MORPHOLOGICAL-STUDY OF PITUITARY TUMORIGENESIS IN TRANSGENIC MICE INDUCED BY HYBRID ONCOGENE OF THE THYROTROPIN BETA-SUBUNIT AND THE SIMIAN-VIRUS-40 LARGE T-ANTIGEN

We have created a transgenic mouse, TTP-1, generating anterior pituita ry tumors by using the simian virus 40 (SV40) large T antigen gene and human thyrotropin beta-subunit gene. To examine characteristics of tu mors, histological details were investigated using light and electron microscopies. The main tumor tissues, composed of small chromophobe ce lls, were located inferior to but clearly separated from the hypothala mus; however, neuron fibers probably derived from the hypothalamus wer e observed to invade some tumor tissues. Some differentiated endocrine cells occupied the caudal region of the tumor. Immunohistochemically, SV40 large T antigen was expressed in the cell nucleus of the undiffe rentiated cell area, whereas cells expressing several hormones were ma inly distributed in the differentiated cell area. Electron microscopic ally, the undifferentiated cells were divided into 2 types; electron-d ense and -lucent cells, the nuclei of which were composed of obscured nucleoli and many notable invaginations of the nuclear membrane. No in tracellular microfilamentous structures were observed. Sometimes it wa s noted that cytoplasmic processes were connected with gap junctions. In the intercellular spaces, there were neuron fibrous and synapse-lik e structures. In the differentiated cell area, the cell membranes dire ctly contacting other cells were relatively smooth, and many gap junct ions were demonstrated. Secretory granules, which were round and less than 100 nm in diameter, were more electron dense in smaller cells tha n in larger cells. They were aligned just below the cell membrane. Imm une-electron microscopically, positive reactions for SV40 were observe d in the nuclei of the undifferentiated cell area. In the differentiat ed cell area, most of the secretory granules were labeled by GH. TTP-1 transgenic mice should provide a valuable animal model for studying t he pathogenesis of anterior pituitary tumors.