Expression and action of transforming growth factor beta (TGFβ1, TGFβ2, TGFβ3) in normal bovine ovarian surface epithelium and implications for human ovarian cancer

The majority of ovarian tumors are derived from the single layer of epithelial cells on the surface of the ovary termed the ovarian surface epithelium (OSE). Stromal. cell-OSE interactions are postulated to be an important aspect of normal OSE biology and the biology of ovarian cancer. Transforming growth factor beta (TGF beta) has been shown to often be a mesenchymal cell-derived growth factor that mediates stromal cell-epithelial cell interactions in a variety of different tissues. The current study investigates the expression and action of TGF beta isoforms (TGF beta1, TGF beta2, and TGF beta3) in OSE and the underlying stroma in both normal bovine and human tumor tissues. Normal bovine ovaries are similar to human ovaries and are used as a model system to investigate normal OSE and stromal cell functions. All three TGF beta isoforms and their receptor, transforming growth factor beta receptor type It (TGF beta RII), proteins were found to be detected in the OSE from normal bovine ovaries using immunohistochemistry. Ovarian stromal tissue also contained positive immunostaining for TGF beta isoforms and TGF beta RII. RNA was collected from normal bovine OSE and ovarian stromal cells to examine TGF beta gene expression. TGF beta1, TGF beta2, and TGF beta3 transcripts were detected in both freshly isolated and cultured bovine OSE and stromal cells by a sensitive quantitative polymerase chain reaction assay. TGF beta1 and TGF beta2 mRNA levels were found to be present at similar levels in freshly isolated OSE and stroma. Interestingly, TGF beta3 mRNA levels were significantly higher in freshly isolated OSE than stromal cells. All but TGF beta3 mRNA in OSE increased when the cells were cultured. Observations indicate that normal bovine OSE and stroma cells express the three TGF beta isoforms in vivo and in vitro. Human ovarian tumors from stage II, stage III and stage IV cases were found to express TGF beta1, TGF beta2, TGF beta3 and TGF beta RII protein primarily in the epithelial cell component by immunohistochemistry analysis. The stromal cell component of the human ovarian tumors contained little or no TGF beta or TGF beta RII immunostaining. TGF beta actions on bovine OSE and stromal cells were also investigated. TGF beta was found to inhibit the growth of OSE, but not stromal cells. To further examine the actions of TGF beta on OSE, the expression of two growth factors previously shown to be expressed by OSE were analyzed. TGF beta1 was found to stimulate the expression of both keratinocyte growth factor (KGF) and kit ligand/stem cell factor (KL) by bovine OSE. Therefore, TGF beta actions on OSE will likely promote a cascade of cell-cell interactions and cellular responses involving multiple growth factors. The effects of regulatory agents on TGF beta expression by the bovine OSE were examined. Transforming growth factor alpha (TGF alpha) stimulated TGF beta1 expression. TGF beta1 stimulated TGF beta2 expression, and follicle stimulating hormone (FSH) stimulated TGF beta3 expression. These results demonstrate that TGF beta isoforms are regulated differently by the regulatory agents tested. In summary, all the TGF beta isoforms are differentially expressed by the OSE and TGF beta appears to have an important role in regulating OSE and possibly stromal-OSE interactions. A complex network of endocrine and paracrine interactions appears to influence the expression and actions of TGF beta on OSE. Abnormal expression and/or action of TGF beta is postulated to in part be involved in the onset and progression of ovarian cancer. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.