RESUMO
Inhibin-α knockout (Inha-/-) female mice develop sex cord-stromal ovarian cancer with complete penetrance and previous studies demonstrate that the pituitary gonadotropins (FSH and LH) are influential modifiers of granulosa cell tumor development and progression in inhibin-deficient females. Recent studies have demonstrated that Inha-/- ovarian follicles develop precociously to the early antral stage in prepubertal mice without any increase in serum FSH. These studies suggest that in the absence of inhibins, granulosa cells differentiate abnormally and thus at sexual maturity may undergo an abnormal response to gonadotropin signaling contributing to tumor development. To test this hypothesis, we stimulated immature wild-type and Inha-/- female mice with gonadotropin analogs prior to tumor formation and subsequently examined gonadotropin-induced ovarian follicle development as well as preovulatory and human chorionic gonadotropin-induced gene expression changes in granulosa cells. We find that at 3 wk of age, inhibin-deficient ovaries do not show further antral development or undergo cumulus expansion. In addition, there are widespread alterations in the transcriptome of gonadotropin-treated Inha-/- granulosa cells, with significant changes in genes involved in extracellular matrix and cell-cell communication. These data indicate the gonadotropins initiate an improper program of cell differentiation prior to tumor formation in the absence of inhibins.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Gonadotropinas/farmacologia , Células da Granulosa/efeitos dos fármacos , Inibinas/genética , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , Animais , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Perfilação da Expressão Gênica , Células da Granulosa/metabolismo , Inibinas/deficiência , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Folículo Ovariano/metabolismo , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Ovulação/efeitos dos fármacos , Ovulação/genética , Ovulação/metabolismo , Ovulação/fisiologia , Estudos de Validação como AssuntoRESUMO
Granulosa cell tumors (GCTs) of the ovary are rare sex cord stromal tumors. Although generally indolent, GCTs recur, and if not diagnosed and treated in early stages, survival rates are significantly shortened. Very little is known regarding GCT etiology. Because of the low incidence of cases and lack of standard diagnostics, mouse models for granulosa cell tumors are a valuable tool for studying GCTs and provide models for developing diagnostic and treatment strategies. We recently developed a novel mouse model of metastatic granulosa cell tumors by genetic deletion of the bone morphogenetic protein signaling transcription factors (SMADs) in granulosa cells of the ovary. Histological and serum hormone analyses reveal that this mouse model most closely resembles the juvenile form of GCT. We further analyzed samples of human juvenile GCT (JGCT) for expression of anti-Müllerian hormone and activation of two major signaling pathways: TGFbeta/SMAD2/3 and wingless-related mouse mammary tumor virus integration site (Wnt)/beta-catenin. The TGFbeta family is active in mouse Smad1-Smad5 double knockout tumors, and here we show that this pathway, but not the beta-catenin pathway, is activated in samples of human JGCT. These data suggest that the SMAD family, possibly through disruption of SMAD1/5 or activation of SMAD2/3 may contribute to the pathogenesis of JGCT in humans.
Assuntos
Modelos Animais de Doenças , Ovário/metabolismo , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo , Adolescente , Animais , Hormônio Antimülleriano/metabolismo , Criança , Pré-Escolar , Feminino , Tumor de Células da Granulosa/genética , Tumor de Células da Granulosa/metabolismo , Tumor de Células da Granulosa/patologia , Humanos , Imuno-Histoquímica , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ovário/patologia , Proteína Smad1/genética , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad5/genética , Análise de SobrevidaRESUMO
Targeted disruption of the inhibin alpha gene (Inha(-)(/)(-)) in mice results in an ovarian phenotype of granulosa cell tumors that renders the animals infertile. Little is known about the reproductive defects prior to tumor development. Here, we report novel data on early follicle dynamics in Inha(-)(/)(-) mice, which demonstrate that inhibin alpha has important consequences upon follicle development. Morphological changes in both germ and somatic cells were evident in postnatal day 12 ovaries, with Inha(-/-) mice exhibiting numerous multilayered follicles that were far more advanced than those observed in age-matched controls. These changes were accompanied by alterations in follicle dynamics such that Inha(-/-) ovaries had fewer follicles in the resting pool and more committed in the growth phase. Absence of inhibin alpha resulted in advanced follicular maturation as marked by premature loss of anti-Müllerian hormone (AMH) in secondary follicles. Additionally, gene expression analysis revealed changes in factors known to be vital for oocyte and follicle development. Together, these data provide key evidence to suggest that regulation of the inhibin/activin system is essential for early folliculogenesis in the prepubertal mouse ovary.
