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    • The aim of this study was to

    2019-05-23

    The aim of this study was to determine the therapeutic relevance of blocking RANKL in Ewing\'s sarcoma by using OPG administered by non-viral gene transfer approaches in two models of human Ewing sarcoma in immunodeficient mice. OPG was administered using amphiphilic polymers constituted by blocks of poly(ethylene oxide) and of poly(propylene oxide) as previously reported for osteosarcoma preclinical studies [22]. These synthetic vectors have been used with high efficiency for in vivo gene transfer in various organs including skeletal and cardiac muscles [27,28] and in lungs [29]. Intramuscular injections of these synthetic vectors led to the synthesis of proteins for local benefit such as dystrophin or of systemic erythropoietin [30].
    Materials and methods
    Results
    Discussion Therapeutic interest has recently increased on bone tumor microenvironment as a new promising target for primary bone diseases. Even if tumor FLAG tag Peptide are still the first targets in cancer therapy, an increased number of data suggest that tumor cell proliferation in bone is highly dependent upon host cells from the bone microenvironment. Indeed, as evidenced for bone metastases, a vicious cycle between osteoclasts, bone stromal cells/osteoblasts and cancer cells have been hypothesized during the progression of primary bone tumors [11]. Tumor cells produce osteoclast activating factors such as Interleukin-6, TNF-α or PTH-rP that induce osteoclast differentiation and activation through the production of RANKL. When they resorb bone, osteoclasts enable the release of growth factors stored in the bone matrix (TGF-β, IGF-1, PDGF, etc.) that in turn activate tumor cell proliferation [11]. Accordingly, inhibition of osteoclast activity represents a promising approach to block the vicious cycle, inhibiting indirectly local cancer growth. By inhibiting osteoclast activity, one possible option relies to bisphosphonates, the synthetic analogs of pyrophosphate that induce osteoclast apoptosis, decrease osteoclast activation and function by inhibition of the mevalonate pathway [32]. Such therapeutic tools have been studied in primary bone tumor models [33,34] and are even used in the French clinical trial OS2006 for pediatric and adult osteosarcoma patients. However, these molecules exhibit secondary events especially renal toxicity and osteonecrosis of the jaw, and may interfere with bone growth when administered to young patients [35]. Therefore, another promising way to block osteoclast activation is to target RANKL, the pivotal cytokine that mediate osteoclast differentiation and activation [36]. Beyond physiological conditions, increased expression of RANKL has been observed in osteolytic malignancies, such as breast cancer and multiple myeloma [37–39]. A previous study demonstrated that the RANKL/OPG ratio was significantly increased in patients suffering from severe osteolysis associated with tumor or not [19]. Therefore, therapeutic strategies that used its decoy receptor OPG have emerged in osteolytic bone tumor pathologies. As an example, OPG was shown to inhibit cancer cell migration and bone metastasis through inhibition of the RANKL-induced effects in RANK-expressing cells from tumor origin [40]. OPG was also shown to inhibit tumor-induced osteoclastogenesis and bone tumor growth in osteopetrotic mice [41], to reduce bone cancer pain by the blockade of the ongoing osteoclast activity [42], to decrease the number and area of radiographically evident lytic bone lesions in a model of mouse colon adenocarcinoma [21], to exhibit beneficial effects in experimental models of myeloma [20,43] and to inhibit osteolytic lesions associated with prostate cancer [44]. In the present study, mice developing Ewing\'s sarcoma models were treated by OPG administered by non-viral gene therapy. In a first step, we confirmed that RANKL was indeed a good therapeutic target in ES, by analyzing its expression both in patients and also in the ES models used in the present study. RANKL expression was indeed found in ES microenvironment in both cases, confirming the results previously published by Taylor et al. in patient biopsies [10]. Moreover, we demonstrate in the present study that ES cells are directly producing RANKL. The availability of a xenograft model of ES enabled us to discriminate from human or murine origin of RANKL production. The antibodies used were specific for each species and results clearly showed that the increased RANKL production in ES tumor model was due to direct synthesis by tumor cells. However, one interesting data is that some ES cell lines (such as TC-71) which express low levels of RANKL in vitro (Fig. 1A and B), show an elevated RANKL production when injected in the mouse and developing a tumor (Fig. 1C). Therefore, it suggests that during tumor development, the stroma may influence tumor cells to produce RANKL. These results constitute the rationale for the therapeutic use of OPG in ES.