Investigating the Effects of Oocytes on Proliferation Rate and Gene Expression of Mouse Ovarian Surface Epithelium-Derived Cancer Lines

The origin of the most common form of ovarian cancer (OC), epithelial OC (EOC), remains a contentious issue. Due to disease heterogeneity, EOC is unlikely to originate from a single progenitor. This research explores an alternative hypothesis for the origin of EOC. During ovarian development, granulosa cells (GC) recruited from the ovarian surface epithelium (OSE) associate with oocytes. During follicular growth, oocyte-secreted growth factors (OSF) facilitate GC phenotype and function. Thus, if oocytes are lost prematurely from non-growing follicles, naïve GC remain. These cells, devoid of their germ cell regulator, may proliferate leading to neoplastic transformation and heterogeneous tumour phenotypes.

This study aimed to elucidate the effects of OSF on (i) proliferation of, and (ii) candidate gene expression in, two mouse OSE-derived cancer cell lines, namely mOSE T2 (p53-/-/Akt/c-myc) and BR (p53-/-/Brca1-/-/Akt/c-myc). The OSF tested were oocyte-secreted media (OSM) containing rat OSF, as well recombinant (rec) porcine (p) BMP15 and pGDF9. Tritiated-thymidine uptake was used as a measure of cell proliferation and quantitative PCR was performed to measure gene expression levels of Cdh1 (epithelial marker), Foxl2 (granulosa cell marker), Dab2 and Muc16 (cancer markers).

Exposure of mOSE T2 cells to OSM, but not rec pBMP15+pGDF9, resulted in decreased (P<0.02) proliferation rate but no change was observed in mOSE BR cells. Additionally, a decrease (P<0.02) in Muc16 mRNA levels was observed only in the T2 cell line incubated with OSM, but not rec pBMP15+pGDF9 and the BR cell line remained unaffected. Interestingly, Muc16 and Bmpr2 mRNA levels were lower overall in the mOSE BR, compared to the T2, cell line.

In summary, both proliferation rate and expression levels of the tumourigenesis marker Muc16 were reduced in the mOSE T2 cell line after the addition of OSF. This supports the alternative hypothesis that proliferation of naïve OSE-derived GC is kept in check by OSF however, upon premature loss of oocytes or more specifically in the absence of OSF, these cells may proliferate and develop into EOC. Importantly, OSF were unable to suppress proliferation rate and Muc16 mRNA levels in cancer cells with a Brac1 mutation.