Mechanism of control of trophoblast invasion in situ.
We have previously shown that first trimester human trophoblast cells share in vitro invasive properties with malignant cells. In this study we show that the in situ control of trophoblast invasion is provided by the uterine microenvironment. Trophoblast cells were labeled with 125I-deoxyuridine and examined for their ability to invade an epithelium-free human amniotic membrane in vitro under various conditions. The degree of invasion was determined as the percentage of the radioactivity retained within the membrane. Conditioned media from first trimester human decidual cells (DCM) suppressed invasion of trophoblast cells in the amnion invasion assay. This suppression was prevented by addition of neutralizing anti-TGF beta antibody or neutralizing antibody to tissue inhibitor of metalloproteinases (TIMP-1) to the DCM, and mimicked by TGF beta 1. These antibodies also augmented invasion beyond control levels, suggesting that trophoblast cells may also produce these factors. A bioassay for TGF beta activity, measured by antiproliferative effect on the mink lung epithelial cell line Mv 1 Lu, revealed that decidual cells produced this factor only in the latent form, whereas the active form was produced by the trophoblast. A decrease in collagenase type IV activity in the conditioned media of trophoblast cultures was observed when TGF beta 1 was added to these cultures. Removal of endogenous TGF beta in trophoblast cultures by addition of anti-TGF beta antibody resulted in down-regulation of TIMP message as determined by Northern analysis. These results indicate that a) decidua-derived (and to a minor extent trophoblast-derived) TGF beta is the prime mediator in the control of invasion by first trimester trophoblast, the latent form of TGF beta likely being activated by trophoblast-derived proteinases; b) induction of TIMP by TGF beta in both trophoblast and decidua is the final pathway in this control.
Graham
C H
CH
Department of Anatomy, University of Western Ontario, London, Canada.
Lala
P K
PK
D000906:Antibodies; D002478:Cells, Cultured; D017364:Collagenases; D003470:Culture Media; D003656:Decidua / Q000166:cytology / Q000502:physiology*; D004792:Enzyme Precursors / Q000235:genetics; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D020780:Matrix Metalloproteinase 9; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D014327:Trophoblasts / Q000502:physiology*
D000906:Antibodies; D003470:Culture Media; D004792:Enzyme Precursors; D006023:Glycoproteins; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D017364:Collagenases; C022440:procollagenase; D003012:Microbial Collagenase; D020780:Matrix Metalloproteinase 9