Alterations in the cell cycle and its components are generally considered to be found only in the stage of progression and not in promotion or preneoplasia. Studies of both mouse mammary tumor development (Said and Medina, 1995) and in human colorectal neoplasia (Polyak et al.,
1996) support this statement, although cyclin A was found to be overexpressed in all hyperpla- sias in mouse mammary glands (Said and Medina, 1995). In addition, Robles and Conti (1995) have demonstrated that premalignant lesions in mouse skin carcinogenesis exhibited an in- creased level of cyclin D1 as investigated by an immunohistochemical technique. Interestingly, Balasubramanian et al. (1998) found dramatic increases in cyclin kinase inhibitors in skin papil- lomas, in contrast to the finding in most neoplasms (Table 15.7). On the other hand, there has been considerable work on the expression of cell cycle components in neoplasms (Draetta and Pagano, 1996); therefore this discussion focuses primarily on this topic.
As noted in Chapter 9, control mechanisms for the cell cycle involve both a cascade of protein phosphorylations that relay a cell from one stage to the next and a set of checkpoints that monitor the completion of critical events and may delay progression to the next stage of the cell cycle if required to maintain cell function (Collins et al., 1997). A diagram of the various regula- tors of the cell cycle is shown in Figure 15.4. In this figure, the crucial role of E2F is noted, as was discussed in Chapter 9 (Figure 9.5). Also noted in the figure by asterisks are those genes
Figure 15.4 Positive (→) and negative (—|) regulators of the cell cycle and the critical role of E2F in this process. Those symbols associated with an * indicate that that gene product is abnormally expressed in neoplasia, many of the abnormalities noted more particularly in Table 15.7. The designations for the com- ponents of the cell cycle, cyclins, phases, and cdks are the same as shown in Figure 9.5. Inhibitors of the cyclins are shown in two families, the INK4 family which encompasses p16, p15, p18, and p19, and the CIP/Kip family, including p21, p27, and p57 (cf. Michalides, 1999). Bub1, gene involved in chromosome segregation; GF, growth factors; adhesion, cell adhesion components and pathways; APC, tumor suppres- sor gene of familial adenomatous polyposis. (Modified from Michalides, 1999, with permission of the au- thor and publisher.)
altered in one or more neoplasms by mutation of one or more mechanisms, e.g. amplification, base mutation, deletion, fusion, etc. In addition to the pathways noted in Figure 15.4, the role of E2F and its association with p53 in growth control, growth arrest, and apoptosis is noted in Fig- ure 15.5. A more detailed listing of the functional abnormalities of these various components scored by an asterisk in Figures 15.4 and 15.5 is given in Table 15.7.
The central role of E2F when activated by release of Rb by phosphorylation is shown in this figure, as in Figure 9.5. In addition, the tempering effects of E2F on members of the INK4 family of cyclin inhibitors, while at the same time enhancing the expression of the cyclins and their kinases, indicate the delicate balance with which the cell cycle is regulated. The examples noted in Table 15.7 of alterations in several cell cycle regulators and components are by no means complete and are only given as examples. Again, it is quite likely that at least one and usually more than one of these components are abnormal through mutation, amplification, or enhanced transcription in virtually all neoplasms in the stage of progression. Furthermore, alter- ations in these components appear to become more severe as progression continues (Said and Medina, 1995). As noted from the table, gene amplification and mutations appear to be the more common changes seen in these various factors. In many instances, the nature of the mutation is unknown and may reflect other allelic changes, including deletion. Alterations in the p27 cyclin-
Figure 15.5 Diagram of the E2F-p19ARF-p53 connection between growth control, growth arrest, and ap- optosis. Those genes having an * indicate abnormalities in neoplastic cells, some of which are considered in Table 15.7 and others, e.g., p53, Rb, in the text previously. See text for discussions of mdm2, bax, ATM, and p19/arf. The figure emphasizes the critical roles of E2F-1 and p53. (Modified from Michalides, 1999, with permission of author and publishers.)
dependent inhibitor in which there is a decrease if not total elimination of expression appear not to result from mutations in most cases (cf. Millard and Koff, 1998). The changes in the cyclins that have been noted are largely due to gene amplification and chromosomal rearrangement, es- pecially in the case of cyclin D1. A variety of neoplasms have exhibited such changes in the expression of this gene as well as in cyclin E, both of which play key roles in entrance into the cell cycle. Mutational inactivation of the Bub1, whose product is concerned with the proper seg- regation of chromosomes in cells, may play a significant role in the development of aneuploidy in neoplastic cells (Cahill et al., 1998).