Regulation of cell-cell adhesion and transcription in the ovary. Implicatons for tumorigenesis

Abstract

In this thesis the expression and localization of the epithelial (E)-cadherin/a- and b-catenin complex was investigated during the normal ovarian cycle and in ovarian tumors of epithelial origin. Furthermore, transcription factors (TFs) such as the proto-oncogene protein c-Myc was investigated for its time- and cell-specific expression during follicular development and the expression of CCAAT/enhancer binding proteins (C/EBPs) were investigated in ovarian tumors of epithelial origin.The development of ovarian follicles is a continuous process. Cyclic stimulation by hormones and growth factors will lead to proliferation and differentiation of granulosa cells (GCs) and theca cells (TCs). This follicular development also involves dramatic changes in the cell s morphology. Cells are held together by junctions i.e. tight-, adherens- (AJ) and gap-junctions. AJs, which are build up by the cadherin/catenin complex, are present between GCs of primary follicles but disappears in the fully developed preovulatory follicle. Regulation of E-cadherin at the transcriptional level could be managed by TFs such as c-Myc, C/EBPs and AP2. The ovarian surface epithelium (OSE) is the origin for approximately 90% of the malignant ovarian tumors. The tumors arise from the inclusioncysts, localized in the ovarian stroma, and grow solid, cystic or in mixed formations. Intra-abdominal spread of the ovarian cancer is common and this is a process closely connected with impaired cell-cell adhesion.In a rat model, where immature rats were stimulated by gonadotropins, normal development of follicles could be studied. Small primary follicles were found with positive E-cadherin and catenin staining. During proliferation and differentiation of the follicle, E-cadherin was only found in TCs and not in GCs, while the catenins were expressed in both celltypes. Just prior to ovulation, the staining of E-cadherin/catenin complex was decreased in the TCs. The E-cadherin protein was not found in OSE of normal ovaries but in inclusioncysts, as well as in benign and malignant ovarian tumors. The soluble form of E-cadherin was found in peripheral blood, cystic- and ascitic fluid. The concentrations were significantly increased in cystic fluids from patients with borderline and malignant tumors when compared to patients with benign adenomas. With a similar approach, as described for E-cadherin, the time and cell-specific expression of c-Myc mRNA and protein was analyzed in rat ovaries. The levels of c-Myc were found to be transiently elevated during the development of the preovulatory follicle. The LH-surge resulted in a rapid increase in c-Myc mRNA (after 1h) and c-Myc protein (after 2h). The change in c-Myc expression was mainly localized to the GCs. The expression of C/EBPs (a, b, d and z) were mainly seen in the epithelial cells of the normal human ovary and ovarian tumors. The most prominent finding in this study was the increased expression of C/EBPb in the nucleus of cells in ovarian adenocarcinoma as compared to the benign adenoma and the normal ovary.