Adenovirus Transformation and Tumorigenicity
Robert P. Ricciardi
In natural infection of humans, adenoviruses generally enter differentiated, quiescent epithelial cells. For successful propagation of virus to occur, these infected cells need to be growth stimulated. This function is performed by the concerted actions of the viral E1A and E1B gene products, which bind key cellular proteins, causing activation of the cell cycle and inhibition of growth arrest and apoptosis. These same E1A and E1B functions are responsible for the ability of each of the approximately fifty human adenovirus serotypes to transform rodent cells in culture. Rodent cells fail to support lytic infection but become transformed through the chance integration and expression of the early region E1A and E1B genes. In addition, rodent cells as well as human cells can be transformed by transfecting E1A and E1B plasmids. Adenovirus-transformed cells exhibit immortalization, proliferative growth capacity and morphological alteration, all of which are hallmarks of cancer cells. However, only a subset of adenoviruses—or the cells which they transform—are actually able to generate tumors in immunocompetent adult rodents. The mechanism responsible for this tumorigenic phenotype is mediated by E1A and is postulated to be a manifestation of the means by which the highly oncogenic viruses escape immunosurveillance during persistent infection in humans. This review briefly describes currently held notions as to how E1A and E1B collaborate to transform cells and then examines the mechanism of E1A-mediated tumorigenesis. The importance of these oncogenic mechanisms as related to the use of adenovirus in gene therapy is discussed. The influence of the E4 ORFs on oncogenesis is reviewed elsewhere and in this volume. Due to space limitations, most of the numerous studies which support the findings and mechanisms described in this chapter are mentioned in recent reviews, where they are covered more extensively.