Heritable granulosa cell (GC) tumors that develop in young SWR and SWR- derived strains of mice follow a predictable course of changes from preneoplastic follicles at 24-28 days, to primary tumors at 42 days, and finally metastatic disease by 7 months. The SWR granulosa cell tumors share remarkable morphologic, endocrinologic, and malignant properties with human Juvenile granulosa cell tumors. The long term objective of research with this murine model is to gain a comprehensive insight to the genetic and biochemical events that result in tumorigenesis of ovarian granulosa cells. Given that the major regulator of granulosa cell proliferation is follicle stimulating hormone (FSH), the hypothesis to be tested in this application is that FSH regulatory control of granulosa cell proliferation is lost as these cells transit through the progressive stage to tumorigenesis. A special genetic stock of mice varying two mutant genes severe combined immune deficiency (scid) and hypogonadal (hpg) has been assembled as double homozygotes, scid/scid,hpg/hpg, to accomplish the following specific aims: 1) To establish whether the initiation of unrestrained granulose cell proliferation,ie. GC tumorigenesis, in the ovary requires a functioning gonadotropin axis; 2) To determine whether proliferation of primary or metastatic GC tumor cells requires the presence of a functional gonadotropin axis; 3) to establish whether gonadotropin replacement therapy, especially with FSH, is essential for either initiation of unrestrained granulosa cell proliferation or in stimulating proliferation of primary or metastatic tumor cells. These studies will be accomplished by grafting: 1) immature, genetically susceptible (SWR x SWXJ-9) F1 ovaries, and 2) dispersed primary or metastatic GC tumor cells into hosts that are either normal for gonadotropins (either scid/scid hpg/+ or scid/scid, +/+; hereafter scid/scid +/?) or are devoid of these hormones (scid/scid,hpg/hpg). grafts will be inspected after 4 weeks for presence of primary tumor, physical dimensions of grafts obtained, histopathological typing of viable grafts done computer-assisted morphometric analyses for tumor growth, and mitotic indices and tumor incidences calculated. RIAs of serum FSH and inhibin levels, as well as corticosterone, insulin-like growth factor-I, and thyroxine are planned for GC tumor graft bearing hosts to identify those hormonal axes thought to play important secondary roles in GC tumorigenesis. With establishment of the gonadotropin role in each stage of GC tumor cell proliferation, the SWR model can then be used for testing efficacy of gonadotropin intervention therapies for primary and metastatic GC tumors. Finally, the scid/scid,hpg/hpg mice are expected to accept tissue xenografts. Thus, these immune deficient, gonadotropin deficient mice will also be capable of accepting grafts from human ovarian epithelial or sex cord/stromal tumors to establish their requirements for gonadotropin support of tumor cell proliferation.
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| Beamer, W G; Shultz, K L; Tennent, B J et al. (1993) Granulosa cell tumorigenesis in genetically hypogonadal-immunodeficient mice grafted with ovaries from tumor-susceptible donors. Cancer Res 53:3741-6 |
