A mouse model for endometrioid ovarian cancer arising from the distal oviduct

Abstract

Ovarian cancer is the deadliest gynecological malignancy in Western countries. Early detection, however, is hampered by the fact that the origin of ovarian cancer remains unclear. Knowing that in a high percentage of endometrioid ovarian cancers Wnt/b-catenin signaling is activated, and in view of the hypothesis that ovarian cancer may originate from the distal oviduct, we studied mice in which Wnt/b-catenin signaling was activated in M€ ullerian duct-derived tissues. Conditional adenomatous polyposis coli (Apc) knockout mice were used to study the activation of Wnt/b-catenin signaling in M€ ullerian duct-derived organs. These Pgr Cre/1 ;Apc ex15lox/lox mice (n 5 44) were sacrificed at 10, 20, 40 and 80 weeks and uterus, oviduct, ovaries and surrounding fat tissues were assessed using immunohistochemistry. Using nuclear b-catenin staining, Wnt/b-catenin signaling activation was confirmed in the entire epithelium of the adult M€ ullerian duct (fimbriae, oviduct and endometrium), but was absent in ovarian surface epithelium cells (OSEs). Besides endometrial hyperplasia, in 87.2% of mice intraepithelial lesions of the distal oviduct were found, whereas OSEs remained unaffected. In addition, 62.5% of mice developed tumors in the distal and fimbrial part of the oviduct. In the ovaries, mainly at young age, in 16.3% of mice, simple epithelial cysts were noted, which developed further into endometrioid ovarian tumors, resembling human endometrioid ovarian cancer (27.9% of mice). Next to this, locoregional growth in the utero-ovarian ligament was also shown. Here, for the first time, mutations (activation of Wnt/b-catenin) in the distal oviduct result in precursor lesions that develop into ovarian tumors, resembling human endometrioid ovarian cancer.Epithelial ovarian cancer is the deadliest gynecological malignancy in Western countries, accounting for more than 140,000 deaths each year worldwide. 1 As ovarian cancer survival is highly dependent on the tumor stage at diagnosis, early detection is key to decreasing death rate. Unfortunately, the origin of ovarian cancer remains unclear, making early discovery very difficult.For decades, ovarian surface epithelial cells (OSEs) have been appointed as the primary origin of epithelial ovarian cancer despite the fact that precursor lesions were never found.2 Over recent years, however, researchers have proposed different origins for epithelial ovarian cancer: the secondary M€ ullerian system, 3 the distal oviduct and fimbriae 4,5 and recently the transitional zone between OSEs and mesothelium at the hilial region of the ovary.6 Dubeau 3 and Piek et al. 7 were among the first to question OSEs as the only origin of ovarian cancer. In his original article, Dubeau 3 argues that the strong resemblance of ovarian epithelial tumors to tumors arising from organs embryologically derived from the M€ ullerian ducts and warrants the consideration that components of the secondary M€ ullerian system play a role in ovarian tumorigenesis. Piek et al. described dysplastic lesions in prophylac...

Integrating modern approaches to pathogenetic concepts of malignant transformation of endometriosis

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Impact of oviductal versus ovarian epithelial cell of origin on ovarian endometrioid carcinoma phenotype in the mouse

“…Interestingly, van der Horst et al recently employed the progesterone receptor (Pgr) promoter to drive Cre-mediated inactivation of Apc in Müllerian epithelium, including the endometrium and oviduct. These mice develop endometrial hyperplasia and oviductal intraepithelial lesions and carcinomas, as well as ovarian ECs proposed to arise from ovarian inclusion cysts and glands [34]. Although we are fully aware that the majority of human 'ovarian' ECs are not thought to arise from the Fallopian tube, neither do they likely arise from the OSE.…”

Epithelial ovarian cancer: Evolution of management in the era of precision medicine

“…Loss of expression of mismatch‐repair genes (mutS homolog 6 [ MSH6 ], MSH2 , MLH1 , and PMS1 homolog 2, mismatch repair system component [ PMS2 ]) is a characteristic of Lynch syndrome and is found in nearly 8% of Lynch syndrome‐associated endometrioid and clear cell ovarian cancers . An animal model has shown that deregulated WNT/β‐catenin and PI3K/PTEN signaling pathways are pivotal in the development of murine cancers that resemble human endometrioid ovarian cancer and has implicated the distal oviduct as the site of origin because of notable precursor lesions that lead to endometrioid ovarian cancer . Molecular profiling of human endometrioid ovarian cancers revealed that the most prevalent mutations are similar to those observed in OCCC and include PIK3CA (40%), ARID1A (30%), KRAS (30%), PTEN (16%), and PPP2R1A (16%) .…”