Insulin-like growth factor binding protein 3 as an anticancer molecule in Ewing's sarcoma

The IGF/IGF-IR system plays a major role in the pathogenesis and progression of Ewing's sarcoma. In this article, the authors evaluated whether the insulin-like growth factor binding protein-3 (IGFBP-3), a molecule with growth-inhibitory and proapoptotic activities, may be exploited for therapeutic applications in the treatment of Ewing's sarcoma (EWS). Expression of IGFBP-3 was analyzed in a panel of EWS cell lines and clinical samples. Parameters related to malignancy (growth in anchorage-independent conditions, migration, invasion and angiogenesis properties) were studied to establish the potential in vitro anticancer effects of exogenous IGFBP-3. The activity of the molecule against metastasis was analyzed by taking advantage of selected clones in which IGFBP-3 endogenous production was induced by gene transfection. The authors observed a generally low expression of IGFBP-3 either in a panel of EWS cell lines or clinical samples. Exogenous IGFBP-3 remarkably inhibits EWS growth, both in monolayer and anchorage-independent conditions, and significantly reduces cell motility. Forced expression of IGFBP-3 in TC-71 EWS cells confirms the growth and migratory effects observed with the exogenous protein, decreases the production or activity of the matrixmetalloprotease MMP-9 and vascular endothelial factor (VEGF)-A and abrogates EWS metastasis ability. IGFBP-3 acts mainly through IGF-dependent mechanisms and the protein may therefore represent an alternative strategy to inhibit IGF-IR functions. The data indicate IGFBP-3 as a molecule of therapeutic potential in EWS.