Transgenic mouse models for gonadal tumorigenesis

The versatile transgenic (TG) techniques allow the production of in vivo an imal models for a variety of diseases, including malignant tumors, through tissue-specific expression of oncogenes. We have created a TG mouse model f or gonadal somatic cell tumors by expressing the powerful viral oncogene, S imian virus 40 T-antigen (Tag) under regulation of the murine inhibin alpha -subunit promoter (inh alpha). Ovarian granulosa and theca cell tumors were formed in the female, and those of testicular Leydig cells, in the male TG mice at the age of 5-6 months, with 100%; penetrance. The tumors produced high levels of inhibin peptides, especially the a-subunit, and were steroid ogenically active, mainly producing progesterone. The gonadal tumorigenesis was gonadotropin-dependent, since TG mice rendered gonadotropin-deficient by crossbreeding them into the hypogonadotropic hpg genetic background, or by treating them with a gonadotropin-releasing hormone (GnRH) antagonist, d id not develop tumors. In order to study the possibility of using the tumor mouse model for testing gene therapy, we created another TG mouse model ex pressing under the same inhibin-a promoter the Herpes Simplex virus (HSV) t hymidine kinase (TK) transgene. The inh alpha/HSV-TK mice were crossbred wi th the: inh alpha/Tag mice and the double mutant mice also developed gonada l tumors. When they were treated with antiherpes drugs (acyclovir or gancyc lovir), further growth of the tumors was blocked. These preliminary finding s prove the principle that tumor ablation in our TG mouse model can be achi eved by transduction of the HSV-TK gene into the tumor cells. Besides studi es of formation, regulation and therapy of the tumors in vivo, immortalized cell lines derived from them provide models for studies of gonadal somatic cell functions in vitro. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.