Article

Genetic Analysis of the Early Natural History of Epithelial Ovarian Carcinoma

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
PLoS ONE (Impact Factor: 3.53). 04/2010; 5(4):e10358. DOI: 10.1371/journal.pone.0010358
Source: PubMed

ABSTRACT The high mortality rate associated with epithelial ovarian carcinoma (EOC) reflects diagnosis commonly at an advanced stage, but improved early detection is hindered by uncertainty as to the histologic origin and early natural history of this malignancy.
Here we report combined molecular genetic and morphologic analyses of normal human ovarian tissues and early stage cancers, from both BRCA mutation carriers and the general population, indicating that EOCs frequently arise from dysplastic precursor lesions within epithelial inclusion cysts. In pathologically normal ovaries, molecular evidence of oncogenic stress was observed specifically within epithelial inclusion cysts. To further explore potential very early events in ovarian tumorigenesis, ovarian tissues from women not known to be at high risk for ovarian cancer were subjected to laser catapult microdissection and gene expression profiling. These studies revealed a quasi-neoplastic expression signature in benign ovarian cystic inclusion epithelium compared to surface epithelium, specifically with respect to genes affecting signal transduction, cell cycle control, and mitotic spindle formation. Consistent with this gene expression profile, a significantly higher cell proliferation index (increased cell proliferation and decreased apoptosis) was observed in histopathologically normal ovarian cystic compared to surface epithelium. Furthermore, aneuploidy was frequently identified in normal ovarian cystic epithelium but not in surface epithelium.
Together, these data indicate that EOC frequently arises in ovarian cystic inclusions, is preceded by an identifiable dysplastic precursor lesion, and that increased cell proliferation, decreased apoptosis, and aneuploidy are likely to represent very early aberrations in ovarian tumorigenesis.

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    • "The concept of OSE as stem cells is in keeping with other stem cell-like characteristics [14] [15], and with the ability of OSE to differentiate structurally and functionally to a fibroblastic phenotype in response to microenvironmental changes and growth factors [4] [16]. In OSE-lined inclusion cysts, serous metaplasia of the flat-to-cuboidal mesothelial OSE to columnar epithelium resembling fimbrial epithelium occurs not only morphologically (Fig. 1) [17] [18] [19] but also functionally, as shown by the immunohistochemical demonstration of the tubal epithelial differentiation markers E-cadherin, Epcam, cilia, and oviduct-specific glycoprotein (OVGP1) in columnar cells adjacent to flat OSE cells within the same inclusion cysts (Fig. 2) [20]. Such gradual transitions from flat mesothelial cells to columnar fimbria-like cells within epithelial inclusion cysts and on the ovarian surface [21] exclude the likelihood that the columnar cells are 'implants' of normal fimbrial epithelium. "
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    ABSTRACT: There has been increasing evidence that high grade serous ovarian carcinomas (HGSOCs), the most common and most lethal of all ovarian cancers, originate in oviductal fimbriae and metastasize to the ovary. The alternate hypothesis, that ovarian carcinomas may originate within the ovarian stroma in inclusion cysts lined by ovarian surface epithelium (OSE), has been criticized and often dismissed on the basis of the OSE's embryonic origin, mesothelial phenotype, tissue-specific markers, questionable ability to undergo metaplasia, and the lack of identifiable precursor lesions. This review analyzes these criticisms and summarizes evidence indicating that OSE as a source of ovarian cancers cannot be ruled out.
    Gynecologic Oncology 04/2013; 130(1). DOI:10.1016/j.ygyno.2013.03.021 · 3.69 Impact Factor
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    • "Although these populations appear distinct, recent evidence of premalignant lesions within the fimbria (Kindelberger et al., 2007; Folkins et al., 2009; Semmel et al., 2009) and ovarian cysts (Pothuri et al., 2010) of BRCA mutant carriers, genetic evidence highlighting the similarity of high-grade serous tumors to FE and OSE (Marquez et al., 2005), developmental similarities (Auersperg et al., 2008) and data presented here suggest the commonalities among FE and OSE are more significant than differences. If FE-to-OSE conversion occurs, permanent OSEx may not be feasible, but could still reduce risk without sacrificing ovarian function. "
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    ABSTRACT: The fifth leading cause of cancer deaths among women is ovarian cancer (OC), which originates primarily in the ovarian surface epithelium (OSE) that surrounds the ovary. Permanent removal of the OSE could provide a novel strategy to substantially reduce OC risk, while retaining the benefits of ovarian function, including gameto- and steroidogenesis. It must be determined whether ovarian surface epitheliectomy (OSEx) carries deleterious side effects, including loss of menstrual cyclicity, infertility or scarring (e.g. adhesions), prior to any clinical application of this strategy. To achieve this, we selected the non-human primate, rhesus macaque, for long-term (12 month) studies on the effects of OSEx. Rhesus macaque females underwent OSEx by detergent treatment and were then monitored for menstrual cyclicity (menstruation, steroidogenesis and follicle development) and adverse side effects (tissue scarring or adhesions). Ovaries were collected at 6 or 12 months and examined for evidence of tissue damage, follicle rupture and regression of the corpus luteum. The ovarian surface was examined immunohistologically for signs of epithelial replacement, using markers for OSE and fimbrial epithelium (FE), a possible alternative source of pelvic tumors diagnosed as OC. After OSEx, menstrual cycle length, estrogen and progesterone production, follicle rupture and luteal regression appeared normal. No evidence of adhesions was seen. At 6 and 12 months post-OSEx, the ovarian surface was sparsely populated by cells expressing OSE and FE markers. Proliferative activity in this population was notably low. OSEx may provide a novel method to reduce the risk of OC, without sacrificing ovarian function, although the effects on fertility remain to be tested. The absence of epithelial replacement via enhanced proliferation suggests OSEx does not increase malignant potential. Complete and permanent OSEx may be feasible.
    Human Reproduction 03/2011; 26(6):1422-30. DOI:10.1093/humrep/der061 · 4.59 Impact Factor
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    • "On the basis of available data, it may be hypothesized that the human OSE undergoes dynamic regulation during the natural menstrual cycle, as seen in non-primates. This could include up-and downregulation of E and P receptors in response to cyclic patterns of E and P production (Chaffin et al., 1999; Mukherjee et al., 2005; Giles et al., 2006); low basal levels of proliferation (Werness et al., 1999; Heller et al., 2003; Piek et al., 2003; Slot et al., 2006; Pothuri et al., 2010), punctuated by higher levels following ovulation (Osterholzer et al., 1985; Bai et al., 2000; Doyle and Donadeu, 2009), and; increased cell death prior to ovulation and in the presence of high levels of P produced by the corpus luteum (CL) (Murdoch et al., 2001; Rodriguez et al., 2002). Changes in cellular morphology may also occur as the ovarian surface expands and contracts in response to follicle growth, ovulation and luteal regression. "
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    ABSTRACT: Epithelial ovarian cancer (EOC) risk correlates strongly with the number of ovulations that a woman experiences. The primary source of EOC in women is the ovarian surface epithelium (OSE). Mechanistic studies on the etiology of OSE transformation to EOC cannot be realistically performed in women. Selecting a suitable animal model to investigate the normal OSE in the context of ovulation should be guided by the model's reproductive similarities to women in natural features that are thought to contribute to EOC risk. We selected the non-human primate, rhesus macaque, as a surrogate to study the normal OSE during the natural menstrual cycle. We investigated OSE morphology and marker expression, plus cell proliferation and death in relation to menstrual cycle stage and ovulation. OSE cells displayed a morphological range from squamous to columnar. Cycle-independent parameters and cycle-dependent changes were observed for OSE histology, steroid receptor expression, cell death, DNA repair and cell adhesion. Contrary to findings in non-primates, primate OSE cells were not manifestly cleared from the site of ovulation, nor were proliferation rates affected by ovulation or stage of the menstrual cycle. DNA repair proteins were more highly expressed in OSE than in other ovarian cells. This study identifies significant differences between primate and non-primate OSE. In contrast to established views, ovulation-induced death and proliferation are not indicated as prominent contributors to EOC risk, but disruption of OSE cadherin-mediated adhesion may be, as could the loss of ovary-mediated chronic suppression of proliferation and elevation of DNA repair potential.
    Human Reproduction 03/2011; 26(6):1408-21. DOI:10.1093/humrep/der057 · 4.59 Impact Factor
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