HUMAN CYTOTROPHOBLAST INVASION IS UP-REGULATED BY EPIDERMAL GROWTH-FACTOR - EVIDENCE THAT PARACRINE FACTORS MODIFY THIS PROCESS

Formation of the human placenta requires a subset of cytotrophoblast s tem cells to acquire an invasive phenotype. We examined the effect on cytotrophoblast invasiveness of growth factors that control the differ entiation of other cells. Exogenous TGF-beta 1, PDGF-AA, PDGF-BB, and TNF-alpha affected neither cell morphology nor the rate of cytotrophob last invasion in vitro. In contrast, addition of EGF to first trimeste r cytotrophoblast cultures produced dramatic changes in morphology and a severalfold increase in invasive capacity. The effects of EGF on la ter gestation cytotrophoblasts, whose invasive capacity is diminished, were much less pronounced. Next we investigated whether cytotrophobla sts themselves produce ligands that interact with the EGF receptor. A radioimmunoassay and a radioreceptor assay failed to detect EGF recept or ligands in cytotrophoblast-conditioned medium. Likewise, by RT-PCR cytotrophoblasts expressed neither EGF nor TGF-alpha mRNA. In contrast , EGF receptor mRNA was expressed and its protein levels remained cons tant during the experiment. Immunolocalization using F(ab') fragments of an anti-human EGF antibody failed to detect this growth factor in t he chorionic villus. We conclude that maternal ligands that interact w ith the EGF receptor could play an important role by up-regulating tro phoblast invasion, particularly during the early stages of pregnancy. (C) 1994 Academic Press, Inc.