トロフォブラストの浸潤に関するメカニズムの解析  [in Japanese] Analysis of the Mechanism of Trophoblast Infiltration  [in Japanese]

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Abstract

正常初期絨毛においてcytotrophoblast (以下CTと略す)は間質組織に浸潤していわゆるextravillous trophoblast (以下EVTと略す)という形態をとる. しかし, そのメカニズムは癌細胞の浸潤とは異なり厳密に管理されていると考えられるが詳細は明らかではない. そこで, トロフォブラストの浸潤に関するメカニズムを解明するために, 癌の浸潤, 転移に深く関与しているmatrix metalloproteinase 2, matrix metalloproteinase 9 (以下MMP2, MMP9と略す)の発現とこれらMMPsの発現を調節し上皮細胞に対して増殖抑制作用を示すTransforming growth factorβ1 (以下TGFβ1と略す)に対する反応性を, 正常妊娠6週絨毛由来CT(以下初期CTと略す), 正常妊娠37週絨毛由来CT (以下満期CTと略す)とchoriocarcinoma cell line BeWo (以下BeWoと略す)を用いて検討した. それぞれの細胞がもつin vitroでの増殖能や浸潤能を, northern blotting法, gelatin zymography法, およびinvasion assay法を用いて解析した. 初期CTは, 満期CTに比べ高い浸潤能を有していた. この初期CTの浸潤能はBeWoと同じ程度であった. 初期CTはMMP2とMMP9の発現を認めたが, 満期CTではMMP9のみの発現しか観察されなかった. またMMP2を活性化するmembrane type matrix metalloproteinase (以下MT-MMPと略す)の発現が子宮間質由来細胞に認められた. このことは初期CTが間質細胞と接触することによリMMP2の活性化がおこり浸潤を促進すると考えられる. これらのことにより, in vivoやin vitroでの浸潤能の違いはMMP2が関与している可能性が示唆された. BeWoではTGFβ1のもつ増殖抑制作用に非感受性であり増殖が抑制されず, 初期CTではTGFβ1のもつ増殖抑制作用に感受性が認められ増殖の抑制が観察された. 初期CTでは, TGFβ1を添加するとMMP2やMMP9の増加が観察された. そしてこの反応性はBeWoでも同様であった. したがって初期CTが浸潤しEVTとなる機構には, MMP2による細胞の運動能の亢進やTGFβ1によるMMP2, MMP9の増加が関係しているが, 癌細胞のように増殖しないのは, TGFβ1による増殖抑制作用を優位に受けることが関与していると推測された.

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 betal (TGFβ1), 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 TGFβ1, which is a growth inhibiting factor for epithelial cells, the villous carcinoma cell line was insensitive to the growth inhibiting effect of TGFβ1, but the early CT was sensitive to this effect. When TGFβ1 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 TGFβ1, and the predominant inhibitory effect of TGFβ1 on the growth of normal epithelial cells could explain why normal epithelial cells do not grow as cancer cells do.

Journal

  • 日本産科婦人科學會雜誌

    日本産科婦人科學會雜誌 48(3), 191-198, 1996-03-01

    日本産科婦人科学会

References:  21

Cited by:  2

Codes

  • NII Article ID (NAID)
    110002111840
  • NII NACSIS-CAT ID (NCID)
    AN00190060
  • Text Lang
    JPN
  • Article Type
    Journal Article
  • ISSN
    03009165
  • Data Source
    CJP  CJPref  NII-ELS  NDL-Digital 
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