MODULATION OF INSULIN-LIKE GROWTH-FACTOR (IGF) ACTION BY IGF-BINDING PROTEINS IN NORMAL, BENIGN, AND MALIGNANT SMOOTH-MUSCLE TISSUES

The insulin-like growth factor (IGF) system is involved in the growth of uterine leiomyomas (L), as these tumors have higher IGF-II messenge r ribonucleic acid levels, type I IGF receptor levels, and IGF-I pepti de concentrations than myometrium (M). Furthermore, cultured L smooth muscle cells (SMC) respond with greater efficiency to IGF-I than M SMC . Here we investigate a possible modulating role of the binding protei ns for the IGFs (IGFBPs) on the actions of IGFs. IGFBP-3 is the most p redominant IGFBP in conditioned medium from SMC, with. levels ranging from 13-288 ng/mL. Incubation of SMC cultures with IGF-I and the IGF-I analogs long-R(3)IGF-I and des (1-3)-IGF-I, which have decreased affi nity for IGFBPs, revealed a facilitating effect of IGFBPs on the growt h-stimulating activity of a high concentration of IGF-I in cell lines with high IGFBP-3 levels. Both a decreased level of IGFBP-3 and a low concentration of the growth factors added were a disadvantage for the facilitating effect. In M and L tissue sections, IGFBP-3 was found exc lusively bound to the constituting cells, not in the extracellular mat rix. This suggests that a negative modulating role of IGFBP-3 due to s equestration of IGF-I, as occurs in culture medium, is less relevant i n vivo. In leiomyosarcoma sections, IGFBP-3 levels are decreased, indi cating a decreasing role for this binding protein in malignant smooth muscle tissues.