The association of transforming growth factor-beta 1 with myometrial invasion of endometrial carcinomas through effects on matrix metalloproteinase.
OBJECTIVE
The association of transforming growth factor-beta 1 (TGF-beta 1) 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-beta 1 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-beta 1 were measured by enzyme immunoassays. The immunohistochemical expression of MMP-9, TIMP-1, TGF-beta 1, and TGF-beta 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-beta 1. The expression of TGF-beta receptor Type I was higher in KLE cells than in Ishikawa cells, which were unresponsive to exogenous TGF-beta 1. The plasma levels of TGF-beta 1 were greater in Stage-Ib and Stage-Ic patients than in Stage-Ia patients. MMP-9 and TGF-beta receptor Type I were expressed mainly in tumor cells, while TIMP-1 and TGF-beta 1 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-beta 1 and TGF-beta receptor Type I were ubiquitous.


CONCLUSIONS
Myometrial invasion of endometrial cancers involves an increase in gelatinase activity, regulated to some extent by TGF-beta 1 in an autocrine or paracrine fashion.
Department of Obstetrics and Gynecology, Aichi Medical University, Japan.
H
H
Yabushita
H
H
Narumiya
K
K
Hiratake
H
H
Yamada
M
M
Shimazu
K
K
Sawaguchi
M
M
Noguchi
M
M
Nakanishi
D000230:Adenocarcinoma / Q000737:chemistry / Q000201:enzymology / Q000473:pathology*; D003110:Colonic Neoplasms / Q000737:chemistry / Q000473:pathology; D016889:Endometrial Neoplasms / Q000737:chemistry / Q000201:enzymology / Q000473:pathology*; D005260:Female; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009215:Myometrium / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000097:blood* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018125:Receptors, Transforming Growth Factor beta; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D018093:Gelatinases; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9