Abstract
Osteosarcoma is the most common primary malignant bone tumor in children and young adults. The standard-of-care curative treatment for osteosarcoma utilizes doxorubicin, cisplatin, and high-dose methotrexate, a standard that has not changed in more than 40 years. The development of patient-specific therapies requires an in-depth understanding of the unique genetics and biology of the tumor. Here, we discuss the role of normal bone biology in osteosarcomagenesis, highlighting the factors that drive normal osteoblast production, as well as abnormal osteosarcoma development. We then describe the pathology and current standard of care of osteosarcoma. Given the complex heterogeneity of osteosarcoma tumors, we explore the development of novel therapeutics for osteosarcoma that encompass a series of molecular targets. This analysis of pathogenic mechanisms will shed light on promising avenues for future therapeutic research in osteosarcoma.
Highlights
Osteosarcomas are the most common pediatric and adult bone tumor, with more than 1000 new cases every year in the United States alone
The transformation of normal functioning bone cells into osteosarcoma has been demonstrated to occur at multiple levels in mesenchymal stem cell differentiation, whereby mesenchymal stem cells can transform directly into osteosarcoma, or can undergo various stages of differentiation into osteoblasts before becoming tumorigenic
Numerous factors that are involved in osteoblast differentiation can be overexpressed or dysregulated to drive abnormal bone production and osteosarcomagenesis
Summary
Osteosarcomas are the most common pediatric and adult bone tumor, with more than 1000 new cases every year in the United States alone. The various genetic, epigenetic, and environmental factors that drive mesenchymal stem cells to differentiate into bone precursor cells play a role in the development of osteosarcoma. These molecular pathways can serve as the foundation for the development of new therapies for this tumor [2]. Bone morphogenic proteins (BMPs) comprise a family of over 30 different proteins, including TGFβ family members, that regulate mesenchymal stem cell differentiation into osteoblasts by activating and inhibiting several genes that affect the expression of Runx and Sp7 [9]. Osteosarcomas are the most common bone tumor, consisting of 40–50% of bone sarcomas
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