Tsp

stable

^ TSP ^ TSP unstable unstable"

Fig. 6.3 Cancer initiation and progression in the case of stable cells (above), and unstable cells (below). The latter pathway includes an additional step, "activation of CIN". Also, the inactivation of the second copy of the TSP gene is a fast step in the case of unstable cancers. The second pathways takes longer if conditions (a) and (b) are satisfied (see text).

Then a CIN cancer, even with the optimal value of p*, still cannot progress faster than a stable cancer, simply because it requires this extra event, the "activation" of the CIN phenotype. Let us outline the basic reasoning at an intuitive level, by comparing two sequences of events, see Figure 6.3. The first one (for stable cancers) involves two slow inactivation events and clonal expansion. The other (for unstable cancers) involves some mutations leading to the acquisition of the unstable phenotype, two inactivation events (one slow and the other fast), and clonal expansion. Our calculations show that under assumption (1) and (2) above, the second sequence of events can never happen faster than the first one.

The following conclusions can be drawn from this argument. In order for CIN to be selected for, that is, to play the role of the driving force in cancer progression, at least one of the assumptions, (1) or (2), must be wrong. Let us first explore the possibility that (I) is violated, and then move on to (2).

One way to see how CIN could accelerate cancer progression is to assume that CIN comes about by some epigenetic mechanism with a rate much faster than the basic mutation rate [Eden et al. (2003); Gaudet et al. (2003); Lindblom (2001)]. This hypothesis is consistent with the numerous but still unsuccessful attempts to find a "CIN gene" [Amon (1999); Gemma et al. (2000); Kolodner et al. (2002); Michel et al. (2001); Ohshima et al. (2000); Wassmann and Benezra (2001)] and (at least, partially) epigenetic nature of CIN in yeast. If this were true, then the "activation of CIN" step in the diagram of Figure 6.3 would be short, and this would give CIN a chance to be "beneficial" for cancer.

Another possibility is that CIN arises because of alternative reasons, such as environmental factors, so that the unstable phenotype has an advantage compared to the wild type cells. For example, if cells are exposed to high degrees of DNA damage (as a result of carcinogens and metabolic radicals), CIN can be selected for, because it avoids frequent cell cycle arrest upon damage [Gasche et al. (2001)]. The effect of DNA damage on the selection of genetically unstable cells is the subject of the next chapter. In this case, all the steps in the diagram for unstable cancer (Figure 6.3) will be accelerated, which means that the instability indeed facilitates progression to cancer.

Alternatively, CIN might be the consequence of another mutation which confers an advantage to the cell [Cahill et al. (1999)]. It has been proposed that a mutation in the APC gene itself leads to the development of CIN and the generation of aneuploidy in colon cancer [Fodde et al. (2001a); Kaplan et al. (2001)]. This could lead to a number of possibilities, for instance, two steps in the pathway for the unstable cancer combined in one.

6.4 The bigger picture

We have calculated the optimal rate of chromosome loss assuming that cancer is initiated by the inactivation of a TSP followed by a clonal expansion. The resulting rate, p* ss 10~2 per cell division per chromosome, is similar to that obtained experimentally by Lengauer et al. This is a thought-provoking result. A hypothesis consistent with our finding is that the rate at which cancerous cells lose chromosomal material is under selection pressure, and as a result, the optimal rate, is the one that survives the competition. In other words, out of many possibilities, we will mostly see the cancers that have the optimal rate of chromosome loss, because these are cancers that are initiated and progress at the fastest rate.

The next natural question is the following. What happens if there are more TSP's which need to be inactivated down the line, as cancer progresses? It is easy to see that adding another TSP to the pathway will not change the value of p* significantly. This is because every new TSP gene takes much less time to be inactivated than a previous one; this is a consequence of a growing size of the lesion.

The optimal rate of chromosome loss calculated in this chapter is indeed optimal during early and intermediate stages of cancer progression as long as they involve TSP's. However, at later stage of carcinogenesis, the selective pressures optimizing the rate of LOH change drastically. It is well-known that a lesion cannot grow above a certain small size (about 2 mm) without extra blood supply (angiogenesis). A larger or metastasizing tumor is hard to maintain, and the price of losing chromosomes becomes too high to be balanced by an elevated variability. Therefore, we predict that at later stages, the optimal rate of LOH will decrease to nearly zero [Komarova (2004)]. This is consistent with observations that late stage cancers are sometimes (surprisingly) stable. In their recent review, Al-bertson et al. [Albertson et al. (2003)] note that chromosome aberration spectra seem to stabilize in advanced cancers. Some evidence comes from comparing tumor genomes (in the same individual) of in situ and invasive lesions [Kuukasjarvi et al. (1997b)], primary and recurrent tumors [Wald-man et al. (2000)] and primary and metastatic tumors [Kuukasjarvi et al. (1997a)]. Also, some established cancerous cell lines exhibit remarkable stability [Yoon et al. (2002)], suggesting that they may originate from a system where an optimal, stable phenotype has been shaped by selective forces.

Similarly, if the activation of oncogenes (rather than the inactivation of tumor suppressor genes) plays a major role in the progression of cancers, then chromosomal instability is likely to be detrimental to the cancer. Indeed, to turn on an oncogene, a small scale mutation is often needed rather than a chromosome loss event or another crude chromosomal change. Moreover, a chromosome loss event may lead to the inactivation of a functioning oncogene which will revert the process of oncogenesis. Further mathematical work will be required to investigate the effect of CIN in the context of both oncogenes and tumor suppressor genes.

To leave the reader with an important message, we note that our analysis leads to the insight that CIN does not arise simply because it allows a faster accumulation of carcinogenic mutations. Instead, CIN must arise because of alternative reasons, such as environmental factors, fast/epigenetic events, or as a direct consequence of a TSP inactivation. The increased variability alone is not a sufficient explanation for the presence of CIN in the majority of cancers.

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