[Analysis of the mechanism of trophoblast infiltration].

A cytotrophoblast (CT) infiltrates into the stroma, forming an extravillous trophoblast (EVT) in the placenta early in gestation and the phenomenon is strictly controlled, differing from the infiltration of cancer cells. The expression of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9), which deeply involve infiltrative metastasis of cancer, and the reactivity to transforming growth factor beta 1 (TGF beta 1), which controls the expression of these MMPs and inhibits the growth of epithelial cells, were investigated in CT derived from villi at normal gestational week 6 (early CT) and CT derived from villi at normal gestational week 37 (full-term CT), and also the choriocarcinoma cell line BeWo (BeWo). The ability of normal epithelial cells and BeWo cells to proliferate and infiltrate were evaluated in vitro by northern blotting, gelatin zymography, and invasion assay. It was revealed that early CT had a higher capacity for infiltration than full-term CT as well as BeWo. MMP2 and MMP9 appeared in the early CT, whereas only MMP9 was observed in the full-term CT. MMP2 and MMP9 were more abundantly observed in the early CT and the full-term CT rather than in BeWo. In uterine stroma-derived cells, membrane type matrix metalloproteinase (MT-MMP), which activates MMP2, was observed. These results indicated that the motility of normal villous cells was higher in the early CT than in the full-term CT. The expression of MMP2 in the early CT, which was not observed in the full-term CT, was thought to be related to this difference in motility. As for the responsiveness to TGF beta 1, which is a growth inhibiting factor for epithelial cells, the villous carcinoma cell line was insensitive to the growth inhibiting effect of TGF beta 1, but the early CT was sensitive to this effect. When TGF beta 1 was added, MMP2 and MMP9 increased in the early CT. This response was also seen in BeWo. That is, it was assured that the growth capacity was not inhibited in BeWo, but was certainly inhibited in the early CT. The overall results of these evaluations indicated that the development to EVT by infiltration of the early CT was associated with the increase in the mobility of cells caused by MMP2 and the increase in amounts of MMP2 and MMP9 caused by TGF beta 1, and the predominant inhibitory effect of TGF beta 1 on the growth of normal epithelial cells could explain why normal epithelial cells do not grow as cancer cells do.