Genetic Requirements for the Transformation of Human Cells

Abstract

Abstract : Our knowledge of the transformation process has emerged largely from studies of primary rodent cells and animal models. However, numerous attempts to transform human cells using oncogene combinations that are effective in rodents have proven unsuccessful. These findings strongly argue for the study of homologous experimental systems. Here we report that the combined expression of adenovirus E1A, Ha-RasV12, and MDM2 is sufficient to convert a normal human cell into a cancer cell. Notably, transformation did not require telomerase activation. Therefore, activation of telomere maintenance strategies is not an obligate characteristic of tumorigenic human cells. Activation of telomerase, and consequently telomere maintenance, is a common characteristic of human tumors. Existing models of human cancer cells, created by the introduction of defined genetic alterations, all include telomerase activation as an obligate component of the transformed phenotype. Here we demonstrate that normal human cells can be converted into cancer cells, capable of forming tumors in immunocompromised mice in the absence of telomerase activation or an alternative telomere maintenance strategy. This suggests that alterations in telomere biology must be viewed similarly to genomic instability as catalysts of transformation rather than as central components of the transformed phenotype.