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1 Modeling Cancer As a Complex Adaptive System: Genetic Instability and Evolution. by Kenneth J. Pienta, M.D., University Of

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1 Modeling Cancer As a Complex Adaptive System: Genetic Instability and Evolution. by Kenneth J. Pienta, M.D., University Of Modeling cancer as a complex adaptive system: Genetic instability and evolution. By Kenneth J. Pienta, M.D., University of Michigan Correspondance may be addressed to: Kenneth J. Pienta, M.D. University of Michigan Comprehensive Cancer Center 1500 E. Medical Center Drive 7303 CCGC Ann Arbor, MI 48109-0946 P: 734-647-3421 F: 734-647-9480 Email: [email protected] 1 Introduction Generally, we consider evolution as the fundamental strategy of life at the level of the organism. It is how we became who we are via an interplay of genetic variation and phenotypic selection [1]. The premise of evolution is that genes and hence, gene variants, are selected because they encode functions that in some way improve the chance of organism survival [2, 3]. This premise can be passed onto the level of the cancer cell. A tumor can be considered to be an organism or species that is able to speed up the evolutionary process by millions of years to select properties that help it survive and thrive within the macrocosm of the human body. In cancer (or tumors), the welfare of the single cancer cell becomes independent of its neighbors. Although cancer is known to be a multitude of diseases that involves multiple phenotypes, this is a single and unifying theme for all cancer cells [4]. As we build a model of cancer as a complex adaptive system based on natural selection and Darwinian laws, we need to use this unifying principle to understand the genesis of a metastatic cancer [5, 6]. Cancer risk in the context of an evolutionary paradigm How then does a cancer cell evolve from a normal cell (see Figure 1). At the most basic level, it is the result of DNA damage that counts towards a survival advantage [2]. A mutation to the genome must occur in a place where it A) does not lead to the death of the cell; B) does not occur in a sequence of DNA that does not change behavior, and C) occurs in a place that conveys a growth or survival advantage. Meaningful DNA damage is the result of gene – environment interactions on multiple levels. First, cells may inherit “susceptibility” for damage from parental alleles. This can be at a very recognizable and measurable level, for example, a damaged DNA repair enzyme in Li-Fraumeni syndrome [4]. On this genetic background, the cells are assaulted by a variety of genome damaging exposures. These include radiation, viruses, microbes, carcinogens, chemicals, hormones, and other agents that are too numerous to list. But these risk factors to the genome are modulated in two important ways prior to their ability to damage the DNA. First, these factors must pass through a phalanx of both organ- and non-organ specific intrinsic risk modulators. Intrinsic risk modulators are inherited traits that do not contribute directly to DNA damage, but modulate the environment that the cells are exposed to. Examples include how well metabolizing enzymes function to modulate drug and hormone activity (pharmacogenomics) as well as how well a hormone such as testosterone binds to the androgen receptor based on the number of CAG repeats in the promoter region [7]. In addition, before the damaging agent can cause mutation, it must evade extrinsic risk modulators. Extrinsic risk modulators are best characterized by chemoprevention agents such as antioxidants. Dietary factors such as selenium and vitamin E have been demonstrated to remove damaging oxygen radicals from the intracellular environment by catalyzing their breakdown to water [8, 9]. If the damaging agent escapes all of these potential protective mechanisms, it still must damage the DNA in a susceptible place that will allow a survival advantage [2,4]. Most mutations to the DNA are either deleterious or neutral – very few are adaptive [1]. In bacteria, for example, it is estimated that only one in 10,000 mutations provide an adaptive advantage [1, 10]. It is probable that in for the much more complex human genome that this ratio would be much higher. 2 These gene – environment interactions that contribute to cancer can be understood in the context of any number of evolutionary paradigms (Table 1). In breast cancer, a woman may inherit the allele that contains BRCA-1, a gene important in maintaining normal breast cell function. This starts the cell down the cancer pathway. Similarly, an antelope could inherit a rare allele and is born an albino, immediately putting it at a disadvantage to the other, camouflaged, members of the herd. Cancer cells are subject to a wide variety of genotoxic insults that could potentially cause mutation and selective pressure. These are mirrored by the same types of insults that a herd of animals must survive, for example, changes in weather, ability to withstand infections, etc. These risks are modulated by inherent factors. In cells, for example, drug metabolizing enzymes. In animals, muscle fiber length (running speed). The risks are also modulated by extrinsic agents. For cells, are there chemoprevention agents present? For animals, presence of other protective species, the ability to migrate, and the number of adult males present to ward off attack. Cancer evolution in the context of recent human evolution Each cancer and the cancer cells that compose it has a distinct phenotype, however, cancers do share a group of common characteristics [4, 11, 12]. A tumor is the result of a collection of cancer cells that are actively acquiring mutations that allow the emergence of a successful clone of cells. This is a highly inefficient process and tumors are filled with clones of cells that will not survive long term and are undergoing apoptosis (programmed cell death) as a result of harmful mutations, hypoxia, immune surveillance, etc. Some cells, however, manage to acquire enough mutations and acquire the characteristics of a successful cancer cell. This can be compared, at least on one level, to the evolution of human civilization. A key difference in these two types of evolution is that we believe that as human beings we evolved our societies as a result of conscious decisions that increased our chances for species survival. To understand cancer clonal expansion we have to explain cancer cell growth and survival in terms of an unconscious process. This is much more likely to be modeled by early evolution as we pulled ourselves out of the sea and became multicellular organisms. However, the exercise in comparing the successful cancer cell successfully colonizing a new metastatic site to human civilization and colonization is worthwhile (see Table 2). 1) Unlimited replicative potential Cancer cells are immortal. This does not mean that each cell itself lives forever (just like humans). This means that the cell population doubles without limit and creates uncontrolled clonal expansion. In non-cancerous cells, a cell can double approximately 50 times before it undergoes senescence and dies [13]. This has been termed the Hayflick number and is the result of an internal cell doubling clock built onto the end of each chromosome termed the telomeres [14]. Telomeres are specific strands of DNA that shorten with each cell division. At a critical shortened length, the cells undergo apoptosis, or programmed cell death. Cancer cells reactivate and enzyme, telomerase, which maintains the length of telomeres with each cell division by adding base pairs back onto the telomeres, thereby maintaining length integrity. 2) Adaptation, mutation, and natural selection 3 A fundamental characteristic of cancer is the generation of tumor cell heterogeneity, i.e, cells with multiple mutated phenotypes, through a mechanism of genetic instability [15-20]. There are multiple ways that genetic instability can be generated (chromosomal instability and microsatellite instability) and observed. For example, tumor cells exhibit karyotypes that are grossly changed in quantity and quality from the complement of normal cell chromosomes Radman and colleagues have suggested that two different models can explain mutations in evolution [1]. In one model, there is a low mutation rate in a very large population. In the second model, there is a high mutation rate in a limited population with coincident intense recombination, permitting the rare adaptive mutation to become separated from frequent deleterious mutations [1]. The latter type of evolution can be seen in bacterial populations under stress. It is likely that the evolution of cancer is a combination of these two models. The initial mutations within a cell destined to become cancer happen as a result of a low mutation rate within a large population of cells. These mutations occur as a result of the interplay between susceptibility alleles and the environment as outlined above. Within the expanding clone, a mutation eventually occurs that induces a “mutator phenotype” with coincident high mutation rates and the generation of tumor cell populations with a heterogeneous set of properties over a relatively short period of time. While this mutator phenotype may occur as a result of chance, it may also be facilitated by the exposure of the cells to stresses, such as hypoxia as the size of the tumor increases. Indeed, it has been demonstrated that hypoxia induces genetic instability in cancer cell populations [21, 22]. The emergence of the mutator phenotype rapidly selects cells with the most robust survival advantages. This robust phenotype can be observed clinically. A cancer can be in remission for many years and then present with metastatic disease that quickly kills the patient over a matter of weeks or months [23]. 3) Protection from death There are multiple redundant pathways in place to maintain the fidelity of the cellular systems to prevent mutation and damage. More often than not, deleterious mutations lead to the initiation of programmed cell death. Teleologically, this is built into systems to protect the rest of the cell population.
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