As discussed in Chapter 7, one of the characteristics of promoting agents is their effectiveness in inhibiting the process of apoptosis in preneoplastic cells. Just as with many other mechanisms that are transiently altered in preneoplastic cells by the presence of the promoting agent, alter- ations in mechanisms of apoptosis, as in cell replication, likely are altered in some way in virtu- ally every malignant neoplasm (cf. Laderoute, 1994). Furthermore, an extensive study by Staunton and Gaffney (1995) suggested that the apoptotic index was characteristic of each histo- genetic type of neoplasm. The apoptotic index generally was greater than or similar to the mi- totic index for the individual type of neoplasm under study. Already discussed is the importance of the increased expression of the bcl-2 proto-oncogene, the apoptotic inhibitor, in follicular lymphomas (Figure 6.8).
While a variety of pathways have been shown to be involved in the induction of apoptosis (Figure 7.14), central themes are now becoming obvious in relation to the development of apop- tosis in normal and neoplastic cells. Figure 15.7 is a simplified diagram of potential mechanisms for the effects of DNA damage- as well as oncogene-induced apoptosis. Already discussed is the importance of the p53 tumor suppressor gene in activating apoptosis in normal cells as a result of DNA damage, the effect apparently mediated through the ATM gene (Figure 15.5). In this figure, it is noted that the p53 protein enhances the expression of the proapoptic gene, bax,
Figure 15.7 Diagram of DNA damage- and oncogene-induced apoptosis. Oncogenes and proto-onco- genes such as E1A and c-myc respectively induce apoptosis through both p53-dependent and -independent pathways as noted in the figure. Both pathways may facilitate cytochrome c release from mitochondria which in turn effects the activation of the caspase cascade. Components of this pathway that have been shown to be mutated in neoplasms are shown in black. Mito, mitochondria; Cyto c, cytochrome c; Apaf-1, caspase adapter; Casp-9, caspase-9 and caspase cascade. (Modified from Lowe and Lin, 2000, with permis- sion of the authors and publisher.)
which effects alterations in mitochondrial permeability, resulting ultimately in activation of the caspase pathway to apoptosis. Similarly, the proto-oncogene c-Myc, as well as the viral onco- gene E1A, inhibits the effect of the specific p53 inhibitor Mdm2 mediated through ARF. By this mechanism p53 is activated and the same situation as noted with DNA damage occurs. Muta- tions of genes, as noted in the figure, can result in alteration of the apoptotic pathway either through the p53 tumor suppressor gene or by bypassing it and acting directly on the bax/bcl-2 pathway or other pathways not completely understood (Lowe and Lin, 2000).
A variety of other methods for the induction of apoptosis through specific ligand/receptor mechanisms are also present in many cells throughout the organism. Several of these are dis- cussed later in the text (Chapter 17). However, as noted in the figure, the extensive potential for alteration in genes required for the basic apoptotic mechanism seen in Figure 15.7 is indicative of the statement that most if not all neoplasms exhibit one or more abnormalities in these steps in this critical process governing the ultimate growth of neoplasms in the host.