CONICET | Buscador de Institutos y Recursos Humanos

Transgenic mice bearing a construct in which the expression of the SV40 oncogene is directed by the AMH promoter (AT mice) develop testicular tumors in adult life. We aimed to study early steps of tumor development and characterize tumors at different ages by histologic, morphometric and immunohistochemical techniques. 1-3 month-old AT mice depicted multifocal Leydig cell hyperplasia. The testicular volume occupied by interstitial tissue was significantly higher in 3 month-old AT mice in comparison with littermate controls. Between 5½ and 7 months microscopic interstitial tumors developed that progressively evolved to form large confluent areas of high mitotic index in 7 to 14 month-old AT mice. Tumor cells had the characteristics and histoarchitecture of Leydig cells, or formed solid cord-like structures reminiscent of those seen in Sertoli cell tumors. Hyperplastic areas and tumors diffusely expressed 3b-hydroxysteroid dehydrogenase (3b-HSD) in Leydig cell areas. AMH expression was negative in Leydig cell conglomerates and tumors and variable in cord-like tumors. The SV40 T antigen and markers of cell proliferation (PCNA) were intensely positive in hyperplastic cells and tumors. Control mice of similar ages showed neither hyperplasia nor tumors, and SV40 T expression was always negative. In conclusion, transgenic mice develop large testicular tumors that are preceded by interstitial hyperplasia and microtumors. The histologic and immunohistochemical phenotype of tumors (Leydig and Sertoli cell differentiation, positive 3b-HSD and variable AMH) suggests a mixed differentiation of somatic cells of the specialized gonadal stroma. The interesting finding that an oncogene directed by a promoter specifically active in fetal Sertoli cells has given rise to testicular tumors of mixed differentiation is compatible with a common origin of Leydig and Sertoli cells from the specific stroma of the gonadal ridge, as supported by double labeling experiments in fetal mice showing colocalization of the transgene with Sertoli and Leydig cell markers.