Why Are Human Cells Resistant to Malignant Cell Transformation in vitro?

Transformation of human cells, both induced and spontaneous, is an extremely rare event, whereas rodent cells are relatively easily transformed when treated with a single carcinogenic agent. The present review addresses the question of why human cells are resistant to malignant transformation in vitro. To facilitate understanding of the problem, the process of transformation is divided operationally into two phases, i.e. phase I, immortalization; and phase II, malignant transformation. In human cells, one‐phase transformation, i.e., the consecutive occurrence of phases I and II due to the action of a single carcinogenic agent, is observed only rarely. Once human cells are immortalized, however, malignant transformation by chemical carcinogens or oncogenes proceeds, suggesting that for human cells, phase I immortalization is a prerequisite for such transformation to take place. To date, about 20 papers have been published describing protocols for the two‐phase transformation of a variety of human epithelial cells and fibroblasts. In most experiments, SV40, human papilloma viruses and their transforming genes are utilized for induction of phase I (immortalization) followed by the use of chemical carcinogens or activated oncogenes for induction of phase II (malignant transformation). Possible mechanisms that would render human cells refractory to transformation are discussed below.