After 5 years of intense effort, we have developed a new approach to study the contribution of viral oncogenes to transformed cell tumorigenicity. This approach defines those viral oncogene induced traits expressed by transformed cells that determine their tumorigenicity in terms of mean tumor producing dose 50% end point (TPD50) values which are estimates of the number of cells required for tumor formation. By determining these values at weekly intervals, in different types of animals that possess different capacities to mount antitumor defenses, the tumorigenic phenotype expressed by transformed cells can be characterized in terms of the kinetics of the tumor cell dose-tumor incidence-tumor latency relationship. Analyzing and comparing these relationships for cells transformed by different viral oncogenes provides methods for: 1) discriminating between oncogene-induced traits that determine tumorigenicity and random low frequency events; 2) detecting tumor latency traits that differ from those traits that determine tumor inducing capacity; 3) demonstrating that viral oncogenes contribute traits in addition to immortalization that are responsible for a transformed cell's tumor inducing capacity; 4) organizing oncogene- induced traits necessary for tumor formation into host responsive and host unresponsive categories; and 5) ranking DNA virus transformed cells according to their relative aggressiveness as tumor cells from nontumorigenic to highly tumorigenic cells that metastasize. This approach integrates in vitro and in vivo models of neoplasia and provides a means of standardizing the definition of tumorigenicity and the measurement of neoplastic processes in experimental models whose endpoints can be analyzed statistically. The application of this approach will contribute to our understanding neoplastic processes and in managing their consequences.
