High-grade serous ovarian cancer arises from fallopian tube in a mouse model

Abstract

Although ovarian cancer is the most lethal gynecologic malignancy in women, little is known about how the cancer initiates and metastasizes. In the last decade, new evidence has challenged the dogma that the ovary is the main source of this cancer. The fallopian tube has been proposed instead as the primary origin of high-grade serous ovarian cancer, the subtype causing 70% of ovarian cancer deaths. By conditionally deleting Dicer, an essential gene for microRNA synthesis, and Pten, a key negative regulator of the PI3K pathway, we show that high-grade serous carcinomas arise from the fallopian tube in mice. In these Dicer-Pten doubleknockout mice, primary fallopian tube tumors spread to engulf the ovary and then aggressively metastasize throughout the abdominal cavity, causing ascites and killing 100% of the mice by 13 mo. Besides the clinical resemblance to human serous cancers, these fallopian tube cancers highly express genes that are known to be up-regulated in human serous ovarian cancers, also demonstrating molecular similarities. Although ovariectomized mice continue to develop high-grade serous cancers, removal of the fallopian tube at an early age prevents cancer formation-confirming the fallopian tube origin of the cancer. Intriguingly, the primary carcinomas are first observed in the stroma of the fallopian tube, suggesting that these epithelial cancers have a mesenchymal origin. Thus, this mouse model demonstrates a paradigm for the origin and initiation of high-grade serous ovarian carcinomas, the most common and deadliest ovarian cancer.epithelial ovarian cancer | oviduct | mesenchymal-to-epithelial transition | carcinoma initiation E pithelial ovarian cancer, accounting for 90% of all ovarian tumors, is grouped into four major histologic types: serous (70%), endometrioid (10-15%), clear-cell (10%), and mucinous (3%) carcinomas (1). The serous-type cancers are also overwhelmingly high-grade (90%)-the culprit of 70% of ovariancancer deaths and a key contributor to an overall ovarian cancer 5-yr survival rate of 31% (2-4). Most cases of high-grade serous ovarian cancers are diagnosed at advanced stages, when the tumors have already metastasized. Despite the steady improvement of surgery and chemotherapy, >90% of women with advanced ovarian cancers die after the cancer relapses (5). Early detection of these high-grade serous carcinomas is thus key to reducing ovarian cancer deaths (6). However, the origin and molecular pathogenesis of these high-grade serous ovarian cancers are largely unknown (1, 6).Despite widespread peritoneal metastasis commonly seen in ovarian cancer at diagnosis, the ovary has long been considered the primary origin of this cancer-hence the name ovarian cancer. However, precursor lesions have not been identified in the ovary (1, 7). Over the past decade, new evidence has emerged to propose a different source of ovarian cancer: the fallopian tube (7,8). After women with hereditary breast and ovarian cancer-susceptibility gene (BRCA1, BRCA2) mutations have their ovaries and fallop...

Stem‐Like Epithelial Cells Are Concentrated in the Distal End of the Fallopian Tube: A Site for Injury and Serous Cancer Initiation

“…It is now believed that dissemination of serous cancers may occur by exfoliation of tumor cells originating from the distally located TICs (reviewed in [7]). Recent mouse models have shown transformation of human and mouse fallopian tube tissue into serous cancers through multiple genetic mutations [35,37]. These data suggest that serous cancers may arise from the fallopian tube.…”

“…The FTE is actively being explored as a site of initiation for serous cancers [35][36][37]. Dysplastic lesions identified typically in the distal end of the fallopian tube have been hypothesized to be precursor lesions for invasive serous cancers [38][39][40][41].…”

Recurrent DICER1 hotspot mutations in endometrial tumours and their impact on microRNA biogenesis

“…This is consistent across both the TCGA dataset (7/304) and our own local tumour bank (6/290; see supplementary material, Tables S1, S7). DICER1 hotspot mutations, although rare, were also identified in brain, colorectal and thyroid cancers (see supplementary material, TableDICER1 hotspot mutations in endometrial cancer 223 tumourigenesis beyond the spectrum of rare paediatric cancers [8][9][10][11][12][13][15][16][17][18]. DICER1 hotspot mutations and subsequent miRNA/mRNA dysregulation may therefore constitute a common oncogenic pathway in a small subset of endometrial tumours.…”

“…We identified an atypical hotspot mutation, G1809R, which is immediately adjacent to the metal-binding residue D1810, and characterized its functional impact on miRNAs and downstream signalling pathways. Using a Dicer1-null mouse fallopian tube carcinoma-derived cell line [17], we demonstrated that DICER1 hotspot mutations abolish the inhibitory effects of DICER1 on cell proliferation. Our data also suggested that loss of let-7 family miRNAs may contribute to the oncogenic properties of DICER1 hotspot mutations.…”

“…DKO172 cells, derived from a Dicer1/Pten double-knockout mouse fallopian tube tumour model [17], were maintained in Dulbecco's modified Eagle's medium (DMEM)/F12 (Hyclone) supplemented with 10% fetal bovine serum (FBS) at 37 ∘ C and 5% CO 2.…”