Inhibitory effect of ectopic endometrium on the proliferation ovarian clear cell adenocarcinoma

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Abstract

Ovarian clear cell adenocarcinoma is often associated with pelvic endometriosis. In this study focusing on ectopic endometriotic lesions, we investigated how such lesions affect clear cell adenocarcinoma and what kinds of molecules are involved. Firstly, we evaluated clinicopathologic data of 75 cases of primary ovarian clear cell adenocarcinoma. The rate of patients with the carcinoma accompanied by pelvic endometriosis was 42.7%, and the 5-year survival rate was significantly greater in patients having ovarian clear cell adenocarcinoma with pelvic endometriosis (82.6%) than in those having the carcinoma without it (48.9%, p < 0.05). This phenomenon was supported by the fact that clear cell carcinoma with endometriosis showed significantly lower labelling index(L.I.)of proliferating cell nuclear antigen than that without one. By simultaneously heterotransplanting both RMG-I (an ovarian clear cell carcinoma cell line) and human endometrial tissue into SCID mice, we found the growth of the transplanted RMG-1 cells to be inlubited. BrdU labelling of RMG-1 heterotransplant revealed that its L.I. was also lower when RMG-I was transplanted together with endometrial tissue. Since the concentration of tranfoming growth factor-β1 (TGFβ1) in the chocolate-color contents of endometriotic cysts was approximately 10 tunes that in serum and this cytokine inhibited the proliferation of RMG-1 cells in vitro, unlike other cytokines such as interleukin (IL) 6, IL-8, and tumor necrosis factor-α,we investigated the expression of TGFβ1 in ectopic and eutopic endometrial tissues. An RNase protection assay revealed that the expression of TGFβ1 mRNA was a little higher in the ectopic endometrium than in the eutopic one, and immunohistochemical examination demonstrated that the intensity of the immunoreaction, which was seen mainly in glandular epithelial cells, was much stronger in the ectopic one. Additionally, urokinase-type plasminogen activator (u-PA), which converts plasminogen into plasmin, was strongly expressed in the ectopic endometriotic epithelium, but faintly in the eutopic one. These data suggest that the endometriotic lesion creates an environment where the active form of TGFβ1 may easily increase, because plasmin is one of the activators of latent TGFβ1. In order to know through which receptor TGFβ1 works on clear cell adenocarcinoma cells, we chose RMG-1 and HUOCA-II cells, both derived from clear cell adenocarcinoma, because the former expresses both TGFβ receptor type I(TβRII)and type H (TβRII), while the latter expresses TβRI only. TGFβ1 inhibited the growth of RMG-I cells and up-regulated the expression of cyclin-dependent kinase (Cdk) inhibitors p15 and p57 in a dose-dependent manner. However, HUOCA-II cells did not show such effects of TGFβ1. These results indicate that TβRI and TβRII are necessary for TGFβ1 to exhibit its effects and Cdk inhibitors such as p15 or p57 are involved with its inhibitory effects for cell proliferation. To investigate the significance of TβRI and TβRH expressed on clear cell adenocarcinoma, we carried out immunohistochemical examination of them and reviewed the clinicopathologic data. The 5-year survival rate of the patients with the clear cell adenocarcinoma showing high expression of TβRII(78%) was significantly greater than that of those having low expression of TβRII (42%). On the other hand, the various levels of TβRI-expression did not have any impact on the survival of the carcinoma. Univariate and multivariate analysis showed that earlier clinical stage, the co-existence of pelvic endometriosis and high Tβ Ru-expression could be regarded as prognostic indicators of increased survival of the patients with clear cell adenocarcinoma. hi view of data, we currently propose that a high level of production of TGFβ1 and an acceleration of its activation by plasmin in pelvic endometriotic lesions have an inhibitory effect on the proliferation of clear cell adenocarcinoma cells and consequently contribute to a more favorable prognosis of patients with clear cell adenocarcinoma accompanied by pelvic endometriosis.

Original languageEnglish
Pages (from-to)1150-1161
Number of pages12
JournalActa Obstetrica et Gynaecologica Japonica
Volume52
Issue number8
Publication statusPublished - 2000 Dec 1

Keywords

  • Clear cell adenocarcinoma
  • Ectopic endometrium
  • TGFβ receptor
  • TGFβ1
  • Urokinase type plasminogen activator

ASJC Scopus subject areas

  • Obstetrics and Gynaecology

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