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 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 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 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 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.

scholarly journals A descriptive study on histopathology of fallopian tube in neoplastic surface epithelial ovarian tumors

2019 ◽  
Vol 8 (2) ◽  
pp. 385
Author(s):  
Ashna C. Manuel ◽  
Radhamani M. V. ◽  
Priya V. ◽  
Deepa S.
Keyword(s):  
Ovarian Cancer ◽  
Fallopian Tube ◽  
Protective Factor ◽  
Early Stage ◽  
Oral Contraceptive Pill ◽  
Ovarian Surface Epithelium ◽  
Descriptive Study ◽  
Ovarian Tumors ◽  
Surface Epithelium ◽  
Early Stage Disease

Background: The incidence of cancer is increasing day by day. Ovarian cancer ranks as the fifth leading cause of cancer related death among women worldwide. The cure rate of early stage disease is high. The accepted view is that ovarian cancer arises from ovarian surface epithelium. Recent evidence suggested that around sixty percentage of women without a genetic predisposition who developed sporadic ovarian cancer also have early tubal lesion and cancer. The present study aims to find out the histopathology of fallopian tube in neoplastic surface epithelial ovarian tumour.Methods: A descriptive study was conducted among hundred women who had undergone surgery for malignant and benign surface epithelial ovarian tumor from Govt. Medical College, Kottayam for one year from January-December 2017.Results: Fifty percent of the patients had malignant surface epithelial ovarian tumors.Conclusions: The risk factors of malignant surface epithelial ovarian tumors include age above fifty years and post-menopausal women. Whereas oral contraceptive pill use is a protective factor against malignant surface epithelial ovarian tumors. The fimbrial end of fallopian tube is the site of origin of malignancy in high grade ovarian epithelial carcinoma. So, prophylactic bilateral salpingectomy should be encouraged in all patients who have completed family and undergoing hysterectomy. This will reduce the morbidity and mortality due to ovarian carcinoma.

Risk-Reducing Salpingectomy as Preventative Strategy for Pelvic Serous Cancer

2013 ◽  
Vol 23 (3) ◽  
pp. 417-421 ◽  
Author(s):  
Charles K. Anderson ◽  
Shannon Wallace ◽  
Maryam Guiahi ◽  
Jeanelle Sheeder ◽  
Kian Behbakht ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fallopian Tube ◽  
Early Stage ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
New Paradigm ◽  
Preventative Strategy ◽  
Risk Reducing ◽  
Low Risk Women ◽  
Early Stage Ovarian Cancer

AbstractThe systemic failure to detect early-stage ovarian cancer may be attributed to a significant amount of pelvic serous cancers arising from the fallopian tube rather than the ovarian surface epithelium. This article reviews the possibility of applying risk-reducing salpingectomy as a new paradigm for the prevention of pelvic serous cancer in both high- and low-risk women.

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