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Results for “ovarian surface epithelium”

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PubMed1999

E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium.

Ovarian carcinomas are thought to arise in the ovarian surface epithelium (OSE). Although this tissue forms a simple epithelial covering on the ovarian surface, OSE cells exhibit some mesenchymal characteristics and contain little or no E-cadherin. However, E-cadherin is present in metaplastic OSE cells that resemble the more complex epithelia of the oviduct, endometrium and endocervix, and in primary epithelial ovarian carcinomas. To determine whether E-cadherin was a cause or consequence of OSE metaplasia, we expressed this cell-adhesion molecule in simian virus 40-immortalized OSE cells. In these cells the exogenous E-cadherin, all three catenins, and F-actin localized at sites of cell-cell contact, indicating the formation of functional adherens junctions. Unlike the parent OSE cell line, which had undergone a typical mesenchymal transformation in culture, E-cadherin-expressing cells contained cytokeratins and the tight-junction protein occludin. They also formed cobblestone monolayers in two-dimensional culture and simple epithelia in three-dimensional culture that produced CA125 and shed it into the culture medium. CA125 is a normal epithelial-differentiation product of the oviduct, endometrium, and endocervix, but not of normal OSE. It is also a tumor antigen that is produced by ovarian neoplasms and by metaplastic OSE. Thus, E-cadherin restored some normal characteristics of OSE, such as keratin, and it also induced epithelial-differentiation markers associated with weakly preneoplastic, metaplastic OSE and OSE-derived primary carcinomas. The results suggest an unexpected role for E-cadherin in ovarian neoplastic progression.

Actins↗

PubMed2006

Structural changes and cell properties of human ovarian surface epithelium in ovarian pathophysiology.

The surface epithelial cells of the ovary, which are modified peritoneal cells, form a single, focally pseudostratified layer. The Müllerian ducts differentiate after invagination of the coelomic mesothelium over the gonadal ridges during the 6th week of embryonic life. On the basis of the embryologically putative Müllerian potential of this epithelium, endometriosis can be explained by coelomic metaplasia from the peritoneum, including ovarian surface epithelium. Some pelvic endometriosis specimens have shown that epithelial cells on the ovary or pelvis are serially changed to endometriotic gland cells. Immunohistochemistry as well as scanning electron microscopy also reinforce the light-microscopical findings. A three-dimensional culture system demonstrated that human ovarian surface epithelial cells exhibited a glandular-stromal structure when they were cocultured with endometrial stromal cells in an estrogen-rich environment. Ovarian carcinomas in the epithelial-stromal category are thought to arise from the surface epithelium and its inclusions. The ovarian surface epithelium is physiologically involved in follicular rupture, oocyte release, and the subsequent repair of follicle wall during reproductive age. Simultaneously, ovulation may cause a loss of integrity of the surface epithelium, followed by accumulation of multiple mutations. The cortical invagination, surface stromal proliferation, and Müllerian differentiation of these cells are likely not to be an early step in the cancer development. However, the inclusion cysts are closely related with carcinogenesis because they are significantly more common in ovaries contralateral to those containing epithelial cancers than in control ovaries. As an in vitro study, ovarian carcinoma cell lines were established from simian virus 40 large T antigen-transformed human surface epithelial cells of the ovary. Further investigations of these cell lines may lead to insights into the preneoplastic and early stages of carcinomas. To clarify the pathogenesis of endometriosis and epithelial ovarian cancer, specifically designed studies of ovarian surface epithelium are required.

Endometriosis↗

PubMed1990

A simplified method to culture human ovarian surface epithelium.

The ovarian surface epithelium (OSE) is thought to give rise to over 85% of human ovarian carcinomas. In spite of its clinical importance, no animal models for the in vivo investigation of this tissue exist, and available culture methods have yielded limited success. In this study, OSE cells from 55 normal ovarian biopsy specimens were used to improve and simplify the methodology for OSE culture and to define the influence of clinical parameters on cultured OSE cells. An improved explanation method was developed which takes advantage of the tenuous attachment of OSE to underlying tissues: the surface epithelium was scraped off the ovarian surface with a rubber scraper, generating epithelial fragments which produced monolayers in culture, with little contamination by other cell types. The scrape method is superior to the explant method previously described (Siemens CH, Auersperg N: J Cell Physiol 134:347, 1988) in terms of speed, simplicity, higher purity of cultures, and increased cell yield. An improved nutrient medium (199/MCDB105/15%FBS) resulted in OSE lines that maintained the original epithelial phenotype for up to 12 population doublings. OSE, detached from the ovary, remained viable if frozen in liquid nitrogen either before culture or in primary culture on strips of plastic, providing OSE independently of the availability of surgical specimens. Growth was not influenced by diagnosis (nonmalignant gynecologic disorders), patient age (mean range: 40.5, 20 to 62 years), or the presence of inclusion cysts or large follicles in the biopsy specimen. This culture system provides conditions for in depth studies of OSE physiology and pathology.

Adult↗

PubMed2006

Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid by gonadotropins in human immortalized ovarian surface epithelium and ovarian cancer cells.

Although gonadotropin-releasing hormone (GnRH) has been shown to play a role as an autocrine/ paracrine regulator of cell growth in ovarian surface epithelium and ovarian cancer, the factors which regulate the expression of GnRH and its receptor in these cells are not well characterized. In the present study, we employed real-time PCR to determine the potential regulatory effect of gonadotropins on the expression levels of GnRH I (the mammalian GnRH), GnRH II (a second form of GnRH) and their common receptor (GnRHR) in immortalized ovarian surface epithelial (IOSE-80 and IOSE-80PC) cells and ovarian cancer cell lines (A2780, BG-1, CaOV-3, OVCAR-3 and SKOV-3). The cells were treated with increasing concentrations (100 and 1000 ng/ml) of recombinant follicle-stimulating hormone (FSH) or luteinizing hormone (LH) for 24 h. Treatment with FSH or LH reduced GnRH II mRNA levels in both IOSE cell lines and in three out of five ovarian cancer cell lines (A2780, BG-1 and OVCAR-3). A significant decrease in GnRHR mRNA levels was observed in IOSE and ovarian cancer cells, except CaOV-3 cells, following treatment with FSH or LH. In contrast, treatment with either FSH or LH had no effect on GnRH I mRNA levels in these cells, suggesting that gonadotropins regulate the two forms of GnRH and its receptor differentially. In separate experiments, the effect of gonadotropins on the anti-proliferative action of GnRH I and GnRH II agonists in IOSE-80, OVCAR-3 and SKOV-3 cells was investigated. The cells were pretreated with FSH or LH (100 ng/ml) for 24 h after which they were treated with either GnRH I or GnRH II (100 ng/ml) for 2 days, and cell growth was assessed by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide] assay. Pretreatment of the cells with FSH or LH significantly reversed the growth inhibitory effect of GnRH I and GnRH II agonists in these cell types. These results provide the first demonstration of a potential interaction between gonadotropins and the GnRH system in the growth regulation of normal ovarian surface epithelium and its neoplastic counterparts.

Epithelium↗

PubMed1994

Isolation, growth and characteristics of human ovarian surface epithelium.

The ovarian surface epithelium (OSE) is a key tissue in the pathogenesis of ovarian surface epithelial-stromal tumours and ovarian endometriosis, commonly encountered gynaecological diseases. Despite the high incidence of these diseases, experimental in vitro studies of OSE are few and so we used the scraping method with an enzymatic procedure to isolate human OSE and studied its characteristics in vitro. Nineteen normal ovaries were used. After incubation of the ovary for 40 min in collagenase type 1 solution (300 U/ml), the surface cells were removed by gentle scraping with a surgical blade. Cells obtained as a cluster after unit gravity sedimentation with 5% bovine serum albumin in medium 199 were cultured in medium 199 containing 15% fetal bovine serum. The viable cell number in a single ovary was 0.1-2.7 x 10(6). The outgrowth of cells started from a homogeneous population of single cells, and the cell population doubling time was between 7 and 10 days. Confluent monolayers were formed after 13-20 days and subcultured from one to three times. The monolayers mostly had a cobblestone appearance, and fusiform or polygonal cells were also observed. By cytochemistry, immunocytochemistry and scanning and transmission electron microscopy, the cells were shown to have characteristics of mesothelial OSE cells in short-term culture. This experimental approach was efficient in providing cultured human OSE, which can be utilized to investigate pathobiology and carcinogenesis.

Adult↗

PubMed2004

Effects of epidermal growth factor/hydrocortisone on the growth and differentiation of human ovarian surface epithelium.

OBJECTIVE: Ovarian surface epithelium (OSE), the precursor of the epithelial ovarian carcinomas, has limited growth potential in culture. Epidermal growth factor+hydrocortisone (EGF+HC) enhances its growth but induces epitheliomesenchymal transition (EMT). This study was undertaken to define the effects of EGF+HC and their reversibility, to optimize growth-promoting media, and to relate OSE phenotypes in vitro to physiologic states in vivo. METHODS: OSE was cultured in media 199/MDCB105 or EBM (Clonetics) with 2% or 10% fetal bovine serum with or without 10 ng/mL EGF, 1.0 microg/mL HC, and 1.0 microg/mL bovine brain extract. Growth rates and growth potentials (population doublings [PD] to senescence) were defined, and growth patterns and expression of keratin and collagen types III and IV were compared with the ovarian cancer cell lines OVCAR3 and SKOV3. RESULTS: EGF+HC increased growth potentials from 12-14 PD to 40-42 PD and reduced PD time from 53 hours to 20 hours. Without EGF+HC, OSE cells remained uniformly epithelial. EGF+HC induced EMT (mesenchymal shapes, reduced keratin, and production of collagenous extracellular matrix), but the EMT response varied greatly among OSE from different women. EMT was reversed over 1-2 weeks by subculture into EGF+HC-free medium in passage 1, but inconsistently thereafter. EGF+HC had no effect on the differentiation of ovarian carcinoma lines. CONCLUSION: The phenotype of intact OSE in vivo is most closely reproduced in media without EGF+HC. EGF+HC enhances growth but initiates EMT, which likely mimics a repair response. Variations in EGF+HC-induced phenotypes point to the existence of OSE subpopulations with differing responsiveness to growth factors or steroids, which may relate to their susceptibility to malignant transformation.

Adult↗

PubMed2004

Gonadotropin and steroid hormones stimulate proliferation of the rat ovarian surface epithelium.

The ovarian surface epithelium (OSE) is a single layer of flattened or cuboidal cells covering the ovary. Ninety percent of all human ovarian malignancies arise from this layer of cells. Incessant ovulation, hyperovulation induced by infertility treatment, and hormone replacement therapy have been suggested as risk factors for ovarian cancer. In this study, two groups of rats, with and without surgically induced injury to the ovary, were treated with 17beta-estradiol, pregnant mare's serum gonadotropin (PMSG), human chorionic gonadotropin (hCG), or the combination PMSG/hCG, and the proliferative response of the OSE cells was measured using bromodeoxyuridne (BrdU) and (3)H-thymidine. All hormones, alone or in combination with ovarian surgery, were found to increase significantly the rate of proliferation of the rat OSE. These data demonstrate that hormones associated with infertility treatments and hormone replacement therapy, as well as injury- or ovulation-induced rupture of the ovarian surface, stimulate the rat OSE, and hence could have a role in the development of ovarian cancer via proliferation-associated mutagenesis, or alternatively, by promoting the rapid selection of OSE cells with accumulated mutations.

Animals↗

PubMed2006

Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium.

The ovarian surface epithelium (OSE) is the precursor of common epithelial ovarian carcinomas. In the present study, we examined the molecular mechanisms and possible physiological basis for the propensity of OSE cells to undergo epithelio-mesenchymal transition (EMT) in response to environmental influences. We hypothesized that EMT may be a homeostatic mechanism that permits displaced OSE to assume a stromal phenotype within the ovarian cortex. We report that EGF in conjunction with hydrocortisone is the EMT-inducing factor of OSE as shown by changes to a fibroblast-like morphology and growth pattern. EGF increased cell motility, enhanced the activities of secreted pro-matrix metalloproteinase (MMP)-2 and -9, and enhanced expression and activation of Erk and integrin-linked kinase (ILK). Increased ILK expression correlated with the activation of PKB/Akt, the phosphorylation of GSK-3beta, and the increased expression of cyclin E and cdk2 kinase. EGF withdrawal resulted in a more epithelial morphology and reversal of the EGF-induced activation of signaling pathways and pro-MMP activity. In contrast, treatment of EGF-treated cells with specific inhibitors of phosphatidylinositol 3-kinase, Mek, or ILK inhibited the inhibitor-specific pathways. The inhibitors caused suppression of EGF-induced migration and pro-MMP-2/-9 activities but did not lead to any change in EGF-induced mesenchymal morphology. ILK small interfering RNA inhibited Akt phosphorylation and reduced pro-MMP-2/-9 activities but had no effect on Erk activation or cell morphology. These results indicate that the EGF-induced morphological and functional changes in OSE cells are controlled by distinct signaling mechanisms working in concert. EMT of OSE cells displaced by ovulation likely permits their survival and integration with a fibroblast-like identity within the stroma. Failure to do so may lead to the formation of epithelium-derived inclusion cysts, which are known preferential sites of malignant transformation.

Adult↗

PubMed2001

Differential expression of activin/inhibin subunit and activin receptor mRNAs in normal and neoplastic ovarian surface epithelium (OSE).

Ovarian surface epithelium (OSE) is the tissue of origin for the majority of ovarian cancers. The mechanism underlying the neoplastic transformation of OSE to ovarian cancer is poorly understood. Activin, a member of the transforming growth factor-beta superfamily, has been shown to increase cell proliferation in ovarian cancer cells. The present study was carried out to investigate the expression and regulation of activin/inhibin subunits and activin receptors in normal and neoplastic OSE. Using reverse transcriptase-polymerase chain reaction and Southern blot analysis, the mRNA levels of alpha, betaA and betaB subunits and activin receptor type IIA and IIB were analyzed in normal OSE and the ovarian cancer cell line, OVCAR-3 cells. The alpha and betaA subunits were highly expressed in normal OSE when compared to OVCAR-3 cells. By contrast, betaB subunit was highly expressed in OVCAR-3 cells, when compared to normal OSE cells. Interestingly, activin receptor IIB mRNA levels were significantly higher in OVCAR-3 when compared to normal OSE cells, whereas activin receptor IIA mRNA levels were the same in both cell types. To characterize the growth modulatory role of activin during neoplastic progression, normal OSE and OVCAR-3 cells were treated with recombinant human activin A (rh-activin A). At concentrations of 1,10 and 100 ng/ml, rh-activin A stimulated the growth of OVCAR-3 cells, but not of normal OSE. Treatment with follistatin, binding protein of activin, attenuates the stimulatory effect of activin. To determine whether the growth stimulatory action of activin in the neoplastic OSE is mediated via an autocrine regulatory mechanism, OVCAR-3 cells were treated with rh-activin A in a dose- and time-dependent manner and the expression levels of activin/inhibin subunits and activin receptors were investigated. Treatments with activin increased the alpha and betaA subunit mRNA levels in a dose- and time-dependent manner. However, no difference was observed in levels of betaB subunit, or in activin receptor type IIA and IIB mRNAs following activin treatments in OVCAR-3 cells. Taken together, these results suggest that different levels of activin/inhibin and activin receptor isoforms are expressed in normal and neoplastic OSE cells. In addition, the altered expression of the activin/inhibin subunits, as well as the cell proliferative effect of activin observed in OVCAR-3 but not in normal OSE cells, indicate that activin may act as an autocrine regulator of neoplastic OSE progression.

Activin Receptors↗

PubMed2005

Steroid signalling in the ovarian surface epithelium.

Human ovarian surface epithelium (HOSE) undergoes serial injury-repair with each ovulation, which is probably why most ovarian epithelial cancers arise there. Considering the proposed inflammatory aetiology of ovarian cancer, anti-inflammatory steroid signalling might be vital for HOSE regulation. HOSE cells express hydroxysteroid dehydrogenase (HSD) enzymes that undertake prereceptor metabolism of bioinert steroidogenic precursors formed elsewhere in the body. Ovulation-associated cytokines activate anti-inflammatory cortisol from precursor cortisone in HOSE cells owing to up-regulation of the gene encoding 11betaHSD type 1 (HSD11B1) in vitro. Cortisol further enhances its own formation and action through augmentation of cytokine-induced HSD11B1 and glucocorticoid receptor gene expression. Understanding this feed-forward signalling process has implications for the improved diagnosis and treatment of inflammation-associated reproductive disease states such as ovarian cancer.

Epithelial Cells↗

PubMed1993

Secretion of bioactive interleukin-1, interleukin-6, and colony-stimulating factors by human ovarian surface epithelium.

The ovarian surface epithelium (OSE) takes part in the lysis and repair of the ovulatory site. It also forms invaginations and cysts that give rise to the majority of ovarian epithelial carcinomas. In the present study, we investigated the capacity of cultured human OSE to secrete cytokines that may contribute to the regulation of ovarian functions and may influence ovarian carcinogenesis. Bioassays, combined with antibody neutralization experiments, showed that OSE cells in short-term culture secrete bioactive interleukin-1 (IL-1), interleukin-6 (IL-6), macrophage colony-stimulating factor (CSF-1), granulocyte colony-stimulating factor (G-CSF), and limited granulocyte-macrophage colony-stimulating factor (GM-CSF). There was a tendency for these factors to be absent or secreted in reduced amounts in SV40-immortalized OSE lines and in two ovarian carcinoma lines. No IL-2, IL-3, or IL-4 was detected. The results show that normal OSE cells secrete factors that are known to have regulatory effects on follicular growth and differentiation, ovulation, and the distribution of intraovarian cells of the immune system. In addition, the results suggest that the secretion of cytokines by ovarian carcinomas represents the retention of normal precursor cell properties, rather than new characteristics acquired as a result of neoplastic progression.

Animals↗

PubMed2000

Expression and action of hepatocyte growth factor in human and bovine normal ovarian surface epithelium and ovarian cancer.

More than 95% of ovarian cancers originate from the epithelial cells on the surface of the ovary, which are termed ovarian surface epithelium (OSE). These OSE cells are modified peritoneal mesothelial cells separated from underlying ovarian surface stromal tissue by a basal lamina of dense collagenous connective tissue. Mesenchymal-epithelial cell interactions between stromal cells and OSE cells are postulated to be important for normal OSE biology and for the onset of ovarian cancer. Hepatocyte growth factor (HGF) is a mesenchymal-derived growth factor that mediates mesenchymal-epithelial cell interactions in a number of different tissues. The current study was an investigation of the expression and actions of HGF in normal OSE and ovarian cancer. Human epithelial cells from borderline and stage III ovarian cancer cases were found to express HGF protein in the epithelial cell component by immunocytochemistry analysis. The stromal cell component of human ovarian tumors contained little or no HGF immunostaining. Normal bovine ovaries have a similar physiology and endocrinology to human ovaries and are used as a model system to investigate normal OSE functions. HGF protein was detected in the OSE from both normal human and bovine ovaries. Adjacent ovarian stromal tissue contained light but positive HGF immunostaining. RNA was collected from normal bovine ovarian stromal cells to examine HGF gene expression. HGF transcripts were detected in cultured OSE and stromal cells by Northern blot analysis. Using a quantitative reverse transcription-polymerase chain reaction procedure, HGF gene expression was found to be high in freshly isolated OSE but low in freshly isolated stroma. Levels of HGF gene expression after culture of stroma increased. Observations indicate that normal OSE express high levels of HGF in vivo and in vitro. Expression of HGF by normal epithelial cells versus stromal cells was unexpected and suggests that HGF may be important in an autocrine regulation of OSE. HGF actions on normal OSE cells and ovarian cancer cells were investigated. HGF was found to stimulate the growth of normal OSE cells in a manner similar to such growth stimulated by epidermal growth factor. Two ovarian cancer cell lines, SKOV3 and OCC1, were also stimulated to grow in response to HGF. This observation suggests that HGF may be involved in sustaining growth of ovarian tumors. These results are the first to demonstrate the production and action of HGF in normal OSE cells and ovarian cancer cells. This appears to be an example of HGF production by an epithelial cell, such that a mesenchymal-epithelial mixed phenotype is present. The autocrine stimulation of OSE growth by the local production and action of HGF provides insight into how the OSE may develop abnormal growth characteristics involved in the onset and progression of ovarian cancer.

Animals↗

PubMed2000

Expression and action of keratinocyte growth factor (KGF) in normal ovarian surface epithelium and ovarian cancer.

The current study investigates the expression and action of keratinocyte growth factor (KGF) in normal ovarian surface epithelium (OSE) and ovarian cancer tissues. Ovarian tumors are primarily derived from the OSE. KGF is a mesenchymal cell-derived growth factor that mediates stromal cell-epithelial cell interactions in a variety of different tissues. Human ovarian tumors from borderline, stage I and stage III cases were found to express KGF protein in the epithelial cell component by immunocytochemical analysis. The stromal cell component of human ovarian tumors contained little or no KGF immunostaining. Normal bovine ovaries have similarities to human ovaries and are used as a model system to investigate normal OSE functions. KGF protein was detected in the OSE from normal human and bovine ovaries by immunocytochemistry. Ovarian stromal tissue contained light but positive KGF immunostaining. RNA was collected from normal bovine OSE and ovarian stromal cells to examine KGF gene expression. KGF transcripts were detected in cultured OSE and stromal cells by Northern blot analysis. In order to examine and quantitate KGF gene expression in freshly isolated versus cultured tissues, a sensitive quantitative RT-PCR assay for KGF was utilized. KGF gene expression was found to be high in freshly isolated OSE, but very low in freshly isolated stroma. Levels of KGF gene expression after culture of OSE and stromal cells increased. Observations indicate that normal OSE express high levels of KGF in vivo and in vitro. Expression of KGF by normal epithelial cells versus stromal cells was unexpected and suggests KGF may be an important autocrine stimulator of OSE. KGF actions on bovine OSE cells were investigated. KGF was found to stimulate the growth of normal OSE cells to the same level as epidermal growth factor. Two ovarian cancer cell lines, SKOV3 and OCC1, were also stimulated to proliferate in response to KGF. Current results demonstrate the production and action of KGF on normal OSE cells and ovarian cancer cells. Observations can be interpreted to suggest that KGF may in part be involved in the growth of ovarian tumors. This appears to be one of the first reports of KGF production by an epithelial cell. The autocrine stimulation of OSE growth by the local production and action of KGF provides insight into how the OSE may develop abnormal growth characteristics involved in the onset and progression of ovarian cancer.

Adult↗

PubMed2003

Identification of a putative autocrine bone morphogenetic protein-signaling pathway in human ovarian surface epithelium and ovarian cancer cells.

Bone morphogenetic proteins (BMPs) are members of the TGFbeta superfamily of cytokines that are involved in development, differentiation, and disease. In an analysis of normal ovarian surface epithelium (OSE) and ovarian cancer (OC) cells, we observed BMP4 mRNA expression and found that primary OC cells produce mature BMP4. In addition, each member of the downstream signaling pathway was expressed in primary OSE and OC cells. Smad1 was phosphorylated and underwent nuclear translocation in normal OSE and OC cells upon treatment with BMP4. Interestingly, the BMP target genes ID1 and ID3 were up-regulated 10- to 15-fold in primary OC cells, compared with a 2- to 3-fold increase in normal OSE. The growth of several primary OC cells was relatively unaltered by BMP4 treatment; however, long-term BMP4 treatment of primary OC cells resulted in decreased cell density as well as increased cell spreading and adherence. These data demonstrate the existence and putative function of BMP signaling in normal OSE and OC cells, and thus the continued examination of BMP4 signaling in the regulation of these two processes will be critical to further our current understanding of the role of BMP biology in OC pathogenesis.

Biological Transport↗

PubMed2000

Expression and action of transforming growth factor alpha in normal ovarian surface epithelium and ovarian cancer.

Greater than 95% of ovarian cancers originate in the epithelial cells on the surface of the ovary. The current study investigates the expression and action of transforming growth factor alpha (TGFalpha) in ovarian surface epithelium (OSE) and the underlying stroma in both normal and tumorigenic ovarian tissues. Normal bovine ovaries are used in the current study as a model system to investigate normal OSE functions. Transforming growth factor alpha and its receptor, the epidermal growth factor receptor (EGFR), were detected in the OSE from normal ovaries by immunocytochemistry (ICC). Ovarian stromal tissue also contained reduced but positive TGFalpha and EGFR immunostaining. To examine TGFalpha and EGFR gene expression, RNA was collected from normal bovine OSE and ovarian stromal cells. The TGFalpha and EGFR transcripts were detected in both fresh and cultured OSE and stromal cells by a sensitive quantitative reverse transcription polymerase chain reaction (QRT-PCR) assay. Transforming growth factor alpha gene expression was found to be high in freshly isolated OSE, but low in freshly isolated stroma. In contrast, EGFR expression was higher in the stroma compared to the OSE. Both the ICC and QRT-PCR indicate that normal OSE express high levels of TGFalpha in vivo and in vitro. In vitro, normal ovarian stromal cells develop the capacity to express high levels of EGFR. Human ovarian tumors from stage II, stage III, and stage IV ovarian cancer cases were found to express TGFalpha and EGFR protein in the epithelial cell component of the tumor by ICC analysis. The stromal cell component of human ovarian tumors contained little or no TGFalpha/EGFR immunostaining. Observations suggest that tumor progression may in part require autocrine stimulation of the epithelia. Transforming growth factor alpha was found to stimulate the growth of normal bovine OSE and stroma cells to the same level as epidermal growth factor. Two ovarian cancer cell lines, SKOV3 and OCC1, were also stimulated to proliferate in response to TGFalpha. Transforming growth factor alpha was also found to stimulate the expression of two growth factors previously shown to be produced by OSE. Transforming growth factor alpha stimulates both kit ligand/stem cell factor and keratinocyte growth factor production by OSE. The effect of hormones on TGFalpha and EGFR expression by the OSE was also examined. Human chorionic gonadotropin stimulated TGFalpha expression, but not FSH. Both hCG and FSH stimulated EGFR expression by OSE. Combined observations suggest a role of systemic hormones and a locally produced growth factor, TGFalpha, in OSE biology. Insight is also provided into how the OSE may develop abnormal growth characteristics involved in the onset and progression of ovarian cancer.

Animals↗

PubMed1987

Hyperplasia and metaplasia of ovarian surface epithelium in women with endometrial carcinoma. Suggestion for a hormonal influence in ovarian carcinogenesis.

Surface ovarian epithelium and that of related inclusion cysts were comparatively studied in two groups of patients: one group of 50 non-pregnant women without myometrial, endometrial, or cervical hyperplasia and/or neoplasia; a second group of 50 women surgically treated for endometrial cancer and without evidence of ovarian pathology. Papillomatosis, hyperplasia and tubaric, squamoid, endometrioid and mucinous metaplasia were more frequently present in ovarian surface epithelium or in related inclusion cysts in patients with endometrial carcinoma. These findings may be correlated with a hormonal oncogenic stimulus involved in the genesis of endometrial cancer and suggests a new "hormonal" hypothesis in the pathogenesis of common epithelial tumors of the ovary.

Adenocarcinoma↗

PubMed2000

Expression and action of kit ligand/stem cell factor in normal human and bovine ovarian surface epithelium and ovarian cancer.

Greater than 95% of ovarian cancers originate from the epithelial cells on the surface of the ovary termed ovarian surface epithelium (OSE). A normal aspect of OSE function is repeated proliferation after ovulation, and this is postulated to be involved in part in the onset of ovarian cancer. The hypothesis tested is that locally produced growth factors have an important role in controlling OSE proliferation. The current study investigates the potential role of the growth factor kit ligand (KL)/stem cell growth factor and its receptor c-kit in normal OSE biology and ovarian cancer. Human tumors from borderline, stage I, and stage III cases of ovarian cancer were found to express KL and c-kit protein in the epithelial cell component by ICC analysis. The stromal cell component of human ovarian tumors contained little immunostaining. Bovine ovarian physiology and endocrinology are similar to the human such that cow ovaries were used as a model system to investigate normal OSE functions. KL and c-kit proteins were detected in the OSE from both normal human and bovine ovaries. Adjacent ovarian stromal tissue contained less intense but positive KL and c-kit immunostaining. To extend the ICC results, RNA was collected from normal bovine OSE and ovarian stromal cells to examine KL gene expression. KL transcripts were detected in cultured OSE and stromal cells by Northern blot analysis. KL gene expression was found to be high in freshly isolated OSE but low in freshly isolated stroma using a quantitative polymerase chain reaction procedure. Levels of KL gene expression in cultured OSE and stroma increased to high levels. Observations indicate that normal OSE expresses high levels of KL in vivo and in vitro. The actions of KL on the growth of both normal OSE cells and ovarian cancer cells was investigated. KL was found to stimulate the growth of normal OSE cells in a similar manner to epidermal growth factor. Observations demonstrate the production and action of KL by normal OSE cells and ovarian cancer cells. Coexpression of KL and c-kit by normal OSE suggests that KL can act as an autocrine factor for OSE. The local production and action of KL on OSE provides insight into normal OSE biology, and a factor that may be involved in the onset and progression of ovarian cancer.

Animals↗

PubMed1993

Ovarian surface epithelium and human ovarian cancer.

Approximately 80-90% of adult ovarian cancers are assumed to originate from ovarian surface cells. The morphology of the ovarian surface epithelium changes constantly, exhibiting features such as crypts, inclusion cysts, villous processes and different forms of müllerian epithelium. The unique nature of ovarian surface features and their absence in the immediately adjacent peritoneal mesothelium suggest that local factors may play an important part in modifying the growth and morphology of the ovarian surface epithelium. Recent studies tend to emphasize oncogene activation, along with concomitant cytogenetic changes, in the development of ovarian cancer. This review focuses on the roles of exogenous and endogenous factors and ovulation in the pathogenesis of ovarian cancer.

Adult↗