Abstract
Osteosarcoma is the most frequent primary bone tumor diagnosed during adolescence and young adulthood. It is associated with the worst outcomes in the case of poor response to chemotherapy and in metastatic disease. While no molecular biomarkers are clearly and currently associated with those worse situations, the study of pathways involved in the high level of tumor necrosis and in the immune/metabolic intra-tumor environment seems to be a way to understand these resistant and progressive osteosarcomas. In this review, we provide an updated overview of the role of hypoxia in osteosarcoma oncogenesis, progression and during treatment. We describe the role of normoxic/hypoxic environment in normal tissues, bones and osteosarcomas to understand their role and to estimate their druggability. We focus particularly on the role of intra-tumor hypoxia in osteosarcoma cell resistance to treatments and its impact in its endogenous immune component. Together, these previously published observations conduct us to present potential perspectives on the use of therapies targeting hypoxia pathways. These therapies could afford new treatment approaches in this bone cancer. Nevertheless, to study the osteosarcoma cell druggability, we now need specific in vitro models closely mimicking the tumor, its intra-tumor hypoxia and the immune microenvironment to more accurately predict treatment efficacy and be complementary to mouse models.
Highlights
The overall survival (OS) of osteosarcoma (OTS) patients has remained stable for three decades.For that reason, it is important to find new therapeutic strategies and new biomarkers to be able to predict the outcome and refine the prognosis of those children from the diagnosis
A rate of less than 10% viable cells is the witness of good histological response (GR): grade III GRs have less than 10% residual tumor cells and grade IV GRs have a complete tumor necrosis
M2 macrophages, instead, are activated by anti-inflammatory cytokines and the PI3K/AKT/mTOR pathway, and exert immunosuppressive effects associated with enhanced angiogenesis and tumor progression, pushing OTS cells in stemness status [78,82,83]
Summary
The overall survival (OS) of osteosarcoma (OTS) patients has remained stable for three decades. 23% of the patients will have already visible metastases, which are located for more than two-thirds of the cases in the lungs and 16% in bones [4,5] This bone cancer is known as a highly necrotic tumor even at diagnosis, where this histological feature is frequently observed on biopsies. This necrosis might be the consequence of the excessive and rapid growth of cancer cells, which are proficient in creating a hypoxic microenvironment [6,7] and an abnormal neoangiogenesis [8,9]. The hypoxic level can be probably defined in tumors and OTS as the rate of oxygen, which is below physiological oxygen concentration, less than 9% (Figure 1) This hypoxia directly induces the overexpression of hypoxia-inducible factors (HIFs).
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