title: 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.
authors: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand. janet.pitman@vuw.ac.nz
authors: Janet L
authors: JL
authors: Pitman
authors: Alan S
authors: AS
authors: McNeilly
authors: Judy R
authors: JR
authors: McNeilly
authors: Laura E
authors: LE
authors: Hays
authors: Grover C
authors: GC
authors: Bagby
authors: Heywood R
authors: HR
authors: Sawyer
authors: Kenneth P
authors: KP
authors: McNatty
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D055430:Bone Morphogenetic Protein 15 / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D005260:Female; D006106:Granulosa Cell Tumor / Q000235:genetics / Q000473:pathology*; D006107:Granulosa Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009865:Oocytes / Q000166:cytology* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D016601:RNA-Binding Proteins / Q000235:genetics; D012756:Sheep
chemical_list: D055430:Bone Morphogenetic Protein 15; C508515:DAZL protein, mouse; C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; D016601:RNA-Binding Proteins