Biology of Bone Sarcomas and New Therapeutic Developments

Abstract

Bone sarcomas are tumours belonging to the family of mesenchymal tumours and constitute a highly heterogeneous tumour group. The three main bone sarcomas are osteosarcoma, Ewing sarcoma and chondrosarcoma each subdivided in diverse histological entities. They are clinically characterised by a relatively high morbidity and mortality, especially in children and adolescents. Although these tumours are histologically, molecularly and genetically heterogeneous, they share a common involvement of the local microenvironment in their pathogenesis. This review gives a brief overview of their specificities and summarises the main therapeutic advances in the field of bone sarcoma.

Keywords: Chondrosarcoma; Clinical trials; Ewing sarcoma; Giant cell tumour of bone; Immunotherapy; Osteosarcoma; Tumour microenvironment.

Fig. 1

Origin of bone sarcomas. Based on the current knowledge, osteosarcoma, Ewing sarcoma and chondrosarcoma share a common mesenchymal origin. According to their differentiation level and in association with oncogenic events and an adapted microenvironment their common precursor, a “mesenchymal stem cell” could be transformed into an osteosarcoma, chondrosarcoma or an Ewing sarcoma. Sox9 Sry-related high-mobility group box (Sox) transcription factor 9 related to chondrogenic differentiation, Runx2 runt-related transcription factor 2 related to osteoblastogenesis, ALP alkaline phosphatase, OC osteocalcin, BSP bone sialoprotein

Fig. 2

The tumour microenvironment contributes to the control of bone sarcoma formation, their recurrence and associated metastatic process. The bone sarcoma microenvironment is composed of highly diversified cell populations forming specific local niches: vascular niche, immune niche, bone niche, muscular and pulmonary niches (e.g. metastatic niches), neuronal control and activity of neurotrophic factors. These various cell types establish a mutual dialogue with sarcoma cells through physical contact, the release of soluble factors or the formation of extracellular vesicles. All these communications will lead to strong alterations of the microenvironment (e.g. qualitative modifications of the extracellular matrix) and the behaviour of cancer cells, which increase their proliferation, and/or invasion/migration properties

Fig. 3

Recent on-going clinical trials in osteosarcoma. Numerous therapeutic approaches are in clinical development and are based on specific and direct targeting of cancer cells (e.g. DNA repair, cell cycle or glycoprotein targeting), or indirect targeting of cancer cells by modulation of their microenvironment (e.g. immunotherapies). After integration in extracellular tumour bone matrix, alpha radiotherapeutic agents can indirectly kill the cancer cells. NCT: National Clinical Trial NuClinicalTrials.gov registry Number

Fig. 4

Giant cell tumours of bone: a benign entity with malignant features. Giant cell tumours of bone are composed of three main cell populations: stromal cells, macrophages and multinucleated osteoclast-like cells. These tumours are responsible for a marked local bone resorption leading to the formation of large osteolytic foci easily detectable by X-ray radiography. RANKL/M-CSF and/or RANKL/IL-34 released by stromal cell could induce the differentiation of macrophages considered as osteoclast precursors towards immature and mature osteoclasts resorbing bone. Soluble OPG and membrane LGR4 are two receptors that negatively control osteoclastogenesis. OPG acts as a decoy receptor to RANK resulting in blocked RANKL–RANK interactions. LGR4 is expressed by osteoclasts and binds to RANKL leading to Gαq/GS3K-β signalling and repression of the NFATc1 molecular pathway. IL-34 Interleukin-34, LGR-4 G-protein-coupled receptor 4, M-CSF Macrophage Colony-Stimulating Factor, OPG osteoprotegerin, RANKL Receptor of Nuclear factor kappaB Ligand