One of the elsive goals of studying DNA tumor viruses has been to determine how viral oncogenes convey tumor producing capacities to normal cells. The key to tumorigenicity is generally believed to lie in the process of viral oncogene-induced transformation. However, numerous studies have found transformed cells that are non-tumorigenic and viruses that can transform cells but are unable to induce tumors. Thus, in spite of many years of elegant work on the mechanisms of transformation, the role of viral genes in actual tumor development remains a mystery. A new approach seems to be needed. Based on the concepts 1) that transformation as defined by those changes in normal cells that can be recognized in vitro are only part of the process of tumorigenicity and 2) that the differences in tumor inducing capacity as expressed by DNA virus transformed cells represent oncogene functions that are independent of transformation as recognized in vitro, we have developed such an approach. The basis of this approach lies in the biometric analyses of the relationship between tumor cell dose, tumor incidence and tumor latency. These parameters are the fundamental components of the process by which transformed cells induce tumors when injected into animals. From these analyses, we have developed unique graphical formats for displaying and analyzing the tumorigenic phenotype expressed by transformed cells. Using this format we have found that the tumor inducing capacity of transformed cells is composed of at least 4 distinct viral oncogene controlled processes. Only one of these processes can be detected by studies of cell transformation in tissue culture.
