Figure 3.

Illustration of our three-hit hypothesis. Coupling the traditional two-hit principle with the initiation-promotion theory leads us to a supposition that the first genetic hit establishes initiated cells that are still mortal and non-autonomous, whereas the second hit creates immortality and autonomy, thus establishing neoplastic cells, either benign or malignant. Since formation of benign neoplasms also requires two genetic hits, we extrapolate that, in some animal models and probably also in many human situations, establishment of malignant morphologies and behaviors requires a third hit on the relevant gene(s).