Elucidating the molecular pathways governing granulosa cell tumorigenesis.

摘要

Granulosa cell tumors comprise approximately 10% of ovarian tumors and, although rare, are clinically important due to their potential for malignancy and recurrence. Although their morphological features have been carefully described, the global changes in gene expression associated with their formation remain undetermined. To initiate this characterization, we utilized a transgenic mouse model where granulosa cell tumors occur with 100% penetrance in CF-1 mice that hypersecrete luteinizing hormone or LH (LHCTP). When this transgene is expressed in other strains of mice, including (C57BL/6 Female x CF-1 Male,Tg) F1 hybrids, luteomas develop even though LH levels remain high. This dichotomous response permits a longitudinal comparison of global changes in transcriptomes uniquely associated with either granulosa cell tumors or luteomas.;This dissertation reports numerous changes in the granulosa cell transcriptome. Furthermore, the constellation of mRNAs identified may serve as new markers for this tumor phenotype. Additional experiments indicated that periodic treatment with human chorionic gonadotropin (hCG) prevented formation of granulosa cell tumors in mice genetically predisposed to tumor development, and instead induced the appearance of luteomas. Importantly, ovarian transcriptomes from hCG-induced luteomas permitted refined confirmation of gene expression changes that were uniquely associated with either granulosa cell tumors in the permissive CF-1 genetic background or in luteomas in the F1 hybrids. Together, these dynamic changes in the ovarian transcriptome indict various signaling pathways potentially involved in mediating the actions of LH and the formation of either a luteoma or granulosa cell tumor.;One pathway identified was the Wnt/beta-catenin signaling pathway. The data suggest that this pathway participates in granulosa cell tumorigenesis and specifically differentiation. Thus, the functional significance of this signaling pathway was investigated in rat primary granulosa cells. Studies revealed that beta-catenin signaling was sufficient to induce granulosa cell steroidogenesis in the absence of contributions from LH or FSH and independently of cAMP. Furthermore, LH receptor activation induced beta-catenin signaling; suggesting that beta-catenin is a mediator of LH-induced differentiation. Additional experiments are proposed that will further elucidate the functional significance of this signaling pathway in ovarian physiology, pathology, and tumorigenesis.