Figure 4.

Illustration of an extended hypothesis on how increased expression of tumor suppressor gene (TSG) may promote carcinogenesis: Overexpression of TSGs or growth inhibitory genes in a given organ such as the liver may induce programmed cell death (PCD; the irregular star) or inhibit cell proliferation (the crossed spot). Some growth arrested cells may later die of PCD as well. Because the cell death triggers compensatory proliferation (regeneration) of the organ but the normal cells are growth arrested, the initiated cells (IC in the smiley phase) that occur sporadically to be resistant to the mitoinhibition will proliferate in a clonal expansion fashion in order to restore the physiological cell number. Continuous proliferation of the initiated cells allows accumulation of genetic alterations, leading to the development of preneoplastic lesions and eventually malignant tumors. The reason for the resistance of the initiated cells to the mitoinhibition varies, including a relatively lower expression level or inactivation of the TSG, but in many cases decreased or lost function of the TGS may occur later as a step of the process towards the malignancy. In this way, a TSG or growth-inhibitory gene may play a positive role in carcinogenesis, although its expression level in the whole organ may be “lower” or “higher” than the normal control, depending on the ratio of the normal cells to the initiated cells in the organ at the time of measurement (“+” indicates promotion of proliferation).