scholarly journals Screening and Prevention for High-Grade Serous Carcinoma of the Ovary Based on Carcinogenesis—Fallopian Tube- and Ovarian-Derived Tumors and Incessant Retrograde Bleeding

Diagnostics ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 120 ◽  
Author(s):  
Isao Otsuka ◽  
Takuto Matsuura
Keyword(s):  
Fallopian Tube ◽  
Ovarian Surface Epithelium ◽  
Serous Carcinoma ◽  
Ca 125 ◽  
Surface Epithelium ◽  
Screening Methods ◽  
High Grade ◽  
Endometrial Cavity ◽  
Screening And Prevention ◽  
Tumor Dna

High-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian carcinoma. Many HGSCs are now believed to originate in the fallopian tube epithelium; ovarian surface epithelium is another possible origin. Thus, current screening methods, i.e., ultrasonography and serum CA-125 measurements, have a limitation in their early detection. Recently, circulating biomarkers, such as tumor DNA, autoantibody, and microRNA, have been investigated to detect HGSCs. As cancer cells in the fallopian tube flow into the endometrial cavity, the detection of exfoliated cells, tumor DNA, and proteome from samples obtained from the endometrial cavity or the cervix may be useful. The risk of ovarian serous carcinoma is affected by the use of oral contraceptive and menopausal hormone therapy (MHT). MHT regimens causing endometrial bleeding increase serous carcinoma risk, hence, incessant retrograde bleeding from the endometrial cavity into the Douglas pouch appears to play an important role in high-grade serous carcinogenesis. In this review, we provide an overview of current and novel screening methods and prevention approaches for ovarian and fallopian tube HGSC.

scholarly journals Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Shuang Zhang ◽  
Igor Dolgalev ◽  
Tao Zhang ◽  
Hao Ran ◽  
Douglas A. Levine ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Fallopian Tube ◽  
Cell Types ◽  
Ovarian Surface Epithelium ◽  
Genetically Engineered ◽  
Surface Epithelium ◽  
High Grade ◽  
Cell Of Origin ◽  
Ovarian Surface ◽  
Serous Ovarian Carcinoma

AbstractThe cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) both considered candidates. Here, by using genetically engineered mouse models and organoids, we assessed the tumor-forming properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation and Tp53 mutation in Pax8 + FTE caused Serous Tubal Intraepithelial Carcinoma (STIC), which metastasized rapidly to the ovarian surface. These events were recapitulated by orthotopic injection of mutant FTE organoids. Engineering the same genetic lesions into Lgr5 + OSE or OSE-derived organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. FTE- and OSE-derived tumors had distinct transcriptomes, and comparative transcriptomics and genomics suggest that human HGSOC arises from both cell types. Finally, FTE- and OSE-derived organoids exhibited differential chemosensitivity. Our results comport with a dualistic origin for HGSOC and suggest that the cell-of-origin might influence therapeutic response.

scholarly journals UnPAXing the Divergent Roles of PAX2 and PAX8 in High-Grade Serous Ovarian Cancer

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 262 ◽  
Author(s):  
Laura Hardy ◽  
Amrita Salvi ◽  
Joanna Burdette
Keyword(s):  
Ovarian Cancer ◽  
Fallopian Tube ◽  
Cancer Progression ◽  
Drug Targets ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cell Of Origin ◽  
Pax8 Expression

High-grade serous ovarian cancer is a deadly disease that can originate from the fallopian tube or the ovarian surface epithelium. The PAX (paired box) genes PAX2 and PAX8 are lineage-specific transcription factors required during development of the fallopian tube but not in the development of the ovary. PAX2 expression is lost early in serous cancer progression, while PAX8 is expressed ubiquitously. These proteins are implicated in migration, invasion, proliferation, cell survival, stem cell maintenance, and tumor growth. Hence, targeting PAX2 and PAX8 represents a promising drug strategy that could inhibit these pro-tumorigenic effects. In this review, we examine the implications of PAX2 and PAX8 expression in the cell of origin of serous cancer and their potential efficacy as drug targets by summarizing their role in the molecular pathogenesis of ovarian cancer.

scholarly journals Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic Factors, and Molecular Alterations

2021 ◽  
Vol 22 (9) ◽  
pp. 4409
Author(s):  
Isao Otsuka
Keyword(s):  
Homologous Recombination ◽  
Fallopian Tube ◽  
Early Stage ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
Intratumor Heterogeneity ◽  
High Grade ◽  
Tp53 Mutations ◽  
Molecular Alterations ◽  
Brca 1

Ovarian high-grade serous carcinomas (HGSCs) are a heterogeneous group of diseases. They include fallopian-tube-epithelium (FTE)-derived and ovarian-surface-epithelium (OSE)-derived tumors. The risk/protective factors suggest that the etiology of HGSCs is multifactorial. Inflammation caused by ovulation and retrograde bleeding may play a major role. HGSCs are among the most genetically altered cancers, and TP53 mutations are ubiquitous. Key driving events other than TP53 mutations include homologous recombination (HR) deficiency, such as BRCA 1/2 dysfunction, and activation of the CCNE1 pathway. HR deficiency and the CCNE1 amplification appear to be mutually exclusive. Intratumor heterogeneity resulting from genomic instability can be observed at the early stage of tumorigenesis. In this review, I discuss current carcinogenic hypotheses, sites of origin, etiologic factors, and molecular alterations of HGSCs.

scholarly journals Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma

2018 ◽  
Author(s):  
Shuang Zhang ◽  
Tao Zhang ◽  
Igor Dolgalev ◽  
Hao Ran ◽  
Douglas A. Levine ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Fallopian Tube ◽  
Ovarian Surface Epithelium ◽  
Genetically Engineered ◽  
Differential Sensitivity ◽  
Surface Epithelium ◽  
High Grade ◽  
Cell Of Origin ◽  
Ovarian Surface ◽  
Serous Ovarian Carcinoma

ABSTRACTThe cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) each suggested as candidates. Here, by using genetically engineered mouse models and novel organoid systems, we assessed the tumor-forming capacity and properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation (via T121 expression) and Tp53 mutation in Pax8+ FTE caused transformation to Serous Tubal Intraepithelial Carcinoma (STIC), which rapidly metastasized to the ovarian surface. This mouse model was recapitulated by FTE organoids, which, upon orthotopic injection, generated widely metastatic HGSOC. The same genetic lesions in Lgr5+ OSE cells or organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. Comparative transcriptome analysis was consistent with different human HGSOCs arising from FTE and OSE. Furthermore, FTE- and OSE-derived organoids showed differential sensitivity to HGSOC chemotherapeutics. Our results comport with a dualistic origin for HGSOC and suggest the cell-of-origin could influence therapeutic response.SIGNIFICANCEThe cell-of-origin for high grade serous ovarian carcinoma (HGSOC) has been controversial. By generating novel GEMMs and organoid models with the same oncogenic defects, we demonstrate that HGSOC can originate from either fallopian tube epithelium (FTE) or ovarian surface epithelium (OSE). Importantly, FTE- and OSE-derived tumors differ significantly in biologic properties.

The Fallopian Tube: Primary Site of Most Pelvic High-grade Serous Carcinomas

2009 ◽  
Vol 19 (1) ◽  
pp. 58-64 ◽  
Author(s):  
Shannon Salvador ◽  
Blake Gilks ◽  
Martin Köbel ◽  
David Huntsman ◽  
Barry Rosen ◽  
...  
Keyword(s):  
Oral Contraceptive ◽  
Fallopian Tube ◽  
English Language ◽  
Contraceptive Use ◽  
Early Stage ◽  
Tubal Ligation ◽  
Serous Carcinoma ◽  
Screening Methods ◽  
High Grade ◽  
Pelvic Serous Carcinoma

Epithelial ovarian cancer is the most common cause of mortality from gynecologic malignancy, and most of epithelial cancers are of serous type. The site of origin of pelvic high-grade serous carcinoma has been the subject of debate for 60 years. This paper reviews the evidence that pelvic serous carcinoma originates from the fallopian tube mucosa and puts forward a theory that inflammation in the tube, caused by menstrual cytokines or infection, is critical to the genesis of these tumors. Other risk factors for pelvic serous carcinoma will be reviewed, including oral contraceptive use, parity, infertility, and tubal ligation.Studies were identified for this review by searching the English language literature in the MEDLINE database between the years 1995 and 2007 using the following keywords: fallopian tube neoplasia, ovarian serous adenocarcinoma, pregnancy, oral contraceptive, infertility, pelvic inflammatory disease, cytokines, menstruation, and tubal ligation, followed by an extensive review of bibliographies from articles found through the search.The clinical implications of this theory are discussed, and a change in surgical practice is recommended, with salpingectomy at the time of simple hysterectomy. This theory also has implications for the development of new methods of screening for pelvic serous carcinomas, as there are no screening methods that are currently available to find this form of cancer in an early stage. Inflammatory markers could be detected in the vagina from the fallopian tube indicating possible chronic inflammation and a risk factor for mutagenesis leading to serous carcinoma.

scholarly journals Primary High Grade Serous Carcinoma of the Fallopian Tube: A Case Report

2020 ◽  
Vol 58 (231) ◽  
Author(s):  
Ramesh Dhakhwa ◽  
Anshu Vaidya ◽  
Amrita Giri ◽  
Archana Shakya ◽  
Achala Vaidya
Keyword(s):  
Fallopian Tube ◽  
Lower Abdominal Pain ◽  
Abnormal Uterine Bleeding ◽  
Total Abdominal Hysterectomy ◽  
Figo Stage ◽  
Abdominal Hysterectomy ◽  
Serous Carcinoma ◽  
Ca 125 ◽  
High Grade ◽  
Anatomic Site

A 49-year-old, perimenopausal nulliparous woman with lower abdominal pain and abnormal uterine bleeding. Clinical and radiological findings suggested a right adnexal tumor. CA-125 level was moderately elevated. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was done. Peroperative findings revealed a soft to friable growth arising from right fallopian tube with no involvement of ovaries. Histopathologic examination confirmed it to be a high grade serous carcinoma, FIGO stage IA. The histomorphology resembled high grade serous carcinoma of ovary, however ovaries on both sides appeared unremarkable. Surgery was uneventful and the patient was discharged after seven days of hospital stay. She did not receive postoperative chemotherapy or radiotherapy and is under follow-up. The case is reported for its occurrence in an uncommon anatomic site and preoperative dilemma with relevant review of literature.

Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance

2008 ◽  
Vol 18 (3) ◽  
pp. 487-491 ◽  
Author(s):  
R. SALANI ◽  
R. J. KURMAN ◽  
R. GIUNTOLI ◽  
G. GARDNER ◽  
R. BRISTOW ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mutation Frequency ◽  
Clinical Stage ◽  
Serous Carcinoma ◽  
Low Grade ◽  
High Grade ◽  
Mutation Status ◽  
Tumor Dna ◽  
Serous Tumors

The TP53 mutation frequency in ovarian serous carcinomas has been reported to range between 50% and 80%, but a stringent analysis of TP53 using purified epithelial samples has not yet been performed to accurately assess the mutation frequency and to correlate it with the histologic grade. The purpose of this study was to assess the TP53 mutational profile in a relatively large series of high-grade (53 primary and 18 recurrent) and 13 low-grade ovarian serous tumors using DNA isolated from affinity-purified tumor cells and to correlate it with in vitro drug resistance. All samples were affinity purified, and the tumor DNA was analyzed for TP53 mutations in exons 4–9. In vitro drug resistance assays to carboplatin, cisplatin, paclitaxel, and taxotere were performed on the same tumor samples and correlated with the TP53 mutation status. TP53 mutations were detected in 57 (80.3%) of 71 high-grade carcinomas and in one (7.8%) of 13 low-grade serous tumors (an invasive low-grade serous carcinoma). The mutations were predominantly missense mutations (59.6%). TP53 mutations were associated with high-grade serous carcinomas and recurrent disease (P < 0.0001). There was no statistically significant correlation between TP53 mutation status and drug resistance assays or clinical stage (P > 0.25). The frequency of TP53 mutations using purified tumor DNA from ovarian serous carcinomas was 80.3%, which is much higher than previously reported. Furthermore, we found that TP53 is not directly involved in the development of drug resistance in high-grade ovarian serous carcinomas.

Changes in the Extracellular Matrix Are Associated With the Development of Serous Tubal Intraepithelial Carcinoma Into High-Grade Serous Carcinoma

2017 ◽  
Vol 27 (6) ◽  
pp. 1072-1081 ◽  
Author(s):  
Sophieke C.H.A. van der Steen ◽  
Johan Bulten ◽  
Koen K. Van de Vijver ◽  
Toin H. van Kuppevelt ◽  
Leon F.A.G. Massuger
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Serous Carcinoma ◽  
High Grade ◽  
Full Spectrum ◽  
Preinvasive Lesions ◽  
Intraepithelial Carcinoma ◽  
Screening And Prevention ◽  
Step Transition ◽  
Intraepithelial Lesions

ObjectiveThe identification of a marker for early progression of preinvasive lesions into invasive pelvic high-grade serous carcinoma (HGSC) may provide novel handles for innovative screening and prevention strategies. The interplay between cancer cells and the extracellular matrix (ECM) is one of the main principles in cancer development and growth, but has been largely neglected in preinvasive lesions. This is the first study addressing the involvement of the ECM in the “step-by-step” transition of normal fallopian tube epithelium into preinvasive lesions, and eventually the progression of preinvasive lesions into invasive HGSC.MethodsThe expression of highly sulfated chondroitin sulfate (CS-E), a characteristic glycosaminoglycan of the cancer-associated ECM, was assessed by immunohistochemistry in a large cohort of precursor lesions of the full spectrum of HGSC development, including 97 serous tubal intraepithelial carcinomas (STICs), 27 serous tubal intraepithelial lesions, and 24 p53 signatures. In addition, the immunological reactivity in the microenvironment was evaluated.ResultsIncreased stromal expression of highly sulfated CS-E was observed in 3.7%, 57.7%, and 90.6% of serous tubal intraepithelial lesions, STICs, and invasive HGSCs, respectively (P < 0.001). No or limited expression was found in p53 signatures and normal tubal epithelium (compared with STIC, P < 0.001). A gradual increase in the amount of CS-E expression between STIC and paired HGSC was demonstrated. Intense stromal CS-E expression in STIC was significantly associated with an immune infiltrate (P < 0.001).ConclusionsOur study showed that increased stromal CS-E expression is related to the degree of the tubal epithelium abnormality. Specific alterations in the ECM (ie, CS-E expression) occur early in pelvic HGSC development and may represent a novel biomarker of early cancer progression, useful for the identification of novel clinical strategies.

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