AUTOCRINE-PARACRINE REGULATION OF HUMAN TROPHOBLAST INVASIVENESS BY INSULIN-LIKE-GROWTH-FACTOR (IGF)-II AND IGF-BINDING PROTEIN (IGFBP)-1

Trophoblast growth and invasion of the uterus are tightly regulated by locally produced factors. Since insulin-like growth factor (IGF)-II i s produced by the invasive human extravillous trophoblast (EVT) cells and IGF-binding protein (IGFBP)-1 by the decidual cells in situ that a re in proximity to each other, we examined the possible influence of t hese molecules on proliferation, migration, and invasiveness of first- trimester EVT cells in culture. These EVT cell functions were respecti vely measured by H-3-TdR uptake, in vitro migration, and invasion assa ys. Secretion of invasion-associated enzymes was assessed by zymograph y, and IGF-binding moieties on the EVT cell were examined by affinity crosslinking. Proliferation of serum-starved EVT cells was stimulated by addition of serum but unaffected by a wide range of IGF-I, IGF-II, and IGFBP-1 concentrations. IGF-II and IGFBP-1 or their combination st imulated EVT cell invasiveness and migration, when assays were conduct ed in serum-reduced media. Affinity cross-linking studies failed to de tect the type 1 IGF receptor, although several IGF-II-specific and IGF -II-preferring binding molecules including type 2 IGF receptor were id entified on the EVT cell surface. IGF-II enhancement of invasion was u naffected in the presence of IGF-1 receptor-blocking antibody and IGF- 1 failed to influence EVT cell invasion, indicating that type 1 IGF re ceptor was not responsible for the IGF-II effects. Secretion of gelati nases or plasminogen activators was unaltered by IGF-II or IGFBP-1. We conclude that trophoblast-derived IGF-II and decidua-derived IGFBP-1 provide autocrine/paracrine enhancement of trophoblast invasiveness la rgely by stimulating migration, an essential step in invasion. (C) 198 8 Academic Press.