DEVELOPMENT AND CHARACTERIZATION OF TESTICULAR TUMORS OF THE SPECIALIZED GONADAL STROMA IN TRANSGENIC MICE OBTAINED BY TARGETED ONCOGENESIS USING AN AMH PROMOTER/SIMIAN VIRUS 40 (SV40) FUSION CONSTRUCT

SILVINA QUINTANA,; MARCELA VENARA,; RODOLFO REY,; MARTIN DUTERTRE,; NATHALIE DI CLEMENTE,; JEAN-YVES PICARD,; FRANCOISE XAVIER,; HÉCTOR E. CHEMES.

Chicago USA

Congreso; 31 reunion American Society of Andrology; 2006

American Society of Andrology

DEVELOPMENT AND CHARACTERIZATION OF TESTICULAR TUMORS OF THE SPECIALIZED GONADAL STROMA IN TRANSGENIC MICE OBTAINED BY TARGETED ONCOGENESIS USING AN AMH PROMOTER/SIMIAN VIRUS 40 (SV40) FUSION CONSTRUCT. Silvina Quintana, Marcela Venara, Rodolfo Rey, Martin Dutertre, Nathalie di Clemente, Jean-Yves Picard, Francoise Xavier,  Héctor E. Chemes. CEDIE, R. Gutiérrez Children’s Hospital, Buenos Aires, Argentina, and Endocrinologie et Génétique de la Reproduction et du Développement (INSERM), Clamart, France Transgenic mice bearing a construct in which the expression of the SV40 oncogen is directed by the AMH promoter (AT mice) develop testicular tumors in adult life. Our aim was to study early steps of tumor development and characterize these tumors at different ages by means of histologic, morphometric and immunohistochemical techniques. 1-3 month-old AT mice depicted multifocal Leydig cell hyperplasia. The testicular volume occupied by interstitial tissue was higher in some (not all) transgenic animals in comparison with littermate controls. Between 5½ and 7 months of life microscopic interstitial tumors developed in some AT mice. These microtumors progressively developed to form large confluent areas of interstitial growth of high mitotic index in 7 to 14 month-old AT mice. Tumor cells had the phenotypic characteristics and histoarchitecture of Leydig cells, or formed solid cord-like structures reminiscent of those seen in Sertoli cell tumors. Both hyperplastic areas and tumors diffusely expressed 3b-hydroxysteroid dehydrogenase (3b-HSD) and inhibin a-subunit in the Leydig cell areas. AMH expression was negative in hyperplastic areas and variable in cord-like tumors. The large T antigen of SV40 (SV40 T) and markers of cell proliferative activity (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, many adult AT mice develop large testicular tumors that are preceded by interstitial hyperplasia and microtumors. The histologic and immunohistochemical phenotype of tumors in AT mice (Leydig and Sertoli cell differentiation, positive 3b-HSD and a Inhibin and variable AMH) suggests a mixed differentiation of somatic cells of the specialized gonadal stroma. The interesting finding that an oncogen directed by a promoter specifically active in early 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. Recent efforts in our laboratory have resulted in the successful isolation of RNA from paraffin tissue sections from control and transgenic animals. These RNA transcripts can be retrotranscribed and PCR to study gene expression. Further efforts to characterize the origin of tumors as well as the mechanisms of hyperplasia and tumorigenesis in these animals are currently under way. Supported by Grants from CONICET (PIP 2565/00), ANPCyT (PICT 9591) and INSERM-CONICET International Cooperation Program.