The fate of granulosa cells following premature oocyte loss and the development of ovarian cancers

Abstract

This review examines the importance of the epithelial origin of granulosa cells and their possible contribution to the development of ovarian cancers in three animal models. We hypothesise that undifferentiated granulosa cells, devoid of their germ cell regulator, retain their embryonic plasticity and may give rise to ovarian cancers of epithelial origin. Dazl-KO and FancD2-KO mice and BMP15-KO sheep are animal models in which germ cells or oocytes are lost at specific stages of follicular formation or growth, leaving behind clusters of residual, but healthy somatic cells. A common feature in Dazl-and Fancd2-KO animals following germ cell/oocyte loss is the presence of sex cords and intraovarian epithelial ducts or tubules. In Dazl-KO mice, cord/tubule-like structures, OSE invaginations and clusters of steroidogenic cells became increasingly prominent with age, but these abnormal structures remained benign. In Fancd2-KO mice, the formation of sex-cords and intraovarian tubules lead to the formation of tumours with multiple phenotypes including luteomas, papillary cysts and malignant carcinomas (e.g. adenocarcinomas). In BMP15-KO sheep, oocytes die as follicles start to grow, leaving 'nodules' containing granulosa cells with a capacity to respond to follicle stimulating hormone and synthesize inhibin. Thereafter, these nodules coalesced and a range of benign solid or semi-solid tumour phenotypes developed. We conclude that premature loss of oocytes, but not granulosa cells, leads to tumour formation with multiple phenotypes. Moreover, the severity of tumour development is linked to both the specificity of the mutation and the timing of oocyte loss relative to that of follicular formation.

Loss of oocytes due to conditional ablation of Murine double minute 2 (Mdm2) gene is p53‐dependent and results in female sterility

“…Another possible explanation may involve the atypical hormonal environment generated within immature ovaries. The use of Zp3-cre has also already proven fully efficient to eradicate all growing oocytes, and in this case somatic cells were proven to undergo some 'precocious luteinization' or form a cord-like structure [7,30]. No indication for such an event was observed here, suggesting that the maintenance of few healthy growing follicles probably maintains an environment prohibiting such abnormal acquisition of precocious steroidogenic features in granulosa cells having lost their oocyte.…”

Constitutive Activation of PI3K in Oocyte Induces Ovarian Granulosa Cell Tumors

“…The development of vaginal adenocarcinoma by in utero exposure to diethylstilbestrol is the best-documented clinical cases of such transformation: diethylstilbestrol causes precancerous lesions by altering epithelial cell fate through disruption of cell-cell communication (40). Ovarian malignancies developed in Fancd2 and Dazl null mutant mice from altered micro and endocrine environments through premature oocyte loss (41). These studies affirm the pivotal role of oocytes in the maintenance of ovarian homeostasis and the repression of malignancies.…”

Mutation in the protease cleavage site of GDF9 increases ovulation rate and litter size in heterozygous ewes and causes infertility in homozygous ewes

“…The clusters of granulosa‐like cells that persist after the collapse of the oocyte in VV ewes were also observed in sheep homozygous of other polymorphisms with a similar phenotype (Pitman et al . ); however, the fate of these cells remain to be elucidated.…”