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New Insights about the Wnt/β-Catenin Signaling Pathway in Primary Bone Tumors and Their Microenvironment: A Promising Target to Develop Therapeutic Strategies?

Abstract : Osteosarcoma and Ewing sarcoma are the most common malignant primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation specifically for Ewing sarcoma, associated with tumor resection. However, patient survival has not evolved for the past decade and remains closely related to the response of tumor cells to chemotherapy, reaching around 75% at 5 years for patients with localized forms of osteosarcoma or Ewing sarcoma but less than 30% in metastatic diseases and patients resistant to initial chemotherapy. Despite Ewing sarcoma being characterized by specific EWSR1-ETS gene fusions resulting in oncogenic transcription factors, currently, no targeted therapy could be implemented. It seems even more difficult to develop a targeted therapeutic strategy in osteosarcoma which is characterized by high complexity and heterogeneity in genomic alterations. Nevertheless, the common point between these different bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Therefore, targeting different actors of the bone tumor microenvironment has been hypothesized to develop new therapeutic strategies. In this context, it is well known that the Wnt/β-catenin signaling pathway plays a key role in cancer development, including osteosarcoma and Ewing sarcoma as well as in bone remodeling. Moreover, recent studies highlight the implication of the Wnt/β-catenin pathway in angiogenesis and immuno-surveillance, two key mechanisms involved in metastatic dissemination. This review focuses on the role played by this signaling pathway in the development of primary bone tumors and the modulation of their specific microenvironment. Keywords: Wnt/β-catenin; bone sarcoma; bone tumor microenvironment 1. Primary Bone Tumors: Osteosarcoma and Ewing Sarcoma Osteosarcoma and Ewing sarcoma are the most common primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation for Ewing sarcoma, associated with tumor resection. However, the 5-year survival rates have not been improved during the last decades reaching 70-80% for patients with localized forms, but less than 30% in metastatic diseases and patients resistant to initial chemotherapy [1-5]. Osteosarcoma that mainly occurs at the ends of long bones is not associated with any clinical signs except severe pain or spontaneous fracture. Osteosarcoma does not express specific oncogenic markers but exhibits a large number and variety of genetic alterations. Ewing sarcoma is a tumor composed of small undifferentiated round cells that can appear mainly in bones but also in soft tissues in 15% of Int.
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Geoffroy Danieau, Sarah Morice, Françoise Rédini, Franck Verrecchia, Benedicte Brounais-Le Royer. New Insights about the Wnt/β-Catenin Signaling Pathway in Primary Bone Tumors and Their Microenvironment: A Promising Target to Develop Therapeutic Strategies?. International Journal of Molecular Sciences, MDPI, 2019, 20 (15), pp.3751. ⟨10.3390/ijms20153751⟩. ⟨inserm-03004122⟩

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