Cell Origins of High-Grade Serous Ovarian Cancer

Abstract

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.

WNT and inflammatory signaling distinguish human Fallopian tube epithelial cell populations

“…Our bulk organoid formation results therefore strengthen the notion that the distal TE's stem/progenitor cells or their environment differ in some way from those of the proximal region. These findings are consistent with observations that the distal region of the Fallopian tube more frequently contains putative HGSC precursor lesion (Kim et al, 2018;Lee et al, 2007;Schmoeckel et al, 2017).…”

“…Ovarian/extra-uterine high-grade serous carcinoma (HGSC) is the most common and most lethal gynecological malignancy, accounting for nearly 14,000 deaths per year in the United States (Siegel et al, 2020). There is mounting evidence indicating that serous tubal intraepithelial carcinomas (STICs) are precursor lesions to some HGSCs (Kim et al, 2018;Labidi-Galy et al, 2017;Soong et al, 2018). Moreover, in vivo perturbations of TP53, MYC, and hTERT and RB family genes, which are associated with pathways frequently perturbed in HGSC (Siegel et al, 2020), cause human TE cells to adopt traits reminiscent of STICs/HGSCs (Yamamoto et al, 2016).…”

“…Moreover, in vivo perturbations of TP53, MYC, and hTERT and RB family genes, which are associated with pathways frequently perturbed in HGSC (Siegel et al, 2020), cause human TE cells to adopt traits reminiscent of STICs/HGSCs (Yamamoto et al, 2016). It has been noted that STICs tend to occur more frequently in the distal region (closer to the ovary) than in the proximal region (farther from the ovary) of the Fallopian tube, also known as the uterine tube (Kim et al, 2018;Lee et al, 2007;Nassar and Blanpain, 2016).…”

Boosting the apoptotic response of high‐grade serous ovarian cancers with CCNE1 amplification to paclitaxel in vitro by targeting APC/C and the pro‐survival protein MCL‐1

“…HGSOC represents a form of epithelial ovarian cancer. 37 It is a fundamentally aggressive disease, which is commonly detected at advance stages and is responsible for the majority of ovarian cancer deaths. 38 Paclitaxel, along with platinum agents, is a component of the front-line therapy for HGSOCs.…”

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

“…It has also been postulated that the detachment of fimbrial secretory cells with a 'p53 signature' adjacent to OSE may also be the origin of HGSOC [2]. These studies indicate the different anatomical origins of HGSOC, which complicates the pathology and molecular characteristics of this cancer [2,30].…”