scholarly journals Progesterone Prevents High-Grade Serous Ovarian Cancer by Inducing Necroptosis of p53-Defective Fallopian Tube Epithelial Cells

Cell Reports ◽  
2017 ◽  
Vol 18 (11) ◽  
pp. 2557-2565 ◽  
Author(s):  
Na-Yiyuan Wu ◽  
Hsuan-Shun Huang ◽  
Tung Hui Chao ◽  
Hsien Ming Chou ◽  
Chao Fang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Cells ◽  
Fallopian Tube ◽  
High Grade ◽  
Serous Ovarian Cancer

scholarly journals Metformin induces distinct bioenergetic and metabolic profiles in sensitive versus resistant high grade serous ovarian cancer and normal fallopian tube secretory epithelial cells

Oncotarget ◽  
2017 ◽  
Vol 9 (3) ◽  
pp. 4044-4060 ◽  
Author(s):  
Melissa Hodeib ◽  
Martin P. Ogrodzinski ◽  
Laurent Vergnes ◽  
Karen Reue ◽  
Beth Y. Karlan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Cells ◽  
Fallopian Tube ◽  
Metabolic Profiles ◽  
High Grade ◽  
Serous Ovarian Cancer

scholarly journals TP53 loss initiates chromosomal instability in high-grade serous ovarian cancer

2021 ◽  
Author(s):  
Daniel Bronder ◽  
Darawalee Wangsa ◽  
Dali Zong ◽  
Thomas J. Meyer ◽  
René Wardenaar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Ovarian Cancer ◽  
Dna Replication ◽  
Epithelial Cells ◽  
Fallopian Tube ◽  
Chromosomal Instability ◽  
Whole Genome ◽  
High Grade ◽  
Serous Ovarian Cancer

ABSTRACTHigh-grade serous ovarian cancer (HGSOC) originates in the fallopian tube epithelium and is characterized by ubiquitous TP53 mutation and extensive chromosomal instability (CIN). While the direct causes of CIN are errors during DNA replication and/or chromosome segregation, mutations in genes encoding DNA replication and mitotic factors are rare in HGSOC. Thus, the drivers of CIN remain undefined. We therefore asked whether the oncogenic lesions that are frequently observed in HGSOC are capable of driving CIN via indirect mechanisms. To address this question, we genetically manipulated non-transformed hTERT-immortalized human fallopian tube epithelial cells to model homologous recombination deficiency (HRD) and oncogenic signalling in HGSOC. Using CRISPR/Cas9-mediated gene editing, we sequentially mutagenized the tumour suppressors TP53 and BRCA1, followed by overexpression of the MYC oncogene. Single-cell shallow-depth whole-genome sequencing revealed that loss of p53 function was sufficient to lead to the emergence of heterogenous karyotypes harbouring whole chromosome and chromosome arm aneuploidies, a phenomenon exacerbated by subsequent loss of BRCA1 function. In addition, whole-genome doubling events were observed in independent p53/BRCA1-deficient subclones. Global transcriptomics showed that TP53 mutation was also sufficient to deregulate gene expression modules involved in cell cycle commitment, DNA replication, G2/M checkpoint control and mitotic spindle function, suggesting that p53-deficiency induces cell cycle distortions that could precipitate CIN. Again, loss of BRCA1 function and MYC overexpression exacerbated these patterns of transcriptional deregulation. Thus, our observations support a model whereby the initial loss of the key tumour suppressor TP53 is sufficient to deregulate gene expression networks governing multiple cell cycle controls, and that this in turn is sufficient to drive CIN in pre-malignant fallopian tube epithelial cells.SUMMARY STATEMENTHigh-grade serous ovarian cancer is defined by TP53 mutation and chromosomal instability, the cause of which remains poorly understood. We developed a novel model system that implicates cell cycle deregulation upon p53-loss as cause of CIN.

scholarly journals Prolactin signaling drives tumorigenesis in human high grade serous ovarian cancer cells and in a spontaneous fallopian tube derived model

2018 ◽  
Vol 433 ◽  
pp. 221-231 ◽  
Author(s):  
Subbulakshmi Karthikeyan ◽  
Angela Russo ◽  
Matthew Dean ◽  
Daniel D. Lantvit ◽  
Michael Endsley ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Fallopian Tube ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Prolactin Signaling

scholarly journals Integrated Molecular Profiling Studies to Characterize the Cellular Origins of High-Grade Serous Ovarian Cancer

2018 ◽  
Author(s):  
Kate Lawrenson ◽  
Marcos A.S. Fonseca ◽  
Felipe Segato ◽  
Janet M. Lee ◽  
Rosario I. Corona ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Cells ◽  
Tumor Development ◽  
Molecular Profiling ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cell Of Origin ◽  
Ovarian Cancers ◽  
Integrative Analyses ◽  
Ovarian Surface Epithelial

AbstractHistorically, high-grade serous ovarian cancers (HGSOCs) were thought to arise from ovarian surface epithelial cells (OSECs) but recent data implicate fallopian tube secretory epithelial cells (FTSECs) as the major precursor. We performed transcriptomic and epigenomic profiling to characterize molecular similarities between OSECs, FTSECs and HGSOCs. Transcriptomic signatures of FTSECs were preserved in most HGSOCs reinforcing FTSECs as the predominant cell-of-origin; though an OSEC-like signature was associated with increased chemosensitivity (Padj= 0.03) and was enriched in proliferative-type tumors, suggesting a dualistic model for HGSOC origins. More super-enhancers (SEs) were shared between FTSECs and HGSOCs than between OSECS and HGSOCs (P< 2.2 × 10−16). SOX18, ELF3 and EHF transcription factors (TFs) coincided with HGSOC SEs and represent putative novel drivers of tumor development. Our integrative analyses support a predominantly fallopian origin for HGSOCs and indicate tumorigenesis may be driven by different TFs according to cell-of-origin.

scholarly journals Cell Origins of High-Grade Serous Ovarian Cancer

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 433 ◽  
Author(s):  
Jaeyeon Kim ◽  
Eun Park ◽  
Olga Kim ◽  
Jeanne Schilder ◽  
Donna Coffey ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Risk ◽  
Fallopian Tube ◽  
Malignant Tumors ◽  
Clinical Importance ◽  
Serous Carcinoma ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Clinical Behavior ◽  
High Risk Women

High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is often not clear where HGSC truly originates. Traditionally, the ovarian surface epithelium (OSE) was long believed to be the origin of HGSC. Since the late 1990s, the fallopian tube epithelium has emerged as a potential primary origin of HGSC. Particularly, serous tubal intraepithelial carcinoma (STIC), a noninvasive tumor lesion formed preferentially in the distal fallopian tube epithelium, was proposed as a precursor for HGSC. It was hypothesized that STIC lesions would progress, over time, to malignant and metastatic HGSC, arising from the fallopian tube or after implanting on the ovary or peritoneum. Many clinical studies and several mouse models support the fallopian tube STIC origin of HGSC. Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations. Yet not all STIC lesions appear to progress to clinical HGSCs, nor would all HGSCs arise from STIC lesions, even in high-risk women. Moreover, the clinical importance of STIC remains less clear in women in the general population, in which 85–90% of all HGSCs arise. Recently, increasing attention has been brought to the possibility that many potential precursor or premalignant lesions, though composed of microscopically—and genetically—cancerous cells, do not advance to malignant tumors or lethal malignancies. Hence, rigorous causal evidence would be crucial to establish that STIC is a bona fide premalignant lesion for metastatic HGSC. While not all STICs may transform into malignant tumors, these lesions are clearly associated with increased risk for HGSC. Identification of the molecular characteristics of STICs that predict their malignant potential and clinical behavior would bolster the clinical importance of STIC. Also, as STIC lesions alone cannot account for all HGSCs, other potential cellular origins of HGSC need to be investigated. The fallopian tube stroma in mice, for instance, has been shown to be capable of giving rise to metastatic HGSC, which faithfully recapitulates the clinical behavior and molecular aspect of human HGSC. Elucidating the precise cell(s) of origin of HGSC will be critical for improving the early detection and prevention of ovarian cancer, ultimately reducing ovarian cancer mortality.

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.

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