Abstract: 254

MECHANISM OF INSULIN-LIKE GROWTH FACTOR (IGF)-II MEDIATED STIMULATION OF EXTRAVILLOUS TROPHOBLAST MIGRATION.

Timothy McKinnon¹ , Louise Gleeson¹ , Chandan Chakraborty¹ , Peeyush Lala^{1 *}
Dept. of Anatomy & Cell Biology, University of Western Ontario, London, Ontario, Canada ¹

It has been shown that invasive extravillous trophoblast (EVT) of the human placenta express IGF-II mRNA in situ. Earlier studies from this laboratory (Lysiak et al, 1994; Irving and Lala, 1995; Hamilton et al, 1998) showed that IGF-II stimulates migration and invasiveness of first trimester EVT cells in vitro without affecting their proliferation; that invasion stimulation was primarily due to enhanced migration rather than matrix degradation, and the effect was independent of IGF receptor type I (IGF R-1). The present study utilized first trimester EVT cells in culture and an in vitro TranswellŽ migration assay to test whether the migration stimulating effects of IGF-II were mediated by IGF R-II (mannose-6-phosphate receptor), independent of binding to IGFBPs, and whether the signals involved the MAPK pathway. Results revealed that : 1) EVT cells expressed IGF R-II as shown by immunostaining with a polyclonal antibody, 2) treatment with recombinant human IGF-II stimulated EVT cell migration in a dose-dependent manner, 3) treatment with both monoclonal and polyclonal IGF R-II blocking antibodies reduced EVT cell migration to subnormal levels and blocked the migration stimulation by exogenous IGF-II, 4) IGF-II analogues with preferential binding affinities for IGF R-II (Leu²⁷ IGF-II which binds to IGF R-II and IGFBPs but not IGF R-I, and QAYL-Leu²⁷ IGF-II which binds to IGF R-II but not IGF R-I or IGFBPs) also stimulated EVT cell migration, 5) pretreatment of EVT cells with the MEK inhibitor PD 098059 caused a significant decrease in migration in the presence or absence of IGF-II. These results suggest that IGF R-II plays a direct role in IGF-II mediated stimulation of migration of EVT cells by signaling via MAPK pathway. (Supported by MRC Canada)

    This abstract is being presented on Monday, August 2 at 8:00 AM to 10:15 AM at CUB 2nd Floor Ballroom.