The Association of Transforming Growth Factor‐β1 with Myometrial Invasion of Endometrial Carcinomas through Effects on Matrix Metalloproteinase

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Abstract
Objective: The association of transforming growth factor‐β1 (TGF‐β1) with a matrix metalloproteinase (MMP) and a tissue inhibitor of metalloproteinase (TIMP), as well as myometrial invasion of endometrial cancer was studied. Methods: The effects of TGF‐β1 on cellular invasiveness, gelatinase activity, and expression of TIMP‐1 were examined in 2 endometrial adenocarcinoma cell lines, KLE and Ishikawa. Plasma was obtained from 8 endometrial cancer patients with Stage‐Ia disease, from 6 with Stage‐Ib disease, and from 4 with Stage‐Ic disease, and the levels of TGF‐β1 were measured by enzyme immunoassays. The immunohistochemical expression of MMP‐9, TIMP‐1, TGF‐β1, and TGF‐β receptor Type I in tumor tissue from the same patients also was detected. Results: Invasiveness, gelatinase activity, and the expression of TIMP‐1 were higher in KLE cells than in Ishikawa cells, and they were increased by treatment with rTGF‐β1. The expression of TGF‐β receptor Type I was higher in KLE cells than in Ishikawa cells, which were unresponsive to exogenous TGF‐β1. The plasma levels of TGF‐β1 were greater in Stage‐Ib and Stage‐Ic patients than in Stage‐Ia patients. MMP‐9 and TGF‐β receptor Type I were expressed mainly in tumor cells, while TIMP‐1 and TGF‐β1 were localized in both tumor epithelial cells and stromal cells. MMP‐9 and TIMP‐1 were expressed only in Stage‐Ib and Stage‐Ic patients, although TGF‐β1 and TGF‐β receptor Type I were ubiquitous. Conclusions: Myometrial invasion of endometrial cancers involves an increase in gelatinase activity, regulated to some extent by TGF‐β1 in an autocrine or paracrine fashion.

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