Novel Signaling Pathways in Osteosarcoma

Abstract

Osteosarcomas are the most common primary malignant bone tumors. Major advances in the treatment of osteosarcoma (OS) have revolutionized their clinical and surgical care. Despite these improvements, no specific targeted therapy has yet been employed for OS treatment. The present review will outline significant cytokine signaling pathways important in OS tumor biology, including the Bone morphogenetic protein (BMP), Hedgehog, and Wnt signaling pathways. Also discussed are the inherent challenges in studying cytokine signaling in OS, including the diversity in tumor location, grade, and lines of differentiation. Multiple BMP ligands and receptors are expressed across most OS cell lines and OS subtypes. Available data suggest that BMP signaling has pro-migratory effects in OS cells, as in the case with other sarcomas. Activation of Hedgehog and Wnt signaling has been observed in OS cell lines and/or primary human OS specimens. Emerging data suggests that Wnt signaling inhibition may prevent osteosarcomagenesis and/or sensitize OS cells to traditional chemotherapeutic agents. Likewise, interference with Hedgehog signaling transduction may reduce OS cell proliferation and in vivo tumor growth. In summary, multiple signaling factors show preclinical promise for cell targeted therapy in osteosarcoma.