The expression and action of granulocyte macrophage-colony stimulating factor and its interaction with TGF-β in endometrial carcinoma

Objective, Previous studies have demonstrated that normal human endometrium expresses granulocyte macrophage-colony stimulating factor (GM-CSF) and GM-CSF receptors. Because GM-CSF is administer to cancer patients following chemotherapy, GM-CSF may directly or through interaction with ovarian steroids and other cytokines alter the behavior of endometrial cancer. The aim of this study was to determine the expression of GM-CSF and receptors in endometrial carcinoma and its direct effect and interaction with transforming growth factor beta (TGF-beta) on Ishikawa cells, a human endometrial carcinoma cell line. Methods. GM-CSF, GM-CSF receptors, TGF-beta1, and TGF-beta type II receptor expression were evaluated using quantitative reverse transcription polymerase chain reaction (Q-RT-PCR), The effect of GM-CSF on DNA synthesis, cell proliferation, expression of GM-CSF, TGF-beta1, and TGF-beta receptor, and their regulation by ovarian steroids was determined by the rate of [H-3]thymidine incorporation, MTT assay, Q-RT-PCR, and ELISA, respectively. Results. Endometrial carcinomas express significantly higher GM-CSF and GM-CSF alpha and beta receptor mRNA compared with normal postmenopausal endometrium. GM-CSF at various doses had no significant effect on the rate of [H-3]thymidine incorporation or proliferation of Ishikawa cells, whereas TGF-beta1 inhibited [H-3]thymidine incorporation. GM-CSF and TGF-beta1 regulate their own expression and the expression of TGF-beta type II receptor, which were both upregulated by 17 beta -estradiol and medroxyprogesterone acetate treatment and reversed following cotreatment with their respective receptor antagonists. Conclusion. Endometrial carcinoma expresses an elevated level of GM-CSF and GM-CSF receptors, GM-CSF is not a mitogen for the endometrial cancer cell line; however, either alone or through interaction with TGF-beta1, it regulates its own expression and the expression of TGF-beta1 and TGF-beta type II receptor which inhabits endometrial cancer cells. This interaction may represent a regulatory feedback mechanism that could serve to suppress endometrial carcinoma growth. (C) 2001 Academic Press.