Identification of candidate genes associated with tubal origin of high‑grade serous ovarian cancer

Park

et al. 2018

Cancers

181

183

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.

Section: Origins Of High-grade Serous Ovarian Cancer (Hgsc)mentioning

confidence: 99%

Cell Origins of High-Grade Serous Ovarian Cancer

Park

et al. 2018

Cancers

181

183

“…DKK3’s role in CSC has not been reported and its role in cancer has been controversial 15 , 34 . DKK3 is an inhibitor of the WNT canonical pathway 15 .…”

Section: Discussionmentioning

confidence: 99%

“…We previously showed that the WNT4 and the noncanonical WNT pathway is activated in MOE:PTEN shRNA and that it contributes to cell motility and ovarian adhesion, which is thought to occur when fallopian-tube-derived tumor cells initially colonize the ovary 15 . One study reported that DKK3 is reduced in HGSOC as compared to fallopian tube control 34 . However, an analysis of the RNA expression of the Singapore dataset for HGSOC patients revealed upregulation of DKK3 when HGSOC is compared to fallopian tube ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Silencing PTEN in the fallopian tube promotes enrichment of cancer stem cell-like function through loss of PAX2

et al. 2021

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy that is primarily detected at the metastatic stage. Most HGSOC originates from the fallopian tube epithelium (FTE) and metastasizes to the ovary before invading the peritoneum; therefore, it is crucial to study disease initiation and progression using FTE-derived models. We previously demonstrated that loss of PTEN from the FTE leads to ovarian cancer. In the present study, loss of PTEN in FTE led to the enrichment of cancer stem cell markers such as LGR5, WNT4, ALDH1, CD44. Interestingly, loss of the transcription factor PAX2, which is a common and early alteration in HGSOC, played a pivotal role in the expression of cancer stem-like cells (CSC) markers and cell function. In addition, loss of PTEN led to the generation of two distinct subpopulations of cells with different CSC marker expression, tumorigenicity, and chemoresistance profiles. Taken together, these data suggest that loss of PTEN induces reprogramming of the FTE cells into a more stem-like phenotype due to loss of PAX2 and provides a model to study early events during the FTE-driven ovarian cancer tumor formation.

“…A substantial percentage (60–88%) of HGSCs originate in the fallopian tube [ 17 , 22 , 25 , 34 , 35 ], both in women with BRCA mutations and in sporadic cases [ 2 , 17 , 36 ]. The molecular profile and immunophenotype of HGSCs are more closely related to the FTE than OSE [ 22 , 37 , 38 ]. Although fallopian tube epithelial secretory cells are believed to give rise to HGSCs [ 28 ], ciliated cells may be another cell-of-origin in the fallopian tube epithelium (FTE) [ 26 ].…”

Section: Sites Of Origin Of Hgscsmentioning

confidence: 99%

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

Otsuka

2021

IJMS

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.