein display the SYGQ domain from EWS and the FLS, ETS and CTA domains from FLI1 (B) EWS-FLI1 binding at GGAA microsatellites near its target gene promoter. EWS-FLI1 is able to bind GGAA microsatellites repetitions in chromatin-opening regions (H3K27ac) and active promoter regions (H3K4me3), allowing the transcription of the target gene by the RNA polymerase II.