Strong Opponents: Overcoming Obstacles of Osteosarcoma Metastatic Adaptation in the Lungs

Osteosarcoma (OS) five-year survival rates drop from approximately 70% to 20% when it has metastasized to the lungs. Thus, there is an urgent need to understand the processes that allow these cancer cells to metastasize. In particular, it is critical to identify how the premetastatic niche is formed and how the cancer cells adapt to the lung microenvironment. This review paper surveys the current literature on the mechanisms of this. Here we describe the role of driver mutations, cancer-associated fibroblasts, extracellular matrix stiffness, extracellular signaling, and other mechanisms contributing to metastasis. OS tumor cells secrete the molecules CXCL14, TRIM66, and Tim-3 to generate alterations to the tumor microenvironment that facilitate lung metastasis through epithelial-to-mesenchymal transition and actomyosin contractility. The activity of the MAPK and Wnt signaling pathways have been shown to correlate with the dysregulation of necessary normal processes including cell apoptosis, proliferation, and tissue homeostasis. These mechanisms can help inform future therapies targeting these essential components of OS lung metastasis.