FUNCTIONAL-ROLE OF CELL-SURFACE INTEGRINS ON HUMAN TROPHOBLAST CELL-MIGRATION - REGULATION BY TGF-BETA, IGF-II, AND IGFBP-1

Trophoblast invasion of the human uterus is stringently controlled by the microenvironment. Invasive extravillous trophoblast cells in situ as well as in culture express a selective repertoire of cell surface integrins. Since migration is a necessary step in the invasion cascade, we tested whether certain integrins or invasion-regulating molecules, i.e., TGF-beta, IGF-II, and IGFBP-1 produced at the fetomaternal interface had a functional role on trophoblast migration. Flow cytometric analysis of integrin expression and the use of an in vitro cell migration assay revealed that exogenous TGF-beta upregulates integrin expression and reduces migratory ability of the invasive trophoblast, whereas IGF-II has no effect on integrin expression but stimulates migration. Trophoblast migration was inhibited in the presence of alpha(5) and beta(1) integrin blocking antibodies, indicating its dependence on the expression of these subunits. Furthermore, IGFBP-1, which contains an RGD sequence recognizing certain integrins, stimulated migration, an effect that was blocked by pretreatment with anti-alpha(5) or -beta(1) blocking Abs. These studies demonstrate that the migration of first trimester invasive trophoblast in vitro (1) requires the expression of alpha(5) and beta(1) integrin subunits, (2) is inhibited by TGF-P, possibly due to increased cell adhesiveness to the extracellular matrix, (3) is stimulated by IGF-II by an as yet undetermined mechanism, and (4) is stimulated by IGFBP-1, likely by interaction with the RGD binding site of the alpha(5) beta(1) integrin. The invasion-regulating effects of TGF-beta, IGP-II, and IGFBP-1 may thus, at least in part, be due to their migration-regulating effects on the invasive trophoblast. (C) 1995 Academic Press, Inc.