Osteosarcoma is the most common primary malignancy of bone. It arises in bone during periods of rapid growth and primarily affects adolescents and young adults. The 5-year survival rate for osteosarcoma is 60%–70%, with no significant improvements in prognosis since the advent of multiagent chemotherapy. Diagnosis, staging, and surgical management of osteosarcoma remain focused on our anatomical understanding of the disease. As our knowledge of the molecular pathogenesis of osteosarcoma expands, potential therapeutic targets are being identified. A comprehensive understanding of these mechanisms is essential if we are to improve the prognosis of patients with osteosarcoma through tumour-targeted therapies. This paper will outline the pathogenic mechanisms of osteosarcoma oncogenesis and progression and will discuss some of the more frontline translational studies performed to date in search of novel, safer, and more targeted drugs for disease management. 1. Introduction Osteosarcoma is a relatively uncommon cancer although it is the most common primary malignancy to arise from bone. While incidence is low, osteosarcoma predominately affects adolescents and young adults, and if untreated it is fatal. Despite modern treatment protocols that combine chemotherapy, surgery, and sometimes radiotherapy, the 5-year survival rate for patients diagnosed with osteosarcoma remains at 60%–70% [1]. Current treatments for osteosarcoma are associated with significant morbidity, and a period of rehabilitation may be required following surgery for osteosarcoma. Hence, there is a real need to optimise current treatment strategies and to develop novel approaches for treating osteosarcoma. Traditionally, our understanding of osteosarcoma has been largely anatomical. Osteosarcoma arises most commonly in the metaphyseal region of long bones, within the medullary cavity, and penetrates the cortex of the bone to involve the surrounding soft tissues. A pseudocapsule forms around the penetrating tumour [2]. Histologically, osteosarcoma is characterised as a highly cellular tumour composed of pleomorphic spindle-shaped cells capable of producing an osteoid matrix. Current standards for staging and surgical resection rely on this anatomical knowledge [3]. However, recent developments in molecular biology have provided insight into the molecular pathogenesis of osteosarcoma. Through the identification of tumour pathways and specific mediators of osteosarcoma progression, novel approaches for targeting osteosarcoma are being developed. This paper will review our current understanding
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