Somatic Evolution of Cells and the Development of Cancer

Dominik Wodarz Department of Ecology and Evolutionary Biology University of California, Irvine, CA, USA [email protected]

Cancer as an Evolutionary Process When cancer develops within a tissue, cells divide in an unregulated fashion. The growth of the cancer cell population first gives rise to a localized or primary tumor. Subsequently, the cells break out into the blood stream and can thus reach and invade other tissues. This is called metastasis, which tends to be the cause of mortality. Cancers can develop in different organs, and each cancer type has unique characteristics. Molecular biology has started to reveal the mechanisms which underlie the generation of tumor cells and which lead to the progression of the disease (Vogelstein et al. 2000). Various mechanisms of gene activation/inactivation have been found, including mutations, chromosomal alterations, and epigenetic events. An increasingly complex picture of gene-to-gene signaling has emerged, revealing specific functions of relevant genes, as well as their synergistic interactions. Mechanisms of cell-to-cell signaling have been discovered that are responsible for the interactions between the tumor and its microenvronment, for example, the induction of angiogenesis. Cellular responses to various environmental factors have been investigated, such as radiation, chemicals, oxidative radicals, and so on. While this information has revolutionized our understanding about the nature of cancer and has opened up avenues for therapy, it is also important to realize that the initiation and progression of cancer is basically an evolutionary process which occurs in vivo (Wodarz 2005; Wodarz and Komarova 2005a) (Figure 1). In healthy organisms, cells within a tissue cooperate, such that the tissue functions. During the lifetime of the organism, cells can acquire a variety of mutations. Most of these mutations are likely to be deleterious; that is, the mutant cells will be selected against. Some of the mutations will

be neutral. Some mutations, however, will confer a selective advantage to the cell. For example, the cell might not die, while all the wild-type cells do. Or it might stop responding to signals that prevent division, and thus give rise to a phase of clonal expansion. Such first-stage cancer cells are not likely to grow to very large numbers. Instead, growth can plateau, until further mutations are accumulated which allow the cells to divide further and which enable the cancer to progress (Figure 1). These mutations are required to overcome selective barriers (Cahill et al. 1999). Therefore, the initiation and progression of cancer can be viewed as an evolutionary process in vivo. Many questions in cancer research thus benefit from evolutionary insights and perspectives. The following sections elaborate on this with two examples. The Mutation Rate of Cancer Cells In many cancers, the cells are characterized by an elevated rate at which they acquire genetic alterations (Lengauer et al. 1997, 1998). This phenomenon has been termed genetic instability, and such cells have been referred to as mutator phenotypes (Loeb 1991, 1998, 2001; Loeb and Loeb 2000). Several forms of genetic instability have been found (Lengauer et al. 1998). These include small-scale changes such as microsatellite instability (i.e., mutations in repeat sequences) and larger-scale changes such as the deletion or duplication of whole chromosomes or of chromosome arms (chromosomal instability). Why is genetic instability observed in cancers? According to one hypothesis, an elevated mutation rate allows the population of cancer cells to accumulate the mutations which are necessary for tumor development and progression, with a faster rate (Loeb 1991). In fact, it has been argued that without genetic instability, cancers could never develop and progress (Loeb and Loeb 2000). This idea has also been formulated in terms of mathematical models (Nowak et al. 2002; Michor et al. 2005). It is unclear, however, how advantageous an elevated rate of genetic alterations is for the cancer cells. This is especially true for chromosomal instability. While such larger-scale changes can certainly contribute to the accumulation of carcinogenic

October 8, 2005; accepted October 15, 2005 c 2006 Konrad Lorenz Institute for Evolution and Cognition Research Biological Theory 1(2) 2006, 119–122. 

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Somatic Evolution of Cells and the Development of Cancer

Figure 1. Diagram explaining the concept of somatic evolution and cancer progression. Cancer originates with the generation of a mutant cell. This cell divides and the population grows. This is called clonal expansion. Further mutations can subsequently arise which have a higher fitness. They grow and expand further. Consecutive mutations and rounds of clonal expansion allow the cancer to grow to ever increasing sizes.

mutations, they can also have destructive consequences for rest of the cell’s genome. For example, if both copies of important genes or both copies of a chromosome are lost, the cell can die. Such a reduction in cell fitness can slow down the growth of the cancer cell population. It is possible that as a consequence, stable cells would give rise to cancer faster than would unstable cells (Komarova 2004; Komarova and Wodarz 2004). While unstable cells can accumulate mutations quicker, the rate of clonal expansion of those cancer cells would be slowed down significantly. This would render the net fitness of stable cells higher than that of unstable ones. Thus, it is possible that the reason for the existence of unstable cancers might not simply be explained by the fact that instability speeds up the process of carcinogenesis. 120

An alternative explanation for the emergence of genetically unstable cells has nothing to do with the speed with which cancer cells progress. Instead, it has been suggested that certain environmental conditions within the body can select for unstable cells, even before a cancer develops (Breivik and Gaudernack 1999a, 1999b; Bardelli et al. 2001; Breivik 2001, 2005; Komarova and Wodarz 2003). In particular, if cells are exposed to relatively high amounts of DNA damage, instability might be advantageous. The reason is as follows: When the genome of cells is damaged, the cells stop to divide and enter cell cycle arrest. This gives them time to repair the damage. Once the damage has been repaired, the cells continue to divide. This has the advantage that the genome integrity is maintained. However, if the rate of DNA damage is high, cells will spend a significant proportion of time in cell cycle arrest, and this will slow down cell division, and thus reduce cellular fitness. If cells lose the repair mechanism, the genomic integrity will not be maintained anymore, but cell cycle arrest will be avoided. Consequently, the population of cells can divide faster. This can result in an overall higher fitness of the cells. Therefore, genetically unstable cells enjoy a selective advantage and invade the population of cells (Komarova and Wodarz 2003). Now the stage is set for these cells to accumulate mutations which will result in the development of cancer. An example of this might be ulcerative colitis (Babbs 1992). This is an inflammatory disease of the colon, where cells experience high levels of DNA damage. Ulcerative colitis renders patients very susceptible to the development of colon cancer. It has been observed that genetic instability is present even in noncancerous tissue in ulcerative colitis patients (Brentnall et al. 1996; Cravo et al. 1998; Park et al. 1998; Rabinovitch et al. 1999; Ishitsuka et al. 2001). Thus, the elevated level of DNA damage in the inflamed colon selects for unstable cells. Once instability has emerged, it can contribute to the generation of cancerous cells. In order to get better insights into these questions, closer interactions between evolutionary biologists and cancer biologists are required. For example, the fitness of cells can be measured under different levels of DNA damage to determine the conditions under which unstable cells will be selected for. If such experiments are combined with population genetic/mathematical models, a quantitative understanding can be obtained about the evolution of genetic instability in vivo. The Evolution of Drug Resistance Another topic where evolutionary biology can contribute to cancer research and even to clinical application is the emergence of drug resistance and the failure of treatment. Recent insights into the signaling pathways of cancer cells have given rise to new treatment opportunities. Traditional chemotherapy is a relatively unspecific way of treating tumors. The agents Biological Theory 1(2) 2006

Dominik Wodarz

basically get taken up by dividing cells, and many of them damage the genome of the cells (Simon et al. 2000). This can lead to cell death. The exact mechanism with which these agents kill the cells is unclear (Simon et al. 2000). Since dividing cells are targeted, severe side effects can occur in tissues characterized by a high turnover rate. In recent years, however, molecular research has identified signaling pathways which are altered in cancer cells. This lead to the development of inhibitors which specifically target these defects and kill the cancer cells. This is called targeted therapy with small molecule inhibitors (Guillemard and Saragovi 2004). The best-known example of this is the treatment of chronic myeloid leukemia (CML) with Gleevec (Deininger and Druker 2003; Melo et al. 2003; John et al. 2004). Gleevec inhibits the product of a fusion gene which is thought to be essential for the survival of the cancer. Patients are treated quite successfully during the early stages of the disease, but drug resistance prevents treatment success during later stages of the disease (Gorre et al. 2001; McCormick 2001). Evolutionary biology can help to elucidate the principles according to which drug-resistant cancer cells emerge and to design strategies which prevent treatment failure as a result of drug resistance. According to mathematical models which describe the evolutionary dynamics of drug resistance in cancer (Komarova and Wodarz 2005; Wodarz and Komarova 2005b), the growth phase of the cancer before the start of treatment is most important for the emergence of resistance. If no resistant cells have been generated by the time treatment starts, it is very unlikely that they will evolve during the treatment phase. Given a certain size of a tumor, it is in principle possible to predict the chances that treatment will be successful and that resistance will not pose a problem. In particular, it is possible to ask how many drugs should be used in combination to ensure success. Combination of different drugs can help prevent the emergence of resistance if resistance to one drug does not confer resistance to a different drug. Basically, one cell has to accumulate multiple resistance mutations in order to escape all drugs used. According to the theoretical framework, the turnover rate of cancer cells is a very important variable in this respect (Komarova and Wodarz 2005; Wodarz and Komarova 2005b). If the death rate of cancer cells is low compared to the division rate, a combination of several drugs is likely to improve the chances of tumor remission. If the death rate of cancer cells is close to the division rate, however, many mutations can accumulate in cells even at very small sizes, and a combination of different drugs is not likely to make therapy more efficient compared to single-drug treatment. Preliminary results from the application of this framework to the treatment of CML with Gleevec suggests that a combination of three or four drugs could prevent treatment failure as a result of resistance even in the advanced stages of the disease (Komarova and Wodarz 2005; Wodarz and Komarova 2005b). New drugs which can potentially be combined with Gleevec Biological Theory 1(2) 2006

are under development (Daley 2003; Shah et al. 2004). Again, a closer collaboration between evolutionary/mathematical biologists and experimental cancer researchers is required to include additional biological complexity into the model and to apply it in a more detailed way to the biology of CML and its treatment. This will give rise to clinically more accurate predictions. Conclusion This discussion has explained with examples that principles from evolutionary biology have a lot to offer for the understanding of cancer biology and cancer therapy. The key for successful future work is that these two disciplines come closer together. Evolutionary theory can generate interesting hypotheses which can be tested by experiments. Experiments in turn often give rise to complicated observations which can be explained with evolutionary principles.

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