scholarly journals Identification of a Putative Autocrine Bone Morphogenetic Protein-Signaling Pathway in Human Ovarian Surface Epithelium and Ovarian Cancer Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (8) ◽  
pp. 3306-3314 ◽  
Author(s):  
Trevor G. Shepherd ◽  
Mark W. Nachtigal
Keyword(s):  
Ovarian Cancer ◽  
Signaling Pathway ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Fold Increase ◽  
Ovarian Surface Epithelium ◽  
Bmp Signaling ◽  
Surface Epithelium ◽  
Ovarian Cancer Cells ◽  
Ovarian Surface

Abstract Bone morphogenetic proteins (BMPs) are members of the TGFβ 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.

scholarly journals Loss of GATA6 Leads to Nuclear Deformation and Aneuploidy in Ovarian Cancer

2009 ◽  
Vol 29 (17) ◽  
pp. 4766-4777 ◽  
Author(s):  
Callinice D. Capo-chichi ◽  
Kathy Q. Cai ◽  
Joseph R. Testa ◽  
Andrew K. Godwin ◽  
Xiang-Xi Xu
Keyword(s):  
Ovarian Cancer ◽  
Nuclear Envelope ◽  
Cancer Cells ◽  
Human Cancer ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
Ovarian Cancer Cells ◽  
Ovarian Surface ◽  
Ovarian Surface Epithelial ◽  
Ovarian Tumorigenesis

ABSTRACT A prominent hallmark of most human cancer is aneuploidy, which is a result of the chromosomal instability of cancer cells and is thought to contribute to the initiation and progression of most carcinomas. The developmentally regulated GATA6 transcription factor is commonly lost in ovarian cancer, and the loss of its expression is closely associated with neoplastic transformation of the ovarian surface epithelium. In the present study, we found that reduction of GATA6 expression with small interfering RNA (siRNA) in human ovarian surface epithelial cells resulted in deformation of the nuclear envelope, failure of cytokinesis, and formation of polyploid and aneuploid cells. We further discovered that loss of the nuclear envelope protein emerin may mediate the consequences of GATA6 suppression. The nuclear phenotypes were reproduced by direct suppression of emerin with siRNA. Thus, we conclude that diminished expression of GATA6 leads to a compromised nuclear envelope that is causal for polyploidy and aneuploidy in ovarian tumorigenesis. The loss of emerin may be the basis of nuclear morphological deformation and subsequently the cause of aneuploidy in ovarian cancer cells.

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

2006 ◽  
Vol 13 (2) ◽  
pp. 641-651 ◽  
Author(s):  
Jung-Hye Choi ◽  
Kyung-Chul Choi ◽  
Nelly Auersperg ◽  
Peter C K Leung
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Ovarian Cancer Cell ◽  
Ovarian Surface Epithelium ◽  
Gonadotropin Releasing Hormone ◽  
Surface Epithelium ◽  
Ovarian Cancer Cells ◽  
Mrna Levels ◽  
Ovarian Surface ◽  
Ovarian Cancer Cell Lines

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.

Spontaneous transformation of the ovarian surface epithelium and the biology of ovarian cancer

1995 ◽  
pp. 145-156 ◽  
Author(s):  
H. Salazar ◽  
A. K. Godwin ◽  
L. A. Getts ◽  
J. R. Testa ◽  
M. Daly ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
Spontaneous Transformation ◽  
Ovarian Surface

Ovarian Cancer Cell Invasiveness Correlates With Increased Cell Deformability

2012 ◽  
Author(s):  
Wenwei Xu ◽  
Roman Mezencev ◽  
Byungkyu Kim ◽  
Lijuan Wang ◽  
John McDonald ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Single Cells ◽  
Metastatic Cancer ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
Ovarian Cancer Cells ◽  
Cell Deformability ◽  
Ovarian Cells ◽  
And Migration

Cancer cells undergo a variety of biochemical and biophysical transformations when compared to identical cells displaying a healthy phenotypic state, cancer cells show a drastic reduction of stiffness upon malignancy[1, 2] and change of stiffness of single cells can indicate the presence of disease [3–6]. Besides, metastatic cancer has a higher deformability than their benign counterparts[7, 8]. Using atomic force microscopy, we demonstrated that cancerous ovarian cells (OVCAR3, OVCAR4, HEY and HEYA8) are substantially softer than the healthy immortalized ovarian surface epithelium (IOSE) cells. In addition, within the different types of cancerous ovarian cells, increased invasiveness and migration are directly correlated with increased cell deformability. These results indicate that stiffness of individual cells can distinguish not only ovarian cancer cells from healthy cells types, but also invasive cancer types from less invasive types. Stiffness may provide an alternative and convenient biomarker to grade the metastasis potential of cancer cells.

scholarly journals Ovarian Surface Epithelium: Biology, Endocrinology, and Pathology*

2001 ◽  
Vol 22 (2) ◽  
pp. 255-288 ◽  
Author(s):  
Nelly Auersperg ◽  
Alice S. T. Wong ◽  
Kyung-Chul Choi ◽  
Sung Keun Kang ◽  
Peter C. K. Leung
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
Neoplastic Progression ◽  
Ovarian Carcinomas ◽  
Genetic Changes ◽  
Ovarian Surface ◽  
Histological Characteristics ◽  
Epithelial Ovarian Carcinomas

Abstract The epithelial ovarian carcinomas, which make up more than 85% of human ovarian cancer, arise in the ovarian surface epithelium (OSE). The etiology and early events in the progression of these carcinomas are among the least understood of all major human malignancies because there are no appropriate animal models, and because methods to culture OSE have become available only recently. The objective of this article is to review the cellular and molecular mechanisms that underlie the control of normal and neoplastic OSE cell growth, differentiation, and expression of indicators of neoplastic progression. We begin with a brief discussion of the development of OSE, from embryonic to the adult. The pathological and genetic changes of OSE during neoplastic progression are next summarized. The histological characteristics of OSE cells in culture are also described. Finally, the potential involvement of hormones, growth factors, and cytokines is discussed in terms of their contribution to our understanding of the physiology of normal OSE and ovarian cancer development.

scholarly journals Inactivation of TRP53, PTEN, RB1, and/or CDH1 in the ovarian surface epithelium induces ovarian cancer transformation and metastasis

2020 ◽  
Vol 102 (5) ◽  
pp. 1055-1064 ◽  
Author(s):  
Mingxin Shi ◽  
Allison E Whorton ◽  
Nikola Sekulovski ◽  
Marilène Paquet ◽  
James A MacLean ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Surface Epithelium ◽  
Genetically Engineered ◽  
Surface Epithelium ◽  
Low Grade ◽  
Type I ◽  
Epithelial Hyperplasia ◽  
Genetically Engineered Mouse Models ◽  
Ovarian Surface ◽  
Tumor Dissemination

Abstract Ovarian cancer (OvCa) remains the most common cause of death from gynecological malignancies. Genetically engineered mouse models have been used to study initiation, origin, progression, and/or mechanisms of OvCa. Based on the clinical features of OvCa, we examined a quadruple combination of pathway perturbations including PTEN, TRP53, RB1, and/or CDH1. To characterize the cancer-promoting events in the ovarian surface epithelium (OSE), Amhr2cre/+ mice were used to ablate floxed alleles of Pten, Trp53, and Cdh1, which were crossed with TgK19GT121 mice to inactivate RB1 in KRT19-expressing cells. Inactivation of PTEN, TRP53, and RB1 with or without CDH1 led to the development of type I low-grade OvCa with enlarged serous papillary carcinomas and some high-grade serous carcinomas (HGSCs) in older mice. Initiation of epithelial hyperplasia and micropapillary carcinoma started earlier at 1 month in the triple mutations of Trp53, Pten, and Rb1 mice as compared to 2 months in quadruple mutations of Trp53, Pten, Rb1, and Cdh1 mice, whereas both genotypes eventually developed enlarged proliferating tumors that invaded into the ovary at 3–4 months. Mice with triple and quadruple mutations developed HGSC and/or metastatic tumors, which disseminated into the peritoneal cavity at 4–6 months. In summary, inactivation of PTEN, TRP53, and RB1 initiates OvCa from the OSE. Additional ablation of CDH1 further increased persistence of tumor dissemination and ascites fluid accumulation enhancing peritoneal metastasis.

Defining the mechanisms by which leptin stimulates proliferation of ovarian cancer cells

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15017-15017
Author(s):  
A. B. Olawaiye ◽  
H. Sakamoto ◽  
T. Serikawa ◽  
A. Friel ◽  
R. Kiyama ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Sufficient Evidence ◽  
Surface Epithelium ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ovarian Cancer Cells ◽  
Ovarian Surface ◽  
Potential Biomarker ◽  
Ovca Cell

15017 Background: Ovarian cancer (OvCa) ranks fourth as the cause of death related to cancer in women in the U.S. The vast majority (>90%) of OvCa originates from the ovarian surface epithelium. There is sufficient evidence to suggest that hormones, especially estrogen, may be involved in the etiopathogenesis of epithelial OvCa. Recent studies indicate that leptin participates either directly or indirectly to promote carcinogenesis in both breast and endometrial cancers. Furthermore it has been proposed that leptin may elicit its action via an estrogen related pathway. Leptin can stimulate proliferation of some OvCa cell lines and has been implicated as a potential biomarker for OvCa. However the mechanism(s) by which leptin contributes to the growth of OvCa has yet to be defined. We hypothesize that leptin’s effect will be mediated in part by estrogen receptor (ER) pathways. Methods: Three epithelial OvCa cell lines (IGROV1, OVCAR5 and TOV21G) and one benign human ovarian surface epithelial cell line (HOSE) were evaluated. Enzyme linked immunosorbent assay (ELISA) and Western blotting were used to assess leptin and leptin receptor (ObR), respectively. Leptin (0.06 nM–6.25 nM) induced effects on cell proliferation were assessed in the presence or absence of an aromatase enzyme inhibitor (Anastrozole) or the ER antagonist (ICI182780). Further, we explored leptin-induced effects on ERα promoter activity as evidenced by change in fluorescence via a dual luciferase promoter reporter. All experiments were conducted in triplicate. All data were subjected to ANOVA followed by Tukey’s post hoc test (p < 0.05). Results: All ovarian cell lines expressed ObR; whereas, no measurable amounts of leptin were detected in conditioned media. Leptin stimulated cell proliferation in both the benign and malignant lines. Leptin-induced cell proliferation was inhibited by Anastrozole and ICI182780. Furthermore, leptin stimulated luciferase activity of the ERα promoter/reporter. Conclusions: Leptin promotes proliferation of benign and malignant ovarian epithelial cells and appears to be mediated, at least in part, via aromatase and ER which may have therapeutic implications. This work was supported by the Vincent Memorial Hospital, SG Komen Foundation and the Advanced Medical Research Foundation. No significant financial relationships to disclose.

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