Epithelialization of mouse ovarian tumor cells originating in the fallopian tube stroma

Abstract

Epithelial ovarian carcinoma accounts for 90% of all ovarian cancer and is the most deadly gynecologic malignancy. Recent studies have suggested that fallopian tube fimbriae can be the origin of cells for high-grade serous subtype of epithelial ovarian carcinoma (HGSOC). A mouse HGSOC model with conditional Dicer-Pten double knockout (Dicer-Pten DKO) developed primary tumors, intriguingly, from the fallopian tube stroma. We examined the growth and epithelial phenotypes of the Dicer-Pten DKO mouse tumor cells contributable by each gene knockout. Unlike human ovarian epithelial cancer cells that expressed full-length E-cadherin, the Dicer-Pten DKO stromal tumor cells expressed cleaved E-cadherin fragments and metalloproteinase 2, a mixture of epithelial and mesenchymal markers. Although the Dicer-Pten DKO tumor cells lost the expression of mature microRNAs as expected, they showed high levels of tRNA fragment expression and enhanced AKT activation due to the loss of PTEN function. Introduction of a Dicer1-expressing construct into the DKO mouse tumor cells significantly reduced DNA synthesis and the cell growth rate, with concurrent diminished adhesion and ZO1 epithelial staining. Hence, it is likely that the loss of Dicer promoted mesenchymal-epithelial transition in fallopian tube stromal cells, and in conjunction with Pten loss, further promoted cell proliferation and epithelial-like tumorigenesis.

CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity

“…The production of ID8 Trp53 −/− cells was described previously 14 . OvidT 479 cells were isolated from tumours arising in Dicer-Pten double knockout (DKO) mice ( Amhr2 cre/ + Dicer flox/flox Pten flox/flox ) as previously described 15 , 27 .…”

In Vivo Cell Fate Tracing Provides No Evidence for Mesenchymal to Epithelial Transition in Adult Fallopian Tube and Uterus

“…Collectively, these studies firmly established that oncogenic transformation of PAX8 + epithelial cells lead to the development of serous ovarian cancer. In contrast, a study described that the deletion of Dicer and Pten in AMHR2 + oviductal stromal cells results in the development of serous ovarian cancer, suggesting the mesenchymal origin of these epithelial cancers ( Hua et al, 2016 ; Kim et al, 2012 ). Here, we performed cell-lineage-tracing analysis of oviductal stromal and epithelial cells and showed that mesenchymal cells do not transdifferentiate to epithelial cells and that the oviductal epithelium in adult mice is maintained by PAX8 + epithelial cells.…”

“…Interestingly, these AMHR2 + or SM22α + stromal-cell-derived epithelial cells are generally not present in the normal endometrial epithelium and only appear after physical or postpartum injury ( Huang et al, 2012 ; Patterson et al, 2013 ; Yin et al, 2019 ). Similarly, oviductal AMHR2 + stromal cells have been shown to undergo epithelialization and, upon oncogenic transformation, develop serous ovarian cancer ( Hua et al, 2016 ; Kim et al, 2012 ). These studies appear to challenge the more traditional view of the adult epithelial regeneration and carcinogenesis in which epithelial cells are known to have a central role ( Daikoku et al, 2008 , 2011 ; Ghosh et al, 2017 ; Perets et al, 2013 ; Russo et al, 2018 ; Sherman-Baustet al, 2014 ; Wu et al, 2016 ).…”

The Functions of MicroRNA-200 Family in Ovarian Cancer: Beyond Epithelial-Mesenchymal Transition

“…Furthermore, our work has shown that nuclear phosphoprotein Pinin and some epigenetic transcriptional co-repressor proteins play key roles in epithelial cell identity, growth and multidimensional adhesion of ovarian cancer cells [ 55 ]. A recent characterization of a mouse model of HGSOC originating in the fallopian tube stroma showed epithelialization of the stromal cancer cells to support tumorigenesis [ 56 ]. Interestingly, increased expression of miR-200 and E-cadherin was also identified in the laying hen model of spontaneous ovarian carcinoma [ 27 , 28 ], implicating the importance of this conserved pathway in ovarian cancer development.…”