• 2018-07
  • 2019-04
  • Introduction Ewing s sarcoma ES is a high grade neoplasm


    Introduction Ewing\'s sarcoma (ES) is a high-grade neoplasm representing the second most common primary bone malignancy in both children and adults. With a peak incidence at 15 years, this disease accounts for 2% of childhood cancers [1–3]. ES is defined as a bone tumor which may occur at any site within the skeleton but preferentially affects the trunk and the diaphysis of long bones. Less commonly, it arises in extraskeletal soft tissues (15%). It is characterized by a rapid tumor growth and extensive bone destruction that can result in bone pain and pathological fracture. A particularity of ES tumors is the occurrence of a typical chromosomal translocation that fuses the EWS gene on chromosome 22q12 to a member of the ETS transcription gene family, most commonly to Fli-1 on 11q24 (>90% of cases) [4,5]. This translocation leads to the production of an aberrant transcription factor that promotes tumorigenicity [6–8]. Due to progress in surgery and chemotherapy, survival rates have increased from less than 10% to 55–60% for patients presenting local disease [9]. However, the survival rates decrease to 15–25% when metastases are detected at diagnosis, or for patient presenting resistance to treatment or relapsed disease. Moreover, a survival plateau seems to have been reached with conventional therapies. Accordingly, new therapeutic approaches should be actively explored, especially for high-risk patients, to increase long-term survival by decreasing metastases development and preventing drug resistance. ES is characterized by extensive bone destruction due to osteolysis. Ewing\'s sarcoma guanabenz are unable to directly degrade the bone matrix and accordingly, osteoclast activation and subsequent bone resorption might be responsible for the clinical features of bone destruction [10]. Indeed, as demonstrated for bone metastases [11], a vicious cycle between bone cells (osteoclasts and osteoblasts) and tumor cells occurs during the development of tumor in bone site. Therefore, targeting the osteoclasts may represent a promising adjuvant strategy for the treatment of bone tumors. Among the factors involved in the regulation of bone remodeling, the molecular triad osteoprotegerin (OPG)/receptor activator of NF-kB (RANK)/RANK Ligand (RANKL) is strongly implicated [12,13]. Osteoclast differentiation and activation is mainly mediated by RANKL, a cytokine member of the tumor necrosis factor (TNF) superfamily (TNFSF11) that binds to its receptor RANK at the surface of osteoclasts [14]. OPG (TNFRSF11B) is a soluble protein that acts as a decoy receptor for RANKL inhibiting osteoclast formation, function and survival by preventing the binding of RANKL to RANK [15]. Transgenic mice overexpressing OPG exhibit an osteopetrotic phenotype, whereas OPG-knockout mice have severe osteoporosis [16,17]. The OPG/RANKL/RANK system is also involved in various pathologies associated with tumors in bone [18,19]. Therefore, OPG has demonstrated increased interest as a therapeutic strategy in malignant bone pathologies associated with osteolytic lesions [20,21]. Concerning primary bone tumors, the inhibition of RANKL activity by OPG induced a significant therapeutic effect on bone lesion and tumor development in two preclinical models of osteosarcoma in mice (POS-1) and in rats (OSRGa) [22]. This effect was also confirmed by using the soluble form of the RANKL receptor, RANK-Fc [15] or by the RNA interference strategy targeting RANKL [23]. In addition, OPG is also able to bind to the TNF Related Apoptosis Inducing Ligand (TRAIL), another member of the TNF superfamily (TNFSF10)[23], thereby limiting its ability to induce apoptosis in tumor cells. It has been even reported that OPG acts as a guanabenz pro-tumoral factor in some cancer cell lines in vitro[24–26]. In addition, Taylor et al. previously reported that the expression of RANKL in Ewing\'s sarcoma cell lines and tissues could support osteoclast activation [10]. Therefore, targeting this cytokine with OPG may represent a promising therapeutic option.