EARLY OCCURRENCE OF METASTATIC DIFFERENTIATED THYROID CARCINOMAS IN TRANSGENIC MICE EXPRESSING THE A2A ADENOSINE RECEPTOR GENE AND THE HUMAN PAPILLOMAVIRUS TYPE-16 E7 ONCOGENE

We report here the characterization of a transgenic mouse model (Tg-A2 aR/Tg-E7) resulting from the coexpression of tao oncogenic transgenes in the thyroid, The two transgenes (Tg-A2aR and Tg-E7) were placed und er control of the thyroid specific thyroglobulin gene promoter, and di rected the expression of either the A2a adenosine receptor that consti tutively activates the cAMP pathway, or the E7 protein of the human pa pillomavirus type 16, that binds and inactivates the retinoblastoma su sceptibility gene product (Rbl), Transgenic mice expressing both trans genes were generated by interbreeding the Tg-A2aR and Tg-E7 transgenic lines, generated and characterized previously (Ledent et al., 1992, 1 995), These mice develop a larger goiter than that of the two parental lines, and a severe hyperthyroidism comparable to that observed in th e Tg-A2aR parental Line, The main feature of the Tg-A2aR/Tg-E7 mice is the rapid occurrence of malignant lesions, and the dissemination of m alignant thyroid tissue through the blood stream, generating multiple differentiated and functional metastases in the lung, These metastases appeared as early as 2 months after birth and their frequency increas ed to 75% over 3 months, They were associated with the presence of lar ge vascular lakes in the thyroid, Electron microscopy of the malignant cells revealed nuclear features similar to those of human thyroid pap illary carcinoma, These mice, in which two oncogenes are co-expressed in the thyroid, represent the first genetic animal model developing me tastatic differentiated carcinomas of the thyroid with a high frequenc y.