cetrorelix and Testicular-Neoplasms

Transgenic (TG) mice, expressing the Simian Virus 40 T-antigen (Tag) under a 6-kb fragment of the murine inhibin alpha-subunit promoter (inh alpha p), develop gonadal tumors of granulosa/theca or Leydig cell origin. We showed previously that adrenocortical tumors develop if the TG mice are gonadectomized but never develop in intact animals. However, if functional gonadectomy was induced by GnRH antagonist treatment or by cross-breeding the TG mice into the hypogonadotropic hpg genetic background, neither gonadal nor adrenal tumors appeared. Since the most obvious difference between the gonadectomized and GnRH-antagonist-treated or Tag/hpg double mutant mice is the elevated gonadotropin secretion in the first group, we examined whether the adrenal tumorigenesis would be gonadotropin-dependent. Surprisingly, both the adrenal tumors and a cell line (C alpha 1) derived from one of them expressed highly functional LH receptors (LHR), as assessed by Northern hybridization, immunocytochemistry, ligand binding, and human CG (hCG)-stimulated cAMP and steroid production. No FSH receptor expression was found in the adrenal tumors by RT-PCR. hCG treatment of the C alpha 1 cells stimulated their proliferation, as measured by [3H]thymidine incorporation. This effect was related to hCG-stimulated steroidogenesis since progesterone, testosterone, and estradiol, at physiological concentrations, also stimulated the C alpha 1 cell proliferation. Different adrenocortical cells expressed initially LHR and Tag, whereas both were highly expressed in the tumor cells. In conclusion, the high level of functional LHR in the adrenal tumors indicates that this receptor can function as tumor promoter when ectopically expressed and stimulated by the ligand hormone.

Topics: Adrenal Cortex Neoplasms; Animals; Antigens, Polyomavirus Transforming; Castration; Cell Transformation, Neoplastic; Chorionic Gonadotropin; Crosses, Genetic; DNA Replication; Female; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Gonadotropins, Pituitary; Granulosa Cell Tumor; Humans; Inhibins; Leydig Cell Tumor; Luteinizing Hormone; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Mutant Strains; Mice, Transgenic; Neoplasms, Hormone-Dependent; Organ Specificity; Ovarian Neoplasms; Peptides; Promoter Regions, Genetic; Receptors, FSH; Receptors, LH; Recombinant Fusion Proteins; Simian virus 40; Testicular Neoplasms; Thecoma; Tumor Cells, Cultured

We have previously developed a transgenic (TG) mouse model expressing the Simian virus 40 T-antigen (Tag), driven by a 6-kb fragment of the mouse inhibin alpha-subunit promoter (inh-alpha). The mice develop metastasizing gonadal tumors, of granulosa/theca or Leydig cell origin, with 100% penetrance by the age of 5-8 months. In the present study, we examined whether the appearance and growth of the gonadal tumors are dependent on gonadotropins. Gonadotropin suppression was achieved either by treatment of 3-month-old mice for 2-3 months with a GnRH antagonist (Cetrorelix, SB-75), or by cross-breeding the TG mice to the genetic background of the gonadotropin-deficient hypogonadal mutant mouse (hpg). Gonadal tumor growth was clearly inhibited by SB-75 treatment in one of the TG mouse lines (IT6-M), as indicated by the absence of macroscopically visible tumors and by reduced gonadal weights. Despite the suppressed gonadotropin secretion and Tag expression, hyperplasia of testicular Leydig, and ovarian stromal cells persisted in some of the treated mice. In another TG mouse line (IT6-F), with more aggressive tumorigenesis, the SB-75 treatment only partially inhibited gonadal tumor growth. None of the hypogonadotropic TG mice, homozygous for the hpg mutation, developed gonadal tumors. Their gonadal histology was indistinguishable from that of the non-TG hpg mice, suggesting total inhibition of gonadal tumorigenesis in the absence of gonadotropin stimulation. Tag expression and Leydig cell hyperplasia were apparent already in the postnatal TG mice but absent in those TG mice homozygous for the hpg mutation. In conclusion, the present results indicate that the gonadal tumorigenesis in our TG mouse model starts in early age as hyperplasia in specific somatic cells. Both this, and the subsequent malignant tumor growth, are gonadotropin dependent. A sufficient level of Tag expression, a prerequisite for gonadal tumorigenesis, only occurs upon gonadotropin stimulation.

Topics: Animals; Antigens, Polyomavirus Transforming; Cell Transformation, Neoplastic; Cloning, Molecular; Disease Models, Animal; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Hormone Antagonists; Hyperplasia; Inhibins; Leydig Cells; Male; Mice; Mice, Transgenic; Ovarian Neoplasms; Ovary; Peptides; Pituitary Gland; Progesterone; Promoter Regions, Genetic; RNA, Messenger; Testicular Neoplasms; Testis; Testosterone; Time Factors