Following binding to its receptors, transforming growth factor-β (TGF-β) signals mainly through Smad3/4 proteins that act as transcription factors following nuclear translocation in both osteosarcoma cells and its microenvironment, promoting osteolysis, angiogenesis, and metastases (for review, see [111]). The gene discussed is TGFB1; the disease is osteosarcoma.