Several sarcoma fusion genes and other molecular anomalies have been shown to upregulate ligand (IGF-1 or IGF-2) or receptor (IGF-1R) expression and, in ES, to downregulation of IGFBP-3 (Table 4) The IGF system, particularly the IGF-1R, has been validated both in vitro and in experimental animal models as a central participant in the induction of malignant transformation in ES, RMS, leiomyosarcoma (LMS), and other sarcomas. This evidence concerns the gene IGF1R and leiomyosarcoma.