Tumorigenic latency and separable stages during fibrosarcoma development in transgenic mice carrying papillomavirus genomes.

Transgenic mice have been established carrying the genomes of bovine papillomavirus type 1 (BPV-1), and human papillomaviruses types 5 and 18. Transcriptional dormancy is characteristic of all three viral genomes in transgenic mouse lines maintained for 2-4 years. Only BPV-1, which induces both dermal and epidermal pathology in its natural host, has been found to elicit abnormalities when carried in transgenic mice. The BPV-1 genome acts in these mice as a tissue specific oncogene, in that it elaborates the development of skin fibrosarcomas. Three abnormal stages are evident: two distinct and successive stages of a proliferative hyperplasia (a mild and an aggressive fibromatoses), and the solid tumors (fibrosarcomas). Analysis of tissue biopsies and of derivative cell cultures from each pathology confirms that this pathway is composed of separate stages. Notably, progression from hyperplasia to neoplasia is accompanied by specific cytogenetic changes, which appear necessary in addition to the actions of the BPV oncogenes. The reproducibility of the tumorigenic pathway induced by the BPV genome is providing inroads into the molecular genetic and biochemical mechanisms of tumor development.