Abstract
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. © 2006 Wiley‐Liss, Inc.