TIMING OF SV40 ONCOGENE ACTIVATION BY SITE-SPECIFIC RECOMBINATION DETERMINES SUBSEQUENT TUMOR PROGRESSION DINING MURINE LENS DEVELOPMENT

We generated mice that carry copies of a dormant transgene encoding th e SV40 tumor antigens. The transgenes are specifically targeted to the lens and contain features that render their expression dependent on t he action of Cre, a site-specific bacteriophage DNA recombinase. Timin g of oncogene activation was controlled by making Cre available either prior to, or coincident with, the onset of primary fiber differentiat ion in the embryonic lens vesicle. Early expression of Cre resulted in oncogene activation in undifferentiated lens epithelial cells that ra pidly proliferated inside the lens capsule. By contrast, when Cre accu mulation was delayed to coincide with the onset of primary lens fiber differentiation, SV40 oncogenes were activated in cells that had begun to elongate and to accumulate lens-specific crystallins. During subse quent proliferation inside the lens capsule, transformed progeny cells maintained the profile of fiber differentiation that their parent cel ls had acquired at the time of oncogenic conversion. Developing lens t umors were confined within the capsule of the embryonic lens. However, if the capsule was perforated in an embryonic eye in organ culture, c ells rapidly grew out while still maintaining features of differentiat ion. Our findings show that the differentiated state of the primary ta rget cells is an important parameter of subsequent lens oncogenesis, a nd that an intact lens capsule can restrict invasive neoplastic growth .