Info

Apoptosis intact

Apoptosis impaired

Low DNA hit rate

S win

M win

High DNA hit rate

M win if Carr > Cdel

S win if Carr < Cdel

A change in the DNA hit rate can reverse the outcome of competition. In the simplest setting, an increase in the DNA hit rate can switch the outcome of competition in favor of cells characterized by a slower intrinsic growth rate. This requires a sufficient difference in the repair rate between the stable and mutator cells, and a condition on the relative values of costs associated with cell cycle arrest and creation of deleterious mutants. The conditions under which genetic instability is selected for depends on the efficacy of apoptosis. In terms of cancer evolution and progression, this gave rise to the following insights (Table 7.2).

• If apoptosis is strong, accumulation of mutations by unstable cells slows down the intrinsic growth rate because of the frequent induction of cell death. Thus, stable cells have a higher intrinsic growth rate than mutators. Consequently, at low DNA hit rates, the stable cells win. The presence of high DNA hit rates can, however, result in the selection and emergence of the genetically unstable cells. This occurs if the cost of cell cycle arrest upon repair is higher than the cost of creating deleterious mutations.

• On the other hand, if apoptotic responses are impaired, accumulation of mutations by unstable cells will not result in frequent cell death upon division. Therefore, the intrinsic growth rate of unstable cells can be higher than that of stable cells if adaptive mutations are acquired. In this case, genetic instability is expected to emerge at low DNA hit rates. At high DNA hit rates, however, genetic instability can be selected against and mutators can go extinct. This occurs if the cost of creating deleterious mutations is higher than the cost of cell cycle arrest.

7.4 Selection for genetic instability

A fascinating question is how much genetic instability can contribute to faster adaptation and evolution of cancer cells [Jackson and Loeb (1998); Jackson and Loeb (2001); Loeb and Loeb (2000); Loeb (1991); Loeb (2001); Tomlinson (2000); Tomlinson and Bodmer (1999); Tomlinson et al. (1996)]. It can be argued that genetic instability can be selected for due to the following two factors:

(i) Genetic instability can be advantageous if it results in a faster accumulation of adaptive mutations compared to stable cells [Loeb (1991)]. This could allow the cancer to evolve faster and to overcome selective barriers and host defenses. An example are tumor suppressor genes where both copies have to be mutated. Instead of the occurrence of two independent point mutations, loss of heterozygocity in genetically unstable cells can result in the loss of suppressor function if one copy has been mutated.

(ii) Genetic instability can be advantageous simply because cells avoid delay in reproduction associated with repairing and maintaining the genome [Breivik and Gaudernack (1999a); Breivik and Gaudernack (1999b)]. When genetic damage is detected, the relevant checkpoints induce cell cycle arrest during which the damage is repaired. If genetic damage occurs often, frequent arrest significantly slows down the replication rate of the cells, and loss of repair can be advantageous. Experimental evidence supports this notion. Bardelli et al. [Bardelli et al. (2001)] have shown that exposure to specific carcinogens can result in the loss of the checkpoint that was induced by the carcinogenic agent used.

At this stage, it is unclear what selective mechanism is responsible for the emergence of genetic instability (or in fact whether genetic instability appears simply as a side effect of other genetic alterations on the way to cancer). It is possible that different types of genetic instability can have different effects on the evolution of the cell populations. The increased rate at which the quasispecies travels up the fitness landscape may or may not be out-weighed by the costs associated with creating deleterious mutations. This in turn may depend on the nature of the instability. In particular, it may be determined by whether the genetic changes are relatively small (such as in MIN) or larger (such as in CIN, see Chapter 6).

If the main driving force for the emergence of genetic instability is avoidance of cell cycle arrest (rather than faster adaptation), this could contribute to explaining why certain instabilities are specific to certain types of cancers or tissues. Different environments can cause different types of genetic alterations which induce separate checkpoints [Bardelli et al. (2001)]. The checkpoints which are lost in the cancer would be the ones which are most often induced in the appropriate environment and tissue surroundings. On the other hand, if genetic instability mainly emerges because it allows the cells to adapt faster, we expect that instability is lost at later stages of cancer progression. This is because the cancer has evolved to an optimal phenotype, and now stability avoids deleterious mutations and thus increases fitness [Cahill et al. (1999)].

7.5 Genetic instability and apoptosis

If genetic instability can result in a faster accumulation of adaptive mutations (case (i) above), it could in principle be the driving force of cancer progression. As pointed out in the previous section, it is unclear whether this is the case, or whether alternative selection pressures are responsible for the emergence of genetic instability. Here, we assume that instability can result in the accumulation of adaptive mutations and explore possible pathways to the emergence of genetic instability and cancer progression. Assume we start from a wild-type cell which is stable and has intact apop-totic mechanisms. The mathematical model suggests that genetic instability can only drive progression toward fitter phenotypes if apoptosis is impaired. This is because in the presence of intact apoptosis, accumulation of mutations results in elevated levels of cell death which slows down the intrinsic growth rates. Thus, to gain a fitness advantage, both apoptosis, and stability genes have to be mutated. This can occur via two pathways (Figure 7.6).

(1) In the first pathway, the initial mutation impairs the apoptotic response in the cell. This variant is selectively neutral compared to the wildtype. The reason is that the cell still has intact repair mechanisms. Therefore, mutations are unlikely to be generated in the time frame considered. As long as mutations do not accumulate, the presence or absence of apoptotic mechanisms does not change the dynamics of cell growth. Following this mutation, a second mutation is generated which

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