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Transgenic mouse models for gonadal tumorigenesis
N A Rahman1, K Kananen Rilianawati, T Paukku
1Department of Physiology, University of Turku, Kiinamyllynkatu, Finland.
Abstract:
The versatile transgenic (TG) techniques allow the production of in vivo animal models for a variety of diseases, including malignant tumors, through tissue-specific expression of oncogenes. We have created a TG mouse model for gonadal somatic cell tumors by expressing the powerful viral oncogene, Simian 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 alpha-subunit, and were steroidogenically 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, did 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 expressing under the same inhibin-alpha promoter the Herpes Simplex virus (HSV) thymidine kinase (TK) transgene. The inh alpha/HSV-TK mice were crossbred with the inh alpha/Tag mice and the double mutant mice also developed gonadal tumors. When they were treated with antiherpes drugs (acyclovir or gancyclovir), further growth of the tumors was blocked. These preliminary findings prove the principle that tumor ablation in our TG mouse model can be achieved by transduction of the HSV-TK gene into the tumor cells. Besides studies 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.
Insights
Transgenic mice expressing Simian virus 40 T-antigen develop gonadal tumors dependent on gonadotropins. Gene therapy using Herpes Simplex virus thymidine kinase blocked tumor growth, demonstrating a potential therapeutic strategy.
Area of Science:
- Oncology
- Genetics
- Endocrinology
Background:
- Transgenic (TG) techniques enable in vivo disease modeling.
- Oncogene expression under tissue-specific promoters creates disease models.
- Gonadal somatic cell tumors are a focus of research.
Purpose of the Study:
- To create a transgenic mouse model for gonadal somatic cell tumors.
- To investigate the role of gonadotropins in tumor development.
- To test gene therapy strategies for gonadal tumors.
Main Methods:
- Created TG mice expressing Simian virus 40 T-antigen (Tag) under the inhibin alpha-subunit promoter.
- Crossbred TG mice with hypogonadotropic hpg mice and treated with GnRH antagonist.
- Developed TG mice expressing Herpes Simplex virus thymidine kinase (HSV-TK) and crossbred with Tag mice.
- Treated double mutant mice with antiherpes drugs (acyclovir, gancyclovir).
Main Results:
- TG mice developed ovarian granulosa/theca cell tumors and testicular Leydig cell tumors with 100% penetrance.
- Tumors were steroidogenically active, producing progesterone and high inhibin levels.
- Tumorigenesis was gonadotropin-dependent; no tumors formed in gonadotropin-deficient mice.
- Treatment with antiherpes drugs blocked tumor growth in double mutant mice.
Conclusions:
- The developed TG mouse model accurately reflects gonadal somatic cell tumorigenesis.
- Gonadotropin dependency is crucial for tumor development.
- HSV-TK gene therapy shows promise for blocking gonadal tumor growth.
- Immortalized cell lines from these tumors can be used for in vitro functional studies.