Cellular immortalization--an essential step or merely a risk factor in DNA virus-induced transformation?

Different activities of DNA viral gene products seem to be involved in the immortalization process, even in cases where continued presence of the viral genome does not seem to be required for the maintenance of the immortalized state of a cell. Immortalization, does not appear to represent a single event as implied earlier and several studies have shown that the process can be reversible. Polyomavirus large T antigen and HPV E7 (or E6 + E7) seem to possess all the activities required in vitro for immortalization of human cells, whereas one of the required activities--that defined in the two-step model as a rare mutagenic event which occurs during cellular crisis--is weaker in SV40 large T antigen and E1A. Viral functions that can activate PCNA expression (or repress Rb1 expression) have to be considered as pivotal activities in immortalization. Finally, the growth factor independence characterizing many immortalized cells could be a result of growth factor-like activities intrinsic to the viral proteins or could reflect their ability to induce autocrine growth mechanisms. These statements all relate to the first aspect of our initial hypothesis concerning cellular immortalization and in general substantiate it. Is immortalization an essential step in malignant transformation? There seems no a priori reason that transformation or tumorigenesis should depend upon cellular immortalization. Notably, many tumors appear to be mortal in culture. Growth factor independence or activation of DNA replication--essential features of immortalization--are probably of little importance for tumors in vivo where a crucial environment is supplied by the surrounding cells.(ABSTRACT TRUNCATED AT 250 WORDS)