GROWTH ADVANTAGE OF HUMAN LEIOMYOMA CELLS COMPARED TO NORMAL SMOOTH-MUSCLE CELLS DUE TO ENHANCED SENSITIVITY TOWARD INSULIN-LIKE GROWTH-FACTOR-I

Human uterine leiomyomas exhibit increased IGF-I binding compared to m yometrium, while both tissues show IGF-I gene expression. In this stud y we have examined the functional importance of these findings by test ing the presence of IGF-I in 15 leiomyoma biopsies and in 18 myometriu m biopsies and the capacity of smooth-muscle cells cultured from these tissues to react to IGF-1 The mean IGF-I peptide concentration in lei omyomas was 3 times higher than in myometrium. This resulted from incr eased IGF-I uptake in leiomyomas rather than from increased synthesis, as these tissues contain higher concentrations of type-I IGF receptor s, as detected by immunohistochemistry, and equal levels of IGF-I mRNA . Blocking IGF-I transport with cytochalasin-B and with the type-I IGF receptor blocking antibody alpha IR3 in cultured cells induced decrea sed immunostaining intensity for IGF-I in most myometrium and leiomyom a cultures, indicating that the detected IGF-I is internalized. Depend ing on the culture conditions, IGF-I administration yielded increased survival or a higher proliferation rate in leiomyoma cultures than in myometrium cultures, indicating the increased importance of exogenous IGF-I for the growth of transformed smooth-muscle cells. We conclude t hat the increased concentrations of type-I IGF receptors in leiomyoma compared to myometrial smooth-muscle cells are functional with respect to the enhanced internalization of IGF-I and that they provide these tumor cells with a growth advantage compared to their normal counterpa rts. (C) 1994 Wiley-Liss, Inc.